Publications by authors named "Wing Leung"

244 Publications

Effect and mechanism of berberine against polycystic ovary syndrome.

Biomed Pharmacother 2021 Mar 16;138:111468. Epub 2021 Mar 16.

Laboratory for Reproductive Immunology, Hospital & Institute of Obstetrics and Gynecology, Shanghai Medical College, Fudan University, Shanghai, China; The Academy of Integrative Medicine, Fudan University, Shanghai, China; Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China. Electronic address:

For women of reproductive age, polycystic ovary syndrome (PCOS) is not a rare heterogeneous endocrine disorder and metabolic dysfunction. Menstrual problems, hyperandrogenism, polycystic ovary (PCO) and infertility often affect these women, and they are also prone to metabolic syndrome (MS) and insulin resistance (IR). As an isoquinoline alkaloid, Berberine (BBR) is the main effective component of Coptis. BBR, as a multi-target, multi-path plant extract, can interfere with the development of PCOS and relate to pathological process from many aspects, with less adverse reactions. It is mentioned in this review that BBR can alleviate IR, reduce the level of serum androgen, regulate lipid metabolism and moderate chronic inflammation. BBR is often used in combination with metformin, compound cyproterone (CPA) and other drugs, in order to achieve better therapeutic effect on PCOS.
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http://dx.doi.org/10.1016/j.biopha.2021.111468DOI Listing
March 2021

Intimate Partner Violence Before Pregnancy, During Pregnancy, and After Childbirth: A New Conceptualization Highlighting Individual Changes in Violence Against Pregnant Women Over Time.

J Interpers Violence 2021 Mar 5:886260521997451. Epub 2021 Mar 5.

Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Pokfulam, Hong Kong.

Intimate partner violence (IPV) against pregnant women is a global public health problem. Yet, the trajectory of IPV during pregnancy and its association with health are unclear. This study set out to investigate the trajectory of IPV by categorizing pregnant women according to changes of IPV exposure before, during, and after pregnancy and to examine the predictive factors of these IPV-related categories. During 2016 and 2017, we conducted a longitudinal study with a sample of 1,083 pregnant women in Hong Kong. Pregnant women reported their IPV experiences, depression, and demographics in the baseline survey (at about 24-week gestation), and their IPV experiences, mental health outcomes, social support, and perceived father's involvement in the follow-up survey (around 4 weeks postpartum). We categorized pregnant women into four groups, including women with (a) sustaining abusive relationship (AR); (b) relationship with decreased violence over pregnancy (DVR); (c) relationship with stress-related violence (SVR); and (d) nonviolent relationship (NVR). Although we found an overall decline of IPV during pregnancy from 24.6% to 14.3%, there were still a considerable proportion of women reporting as a victim of IPV. We observed that a higher proportion of pregnant women were actually suffering from IPV during pregnancy and after childbirth continuously (22.3% of AR and SVR) than experiencing a termination of IPV due to pregnancy (11.4% of DVR). We also observed that more severe maternal depression, lower levels of father's involvement, and poorer social support were significantly associated with the categories that reflected greater severity of IPV over the course of pregnancy. Our findings reflected that the complexity of IPV related to pregnancy should never be overlooked. Mere reporting of prevalence in an aggregate might not sufficiently explain the problem. Father's involvement and social support are two important factors that might help reduce IPV related to pregnancy and childbirth.
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http://dx.doi.org/10.1177/0886260521997451DOI Listing
March 2021

Sonographic measurement of cervical length and head perineum distance before labor to predict time of delivery.

J Matern Fetal Neonatal Med 2021 Jan 17:1-5. Epub 2021 Jan 17.

Department of Obstetrics and Gynaecology, Kwong Wah Hospital, Kowloon, China.

Objectives: This was an observational study on cervical length and head perineum distance and the prediction of time of delivery. One-hundred and twenty-five nulliparous women with uncomplicated, term, singleton pregnancy were recruited when they presented to the labor ward with show or infrequent painful uterine contractions (less than three contractions in ten minutes on a 30 min cardiotocogram). Apart from digital vaginal examination to assess cervical length and dilatation, sonographic cervical length and head perineum distance were measured by two-dimensional ultrasound. We compared women who delivered within 72 h of presentation of labor symptoms, with women who did not. After excluding ten women whose labor was induced and delivered within 72 h of presentation, one hundred and fifteen women were included for final data analysis.

Main Findings: Forty-nine women (42.6%) delivered while sixty-six women (57.4%) remained undelivered at 72 h of presentation of symptoms of labor. There was no statistically significant difference between the two groups on age, presence of show, contractions, fetal head station and presentation and mode of delivery. For the group who had delivered within 72 h of presentation of labor symptoms, the mean sonographic cervical length was 1.87 cm ± 0.62 cm, while the head perineum distance was 6.01 cm ± 1.15 cm. For the other group, the mean sonographic cervical length was 2.10 cm ± 0.83 cm; head perineum distance was 6.03 cm ± 1.18 cm. There was no statistically significant difference between the groups for both sonographic cervical length ( = .90); and head perineum distance ( = .08). We also compared the cervical length measured by digital vaginal examination versus sonography. The median sonographic measurements were 1.47 cm, 2.11 cm and 2.79 cm at "1 cm," "2 cm" and "3 cm" digital vaginal measurement, respectively. However, there was extensive overlap between digitally and sonographically measured cervical length. Prediction accuracy of cervical length and head perineum distance was poor. The area under curve (AUC) of receiver operating characteristic (ROC) curve were 0.433 for sonographic cervical length and 0.501 for HPD.

Conclusion: Transperineal sonographical assessment of cervical length and head perineum distance before labor was not useful in predicting the time of delivery. However, it can be explored as an alternative assessment method when digital vaginal examination is not preferred.
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http://dx.doi.org/10.1080/14767058.2021.1873264DOI Listing
January 2021

Excellent Survival Outcomes of Pediatric Patients With Acute Myeloid Leukemia Treated With the MASPORE 2006 Protocol.

Clin Lymphoma Myeloma Leuk 2021 Mar 1;21(3):e290-e300. Epub 2020 Dec 1.

Duke-NUS Medical School, Singapore; Haematology/Oncology Service, Department of Paediatric Subspecialties, KK Women's and Children's Hospital, Singapore.

Purpose: To determine the prognostic factors in pediatric patients with acute myeloid leukemia (AML) and to assess whether their outcomes have improved over time.

Patients And Methods: Sixty-two patients with AML excluding acute promyelocytic leukemia were retrospectively analyzed. Patients in the earlier cohort (n = 36) were treated on the Medical Research Council (MRC) AML12 protocol, whereas those in the recent cohort (n = 26) were treated on the Malaysia-Singapore AML protocol (MASPORE 2006), which differed in terms of risk group stratification, cumulative anthracycline dose, and timing of hematopoietic stem-cell transplantation for high-risk patients.

Results: Significant improvements in 10-year overall survival and event-free survival were observed in patients treated with the recent MASPORE 2006 protocol compared to the earlier MRC AML12 protocol (overall survival: 88.0% ± 6.5% vs 50.1% ± 8.6%, P = .002; event-free survival: 72.1% ± 9.0 vs 50.1% ± 8.6%, P = .045). In univariate analysis, patients in the recent cohort had significantly lower intensive care unit admission rate (11.5% vs 47.2%, P = .005) and numerically lower relapse rate (26.9% vs 50.0%, P = .068) compared to the earlier cohort. Multivariate analysis showed that treatment protocol was the only independent predictive factor for overall survival (hazard ratio = 0.21; 95% confidence interval, 0.06-0.73, P = .014).

Conclusion: Outcomes of pediatric AML patients have improved over time. The more recent MASPORE 2006 protocol led to significant improvement in long-term survival rates and reduction in intensive care unit admission rate.
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http://dx.doi.org/10.1016/j.clml.2020.11.016DOI Listing
March 2021

Half depletion of Foxp3+ regulatory T cells by diphtheria toxin for long-term study in vivo.

Biosci Trends 2021 Jan 16;14(6):460-462. Epub 2020 Dec 16.

Laboratory for Reproductive Immunology, Hospital & Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, China.

Depletion of regulatory T cells (Tregs) is an appropriate approach to study the function of Tregs in vivo, and most previous studies have focused on complete depletion. The purpose of the current study was to determine an appropriate dose and timing for half depletion of Tregs in vivo. DETREG (DEpletion of REGulatory T cells) mice were produced and injected with different doses of diphtheria toxin (DT) for 7 days and 14 days. The mice were then sacrificed to collect the spleen and mesenteric lymph nodes (MLN) for analysis using flow cytometry. Foxp3+eGFP+ cells were significantly reduced by DT injection. A dose of 5 ug/kg DT led to half depletion and no deaths. A DT dose of 25, 50, or 100 ug/kg led to a progressively higher depletion rate but also a higher mortality rate. In conclusion, a low dose of DT is effective for half depletion of Tregs and long-term study. Half depletion of Tregs may become a new method for the future study of Tregs in vivo.
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http://dx.doi.org/10.5582/bst.2020.03291DOI Listing
January 2021

A validated pediatric disease risk index for allogeneic hematopoietic cell transplantation.

Blood 2021 Feb;137(7):983-993

Center for International Blood and Marrow Transplant Research, Department of Medicine, and.

A disease risk index (DRI) that was developed for adults with hematologic malignancy who were undergoing hematopoietic cell transplantation is also being used to stratify children and adolescents by disease risk. Therefore, to develop and validate a DRI that can be used to stratify those with AML and ALL by their disease risk, we analyzed 2569 patients aged <18 years with acute myeloid (AML; n = 1224) or lymphoblastic (ALL; n = 1345) leukemia who underwent hematopoietic cell transplantation. Training and validation subsets for each disease were generated randomly with 1:1 assignment to the subsets, and separate prognostic models were derived for each disease. For AML, 4 risk groups were identified based on age, cytogenetic risk, and disease status, including minimal residual disease status at transplantation. The 5-year leukemia-free survival for low (0 points), intermediate (2, 3, 5), high (7, 8), and very high (>8) risk groups was 78%, 53%, 40%, and 25%, respectively (P < .0001). For ALL, 3 risk groups were identified based on age and disease status, including minimal residual disease status at transplantation. The 5-year leukemia-free survival for low (0 points), intermediate (2-4), and high (≥5) risk groups was 68%, 51%, and 33%, respectively (P < .0001). We confirmed that the risk groups could be applied to overall survival, with 5-year survival ranging from 80% to 33% and 73% to 42% for AML and ALL, respectively (P < .0001). This validated pediatric DRI, which includes age and residual disease status, can be used to facilitate prognostication and stratification of children with AML and ALL for allogeneic transplantation.
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http://dx.doi.org/10.1182/blood.2020009342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918183PMC
February 2021

Alterations in the intestinal microbiome associated with PCOS affect the clinical phenotype.

Biomed Pharmacother 2021 Jan 7;133:110958. Epub 2020 Nov 7.

Laboratory for Reproductive Immunology, Hospital & Institute of Obstetrics and Gynecology, Shanghai Medical College, Fudan University, Shanghai, China; The Academy of Integrative Medicine, Fudan University, Shanghai, China; Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China. Electronic address:

Polycystic ovarian syndrome (PCOS), characterized by chronic anovulation and hyperandrogenaemia, is a complex endocrine and metabolic disorder commonly seen in women of reproductive age. Multiple factors, including the intestinal microbiome, affect the pathogenesis and development of PCOS. However, the specific mechanisms by which gut microbes play a role in PCOS remain elusive. This review summarizes recent research about the transformational changes in gut microbes revealed in PCOS patients and the possible mechanisms and pathways by which the intestinal microbiome exerts influence on PCOS progression and phenotypes. In addition to the intestinal microbiome, evidence from animal studies suggests changes in the vaginal microbiome under PCOS conditions. The alteration of microbiome could affect oestrus cycle and PCOS phenotypes. Microbiome is closely associated with medicine and therapeutic approaches. Microbiome influences drug and therapy response and itself is a new source of therapy. Accurate modulation of the intestinal and vaginal microbiome is a potential therapy for PCOS patients. Future studies are required to elucidate the specific role of each particular genera of microbiota and the mechanism by which microbiome impacts the pathogenesis, progression and phenotypes of PCOS.
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http://dx.doi.org/10.1016/j.biopha.2020.110958DOI Listing
January 2021

Fecobionics Characterization of Patients with Fecal Incontinence.

Clin Gastroenterol Hepatol 2020 Oct 28. Epub 2020 Oct 28.

Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong.

Fecal incontinence (FI) is characterized by involuntary loss of rectal content. Up to 9.5% of Americans younger than 70 years suffer from FI. The pathophysiology has many causes and is not well understood and diagnosed.
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http://dx.doi.org/10.1016/j.cgh.2020.10.043DOI Listing
October 2020

Irradiation-free RIC HSCT has a tolerable safety profile and is effective therapy for pediatric bone marrow failure syndromes.

Pediatr Transplant 2021 Mar 6;25(2):e13855. Epub 2020 Oct 6.

UCSD School of Medicine, La Jolla, CA, USA.

For patients with bone marrow failure syndromes (BMFS) who may tolerate gradual donor engraftment and achieve adequate disease control with stable mixed chimerism, RIC regimens may be preferable to myeloablative regimens. We performed a retrospective analysis of outcomes for patients who underwent HSCT at our institution between 2009 and 2017 for BMFS using an irradiation-free RIC regimen. Fourteen pediatric patients with BMFS received fludarabine (30 mg/m IV daily × 3), thiotepa (5 mg/kg IV every 12 hours × 2), and melphalan (70 mg/m IV daily × 2) prior to HSCT. Our cohort included the following diagnoses: SAA (n = 7), CAMT (n = 4), SCN (n = 1), DBA (n = 1), and non-Fanconi congenital BMF (n = 1). Seven patients underwent a MSD transplant; seven underwent an unrelated donor transplant. All patients are alive with median follow-up of 1112 days (range 455-2549 days). The median time to neutrophil engraftment was 16 days (range 10-26 days). All were transfusion independent by day + 100. The highest grade of aGVHD was grade 2; 8 (57%) did not develop aGVHD. Four (28.5%) developed extensive cGVHD, 4 (28.5%) developed limited cGVHD, and 6 (43%) did not develop cGVHD. No patients developed SOS. None died from GVHD or infectious complications. HSCT with RIC with fludarabine, thiotepa, and melphalan for BMFS was effective with a tolerable safety profile. Probability of OS at 100 days and 1 year was 100%.
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http://dx.doi.org/10.1111/petr.13855DOI Listing
March 2021

The effects of transcranial direct current stimulation (tDCS) on clinical symptoms in schizophrenia: A systematic review and meta-analysis.

Asian J Psychiatr 2020 Oct 5;53:102392. Epub 2020 Sep 5.

Department of Psychiatry, The University of Hong Kong, Hong Kong.

Objective: This systematic review and meta-analysis aims to examine the effects of transcranial direct current stimulation (tDCS) on clinical symptoms in schizophrenia.

Methods: A literature search was performed for articles published in English using the following databases: MEDLINE, EMBASE, PsycINFO, INSPEC, the Cumulative Index to Nursing & Allied Health Literature Plus (CINAHL Plus), AMED, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, EU Clinical Trials Register, and WHO International Clinical Trials Registry Platform, from their inception to October 2019. The primary outcome variables were the clinical symptoms of schizophrenia including positive symptoms, negative symptoms, and auditory hallucinations.

Results: 16 randomized controlled trials (RCTs) were included in the meta-analysis, with a sample of 326 patients with active and with 310 sham tDCS. Active tDCS was found to be more effective in improving positive symptoms [standardized mean difference (SMD) = 0.17; 95 % confidence interval (CI) 0.001 to 0.33], negative symptoms [SMD = 0.43, 95 % CI 0.11, 0.75] and auditory hallucinations [SMD = 0.36 95 % CI 0.02, 0.70]. Subgroup analyses showed better results in cases of pure diagnosis of schizophrenia, higher frequency and more sessions of stimulation.

Conclusion: tDCS was effective in improving positive symptoms, negative symptoms and auditory hallucination in schizophrenia. It therefore has potential as a safe and well-tolerated adjunctive intervention for schizophrenia.
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http://dx.doi.org/10.1016/j.ajp.2020.102392DOI Listing
October 2020

Prenatal diagnosis and long-term follow-up of a Chinese patient with mosaic variegated aneuploidy and its molecular analysis.

Clin Case Rep 2020 Aug 19;8(8):1369-1375. Epub 2020 May 19.

Department of Obstetrics and Gynaecology Queen Mary Hospital Hong Kong Hong Kong.

Mosaic variegated aneuploidy (MVA) is a rare genetic disorder caused by mutations in , or . We describe the prenatal diagnosis, molecular characterization, and clinical management of a long-lived patient with -related MVA.
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http://dx.doi.org/10.1002/ccr3.2802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455400PMC
August 2020

Rapid production of clinical-grade SARS-CoV-2 specific T cells.

Adv Cell Gene Ther 2020 Jul 31:e101. Epub 2020 Jul 31.

Department of Haematology/Oncology KK Women's and Children's Hospital SingHealth Singapore.

Objectives: To determine whether the frequencies of SARS-CoV-2-specific T cells are sufficiently high in the blood of convalescent donors and whether it is technically feasible to manufacture clinical-grade products overnight for T-cell therapy and assessment of COVID-19 immunity.

Methods: One unit of whole blood or leukapheresis was collected from each donor following standard blood bank practices. The leukocytes were stimulated using overlapping peptides of SARS-CoV-2, covering the immunodominant sequence domains of the S protein and the complete sequence of the N and M proteins. Thereafter, functionally reactive cells were enriched overnight using an automated device capturing IFNγ-secreting cells.

Results: From 1 × 10 leukocytes, a median of 0.98 × 10 (range 0.56-2.95) IFNγ + T cells were produced from each of the six donors, suggesting a high frequency of SARS-CoV-2 reactive T cells in their blood, even though only one donor had severe COVID-19 requiring mechanical ventilation whereas the other five donors had minor symptoms. A median of 57% of the enriched T cells were IFNγ+ (range 20%-74%), with preferential enrichment of CD56+ T cells and effector memory T cells. TCRVβ-spectratyping confirmed distinctively tall oligoclonal peaks in final products. With just six donors, the probability that a recipient would share at least one HLA allele with one of the donors is >88% among Caucasian, >95% among Chinese, >97% among Malay, and >99% among Indian populations.

Conclusions: High frequencies of rapid antigen-reactive T cells were found in convalescent donors, regardless of severity of COVID-19. The feasibility of clinical-grade production of SARS-CoV-2-specific T cells overnight for therapeutics and diagnostics is revealed.
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http://dx.doi.org/10.1002/acg2.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404427PMC
July 2020

Polyclonal Burkholderia cepacia Complex Outbreak in Peritoneal Dialysis Patients Caused by Contaminated Aqueous Chlorhexidine.

Emerg Infect Dis 2020 09;26(9):1987-1997

Whether Burkholderia cepacia complex should be an objectionable organism in antiseptic solutions with acceptable total bacterial counts is controversial. By using next-generation sequencing, we documented a polyclonal B. cepacia complex outbreak affecting peritoneal dialysis patients in Hong Kong that was caused by contaminated chlorhexidine solutions. Epidemiologic investigations at a manufacturing site identified a semiautomated packaging machine as the probable source of contamination in some of the brands. Use of whole-genome sequencing differentiated the isolates into 3 brand-specific clonal types. Changes in exit site care recommendations, rapid recall of affected products, and tightening of regulatory control for chlorhexidine-containing skin antiseptics could prevent future similar outbreaks. Environmental opportunistic pathogens, including B. cepacia complex, might be included in regular surveillance as indicator organisms for monitoring environmental contamination.
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http://dx.doi.org/10.3201/eid2609.191746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454066PMC
September 2020

Maternal Thyroid Dysfunction During Pregnancy and the Risk of Adverse Outcomes in the Offspring: A Systematic Review and Meta-Analysis.

J Clin Endocrinol Metab 2020 12;105(12)

Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.

Context: Previous studies suggested a potential link of maternal thyroid dysfunction with adverse neurocognitive outcomes and impaired development of internal organs in offspring.

Objective: To review the association between maternal thyroid dysfunction and the risk of adverse outcomes in offspring.

Data Sources: PubMed, EMBASE, and Cochrane Library.

Study Selections: Eligible studies reported the association between maternal thyroid hormone function and the risk of adverse outcomes in their children.

Data Extraction: Reviewers extracted data on study characteristics and results independently.

Data Synthesis: Estimates were pooled and reported as odds ratio (OR) with 95% confidence interval (CI). I2 tests were applied to assess the heterogeneity across studies.

Results: We identified 29 eligible articles and found an association between maternal hyperthyroidism and attention deficit hyperactivity disorder (ADHD) (OR: 1.18, 95% CI: 1.04-1.34, I2 = 0%) and epilepsy (OR: 1.19, 95% CI: 1.08-1.31, I2 = 0%) in offspring; as well as an association of maternal hypothyroidism with increased risk of ADHD (OR: 1.14, 95% CI: 1.03-1.26, I2 = 25%), autism spectrum disorder (OR: 1.41, 95% CI: 1.05-1.90, I2 = 63%), and epilepsy (OR: 1.21, 95% CI: 1.06-1.39, I2 = 0%) in offspring.

Conclusion: Routine measurement and timely treatment on thyroid function should be considered for pregnant women.
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http://dx.doi.org/10.1210/clinem/dgaa555DOI Listing
December 2020

Simulated stool for assessment of anorectal physiology.

Am J Physiol Gastrointest Liver Physiol 2020 10 12;319(4):G462-G468. Epub 2020 Aug 12.

Department of Surgery, the Chinese University of Hong Kong, Shatin, Hong Kong.

Fecal continence is maintained by several mechanisms including anatomical factors, anorectal sensation, rectal compliance, stool consistency, anal muscle strength, mobility, and psychological factors. The homeostatic balance is easily disturbed, resulting in symptoms including fecal incontinence and constipation. Current technologies for assessment of anorectal function have limitations. Overlap exist between data obtained in different patient groups, and there is lack of correlation between measurements and symptoms. This review describes a novel technology named Fecobionics for assessment of anorectal physiology. Fecobionics is a simulated stool, capable of dynamic measurements of a variety of variables during defecation in a single examination. The data facilitate novel analysis of defecatory function as well as providing the foundation for modeling studies of anorectal behavior. The advanced analysis can enhance our physiological understanding of defecation and future interdisciplinary research for unraveling defecatory function, anorectal sensory-motor disorders, and symptoms. This is a step in the direction of improved diagnosis of anorectal diseases.
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http://dx.doi.org/10.1152/ajpgi.00242.2020DOI Listing
October 2020

Improving Diagnostic Classification of Stillbirths and Neonatal Deaths Using ICD-PM (International Classification of Diseases for Perinatal Mortality) Codes: Validation Study.

JMIR Med Inform 2020 Aug 3;8(8):e20071. Epub 2020 Aug 3.

Department of Obstetrics and Gynaecology, Kwong Wah Hospital, Hong Kong SAR, China (Hong Kong).

Background: Stillbirths and neonatal deaths have long been imperfectly classified and recorded worldwide. In Hong Kong, the current code system is deficient (>90% cases with unknown causes) in providing the diagnoses of perinatal mortality cases.

Objective: The objective of this study was to apply the International Classification of Diseases for Perinatal Mortality (ICD-PM) system to existing perinatal death data. Further, the aim was to assess whether there was any change in the classifications of perinatal deaths compared with the existing classification system and identify any areas in which future interventions can be made.

Methods: We applied the ICD-PM (with International Statistical Classification of Diseases and Related Health Problems, 10th Revision) code system to existing perinatal death data in Kwong Wah Hospital, Hong Kong, to improve diagnostic classification. The study included stillbirths (after 24 weeks gestation) and neonatal deaths (from birth to 28 days). The retrospective data (5 years) from May 1, 2012, to April 30, 2017, were recoded by the principal investigator (HML) applying the ICD-PM, then validated by an overseas expert (EA) after she reviewed the detailed case summaries. The prospective application of ICD-PM from May 1, 2017, to April 30, 2019, was performed during the monthly multidisciplinary perinatal meetings and then also validated by EA for agreement.

Results: We analyzed the data of 34,920 deliveries, and 119 cases were included for analysis (92 stillbirths and 27 neonatal deaths). The overall agreement with EA of our codes using the ICD-PM was 93.2% (111/119); 92% (78/85) for the 5 years of retrospective codes and 97% (33/34) for the 2 years of prospective codes (P=.44). After the application of the ICD-PM, the overall proportion of unknown causes of perinatal mortality dropped from 34.5% (41/119) to 10.1% (12/119) of cases (P<.001).

Conclusions: Using the ICD-PM would lead to a better classification of perinatal deaths, reduce the proportion of unknown diagnoses, and clearly link the maternal conditions with these perinatal deaths.
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http://dx.doi.org/10.2196/20071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432142PMC
August 2020

Effectiveness of Bath Wipes After Hematopoietic Cell Transplantation: A Randomized Trial.

J Pediatr Oncol Nurs 2020 Nov/Dec;37(6):390-397. Epub 2020 Jul 24.

St. Jude Children's Research Hospital, Memphis, TN, USA.

Bacteremia is a leading cause of morbidity and mortality in children undergoing hematopoietic cell transplantation (HCT). Infections of vancomycin-resistant enterococci (VRE) and multidrug resistant (MDR) gram-negative rods (GNRs) are common in this population. Our objective was to assess whether experimental bath wipes containing silver were more effective than standard bath wipes containing soap at reducing skin colonization by VRE and MDR GNRs, and nonmucosal barrier injury bacteremia. Patients undergoing autologous or allogeneic HCT in a tertiary referral center were randomized to receive experimental or standard bath wipes for 60 days post-HCT. Skin swabs were collected at baseline, discharge, and day +60 post-HCT. The rate of VRE colonization was chosen as the marker for efficacy. Experimental bath wipes were well tolerated. Before the study, the rate of colonization with VRE in HCT recipients was 25%. In an interim analysis of 127 children, one (2%) patient in the experimental arm and two (3%) in the standard arm were colonized with VRE. Two (3%) patients had nonmucosal barrier injury bacteremia in the standard arm, with none in the experimental arm. MDR GNRs were not isolated. The trial was halted because the interim analyses indicated equivalent efficacy of the two methods. Skin cleansing with silver-containing or standard bath wipes resulted in very low and equivalent rates of bacteremia and colonization with VRE and MDR GNRs in children post-HCT. Future studies in other high-risk populations are needed to confirm these results.
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http://dx.doi.org/10.1177/1043454220944061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802025PMC
March 2021

Erratum to: "Macrophage p38 alpha promotes nutritional steatohepatitis through M1 polarization (J Hepatol 2019; 71(1):163-174)".

J Hepatol 2020 Sep 18;73(3):742-743. Epub 2020 Jul 18.

Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2020.06.019DOI Listing
September 2020

Examining service-user perspectives for the development of a good outcome checklist for individuals at clinical high risk for psychosis.

Early Interv Psychiatry 2020 May 26. Epub 2020 May 26.

Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Aims: Around 15% of patients at clinical high risk for psychosis (CHR-P) experience symptomatic remission and functional recovery at follow-up, yet the definition of a good outcome (GO) in this population requires further development. Outcomes are typically designed and rated by clinicians rather than patients, to measure adverse as opposed to GOs. Here we investigate how CHR-P subjects define a GO, with the aim of developing a checklist that could be used to measure GO in this clinical group.

Methods: A set of GO-focused questions were designed in collaboration with a service-user. CHR-P patients (n = 48) were asked to rate the importance of items that could indicate short-term (1 year) and long-term (5 years) GO. These items were then ranked using the relative importance index (RII).

Results: Patients rated improvement in subjective wellbeing (RII = 0.829) and non-specific presenting symptoms (RII = 0.817) amongst the factors most important for indicating GO in the short-term, and improved resilience (RII = 0.879) and negative symptoms (RII = 0.858) as key items for indicating long-term GO. Patients regarded building resilience (RII = 0.842) and having support from mental health services (RII = 0.833) as being protective for their mental health. These measures were included in a preliminary 12-item GO checklist (GO-12) for assessing GO in CHR-P subjects.

Conclusions: Patient-defined measures of GO included items that are not incorporated into conventional measures of outcomes in CHR-P subjects, such as subjective wellbeing and resilience. Integrating patient-defined metrics of GO may improve the assessment of outcomes in the CHR-P population.
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http://dx.doi.org/10.1111/eip.12991DOI Listing
May 2020

Parental-to-embryo switch of chromosome organization in early embryogenesis.

Nature 2020 04 25;580(7801):142-146. Epub 2020 Mar 25.

Institut Curie, PSL Research University, CNRS UMR3215, INSERM U934, UPMC Paris-Sorbonne, Paris, France.

Paternal and maternal epigenomes undergo marked changes after fertilization. Recent epigenomic studies have revealed the unusual chromatin landscapes that are present in oocytes, sperm and early preimplantation embryos, including atypical patterns of histone modifications and differences in chromosome organization and accessibility, both in gametes and after fertilization. However, these studies have led to very different conclusions: the global absence of local topological-associated domains (TADs) in gametes and their appearance in the embryo versus the pre-existence of TADs and loops in the zygote. The questions of whether parental structures can be inherited in the newly formed embryo and how these structures might relate to allele-specific gene regulation remain open. Here we map genomic interactions for each parental genome (including the X chromosome), using an optimized single-cell high-throughput chromosome conformation capture (HiC) protocol, during preimplantation in the mouse. We integrate chromosome organization with allelic expression states and chromatin marks, and reveal that higher-order chromatin structure after fertilization coincides with an allele-specific enrichment of methylation of histone H3 at lysine 27. These early parental-specific domains correlate with gene repression and participate in parentally biased gene expression-including in recently described, transiently imprinted loci. We also find TADs that arise in a non-parental-specific manner during a second wave of genome assembly. These de novo domains are associated with active chromatin. Finally, we obtain insights into the relationship between TADs and gene expression by investigating structural changes to the paternal X chromosome before and during X chromosome inactivation in preimplantation female embryos. We find that TADs are lost as genes become silenced on the paternal X chromosome but linger in regions that escape X chromosome inactivation. These findings demonstrate the complex dynamics of three-dimensional genome organization and gene expression during early development.
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http://dx.doi.org/10.1038/s41586-020-2125-zDOI Listing
April 2020

Longitudinal NK cell kinetics and cytotoxicity in children with neuroblastoma enrolled in a clinical phase II trial.

J Immunother Cancer 2020 03;8(1)

Oncology Department, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

Background: Natural killer (NK) cells are one of the main effector populations of immunotherapy with monoclonal antibody and cytokines, used in combination with chemotherapy to treat children with high-risk neuroblastoma on this phase II trial. However, the impact of chemoimmunotherapy on NK cell kinetics, phenotype, and function is understudied.

Methods: We prospectively examined NK cell properties from 63 children with newly diagnosed neuroblastoma enrolled in a phase II trial (NCT01857934) and correlated our findings with tumor volume reduction after 2 courses of chemoimmunotherapy. NK cell studies were conducted longitudinally during chemoimmunotherapy and autologous hematopoietic cell transplantation (autoHCT) with optional haploidentical NK cell infusion and additional immunotherapy.

Results: Chemoimmunotherapy led to significant NK cytopenia, but complete NK cell recovery reliably occurred by day 21 of each therapy course as well as after autoHCT. Haploidentical NK cell infusion elevated the NK cell count transiently during autoHCT. NK cell cytotoxicity increased significantly during treatment compared with diagnosis. In addition, NK cells maintained their ability to respond to cytokine stimulation in culture longitudinally. Unsupervised cluster analysis of CD56 NK cell count and tumor volume at diagnosis and after two courses of chemoimmunotherapy identified two patient groups with distinct primary tumor sizes and therapy responses.

Conclusion: After profound NK cytopenia due to chemoimmunotherapy, endogenously reconstituted NK cells exhibit enhanced NK cytotoxicity compared with pretherapy measurements. Our data suggest a relationship between CD56 expression and tumor size before and after two courses of chemoimmunotherapy; however, future studies are necessary to confirm this relationship and its predictive significance.

Trial Registration Number: NCT01857934.
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http://dx.doi.org/10.1136/jitc-2019-000176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206969PMC
March 2020

A basic understanding of mucopolysaccharidosis: Incidence, clinical features, diagnosis, and management.

Intractable Rare Dis Res 2020 Feb;9(1):1-9

Laboratory for Reproductive Immunology, Hospital & Institute of Obstetrics and Gynecology, Shanghai Medical College, Fudan University, Shanghai, China.

Mucopolysaccharidoses (MPS) are a group of rare lysosomal storage diseases (LSD) with multi-organic and severe symptoms. MPS occur worldwide in various forms though have relative a low incidence. The prevalent type of MPS varies among different continents, indicating that it may be associated with region and ethnic background. Undegraded glycosaminoglycans (GAGs) induced by deficiency of enzymes are the primary cause of MPS. Clinical features differ depending on the specific enzyme deficiency including coarse facial features, cognitive retardation, hepatosplenomegaly, hernias, kyphoscoliosis, corneal clouding, Symptoms of different types are usually similar especially MPS I and II, but may have distinguishable features such as severe neurological problems in MPS III and hydrops fetails in MPS VII. These clinical features contribute to diagnosis, but early and precisely diagnosis in the asymptomatic stage is imperative for better outcomes. Novel approaches including urinary and blood GAG test, enzyme assay and gene test help to diagnose MPS and to determine its subtype. Hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) are conventional treatment for MPS, but are not effective at treating all MPS. Newer threatments, such as advanced ERT, gene therapy and substrate reduction therapy (SRT), improve therpeutic efficacy. In this review, we update information on the clinical manifestations, diagnosis, and treatment of the different forms of this disease in the hopes of stimulating further interest in MPS.
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http://dx.doi.org/10.5582/irdr.2020.01011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062595PMC
February 2020

The novel role of Hippo-YAP/TAZ in immunity at the mammalian maternal-fetal interface: Opportunities, challenges.

Biomed Pharmacother 2020 Jun 4;126:110061. Epub 2020 Mar 4.

Laboratory for Reproductive Immunology, Hospital & Institute of Obstetrics and Gynecology, Shanghai Medical College, Fudan University, Shanghai, China; The Academy of Integrative Medicine, Fudan University, Shanghai, China; Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases, Shanghai, China. Electronic address:

The Hippo-Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ), originally identified as a regulator of tissue generation and tumorigenesis, has been proven to have a pivotal position in immunity. Its multi-faceted roles in regulating immunity cover both intrinsic mechanism of immune cells and the crosstalk with non-immune cells. Survival of the allogeneic embryo in the maternal uterine environment depends on immune tolerance, supported by the highly orchestrated cooperation between decidual immune cells, decidual stromal cells and trophoblasts at the maternal-fetal interface. The abnormal maternal-fetal dialogue is believed to be associated with adverse pregnancy outcomes such as spontaneous pregnancy loss. Recent breakthroughs shed light on the how the Hippo-YAP/TAZ manipulate the decidualization and trophoblast invasion, while further research is needed to integrate and reconcile existing findings of the Hippo-YAP/TAZ in immunity and to extend them at the context of pregnancy. In this review, we summarized the Hippo-YAP/TAZ pathways, detailed the effects of YAP/TAZ on immune cells, and discussed the role of YAP/TAZ at the maternal-fetal interface and the potential of YAP/TAZ on immunity regulation at the context of pregnancy. Given the remarkable effect of therapeutic intervention of YAP/TAZ in cancer and autoimmune diseases, it is worthy to explore the response to YAP/TAZ inhibition in the maternal-fetal immunity. This may provide a new valuable target for therapy of pregnancy loss, or potentially other pregnancy complications.
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http://dx.doi.org/10.1016/j.biopha.2020.110061DOI Listing
June 2020

Alterations of Several Serum Parameters Are Associated with Preeclampsia and May Be Potential Markers for the Assessment of PE Severity.

Dis Markers 2020 13;2020:7815214. Epub 2020 Jan 13.

Laboratory for Reproductive Immunology, Hospital & Institute of Obstetrics and Gynecology, Shanghai Medical College, Fudan University, Shanghai, China.

The precise pathophysiological mechanisms of preeclampsia (PE) and preventative strategies remain unknown. Laboratory markers which can help in identifying PE patients from pregnant women and assessing the severity of PE during pregnancy are worthy to be explored. In this study, a retrospective case-control study was designed to assess whether the serum levels of albumin (ALB), total protein (TP), prealbumin (PA), alkaline phosphatase (ALP), lactic dehydrogenase (LDH), D-dimer, fibrinogen (Fbg), platelet (PLT) count, mean platelet volume (MPV), and platelet distribution width (PDW) can help in assessing PE and evaluate its severity. 256 pregnant women were enrolled and classified into 3 groups: mild preeclampsia (mPE, = 85), severe preeclampsia (sPE, = 78), and healthy normotensive controls (control, = 93). Our result showed that the serum levels of ALP, LDH, and D-dimer were significantly higher in mild or severe PE patients compared with the healthy controls (66 (52.5-76.5) vs. 168 (141.5-201.25) vs. 182.5 (120-191.5), 152 (139.75-166.25) vs. 183.5 (163.25-307) vs. 282 (215.25-306), 1.05 (0.65-1.57) vs. 3.05 (2.25-4.08) vs. 5.65 (2.29-7.71)), while ALB, TP, and PA are lower (38 (37-42) vs. 31.5 (25.5-34.5) vs. 28.5 (24-33), 65 (63-68.25) vs. 56.5 (52-61) vs. 51.5 (49-58), 219.14 ± 68.25 vs. 167.88 ± 52.21 vs. 143.22 ± 50.46). On the other hand, compared with the mPE group, the sPE group showed significantly lower PLT count but higher level of LDH, D-dimer, and Fbg. No significant differences in MPV or PDW were found between any of the two groups. In conclusion, the above markers except for the MPV and PDW may be correlated with PE severity in this patient cohort, indicating possible values of these potential biomarkers in auxiliary diagnosis and severity assessment of PE.
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http://dx.doi.org/10.1155/2020/7815214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983284PMC
September 2020

A Phase 2 Trial of KIR-Mismatched Unrelated Donor Transplantation Using in Vivo T Cell Depletion with Antithymocyte Globulin in Acute Myelogenous Leukemia: Children's Oncology Group AAML05P1 Study.

Biol Blood Marrow Transplant 2020 04 21;26(4):712-717. Epub 2019 Dec 21.

Bone Marrow Transplant Department, St Jude Children's Research Hospital, Memphis, Tennessee.

Patients with acute myelogenous leukemia (AML) who undergo killer immunoglobulin-like receptor (KIR)-mismatched haploidentical hematopoietic stem cell transplantation (HSCT) have improved survival. Children's Oncology Group AAML05P1 is a prospective phase 2 trial of unrelated donor (URD) HSCT in which KIR typing of donors was available to the treating physician at donor selection, aiming to determine feasibility (defined as the ability to obtain donor samples from URDs and obtain KIR data before transplantation) of prospective selection of KIR-mismatched donors and effect on outcomes. Patients age ≤30 years with high-risk AML at presentation or relapsed AML were eligible; the study accrued 90 evaluable patients. After enrollment, as many as 5 potential URD samples were KIR-typed (including gene expression) in a central laboratory and results reported to the treating physician, who made the final donor selection. Cases were categorized as KIR-matched or KIR-mismatched using different published strategies. Overall survival (OS), disease-free survival (DFS), and relapse did not differ significantly by KIR mismatch status. Acute graft-versus-host disease (GVHD) was significantly lower in recipients of KIR-mismatched stem cells (35% versus 60%; P = .027). We examined DFS according to time to natural killer (NK) receptor recovery after HSCT. NK p44 recovery was significantly associated with KIR mismatch and with decreased DFS and increased relapse risk in multivariate Cox analysis (P = .006 and .009, respectively). We show that prospective selection of URD according to KIR type was feasible, acute GVHD was reduced, but survival did not differ using any model of KIR mismatch. However, the study enrolled mostly matched transplants, so ligand-ligand mismatch was rare, and thus the sample size was insufficient to determine potential benefit according to this model. Cord blood recipients demonstrated a trend toward improved DFS with KIR mismatch, but the study was not powered to detect a difference in this small subset of patients. Our data suggest that recovery of NK receptor expression might influence DFS after HSCT.
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http://dx.doi.org/10.1016/j.bbmt.2019.12.723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198330PMC
April 2020

Novel Fecobionics Defecatory Function Testing.

Clin Transl Gastroenterol 2019 12;10(12):e00108

Department of Surgery, the Chinese University of Hong Kong, Shatin, Hong Kong.

Introduction: Defecation is a complex process that can be easily disturbed. Defecatory disorders may be diagnosed using specialized investigation, including anorectal manometry (ARM) and the balloon expulsion test (BET). Recently, we developed a simulated stool named Fecobionics that integrates several tests and assesses pressures, orientation, and bending during evacuation. The aim was to evaluate the feasibility and performance of Fecobionics for assessing defecatory physiology in normal subjects.

Methods: Physiological expulsion parameters were assessed in an interventional study design. The 10-cm-long Fecobionics probe contained pressure sensors at the front and rear and inside a bag and 2 motion processor units. The bag was distended in the rectum of 20 presumed normal subjects (15 female/5 male) until urge to defecate. ARM-BET was also performed. Three subjects used +2 minutes to evacuate BET, and 1 subject had a high fecal incontinence score. Therefore, the normal group consisted of 16 subjects (13 female/3 male aged 25-78 years).

Results: All subjects reported that Fecobionics evacuation was similar to normal defecation. Fecobionics expulsion pressure signatures demonstrated 5 phases, reflecting rectal pressure, anal relaxation, and anal passage. Preload-afterload loop diagrams demonstrated clockwise contraction cycles. The expulsion duration for BET and Fecobionics was 16 ± 2 and 23 ± 5 seconds (P > 0.2), respectively. The duration of the Fecobionics and BET expulsions was associated (P < 0.001). The change in bending of Fecobionics during defecation was 40 ± 3°.

Discussion: Fecobionics obtained reliable data under physiological conditions. Agreement was found for comparable variables between ARM-BET and Fecobionics but not for other variables. The study suggests that Fecobionics is safe and effective in evaluation of key defecatory parameters.
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http://dx.doi.org/10.14309/ctg.0000000000000108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970554PMC
December 2019

Improved survival rate in T-cell depleted haploidentical hematopoietic cell transplantation over the last 15 years at a single institution.

Bone Marrow Transplant 2020 05 18;55(5):929-938. Epub 2019 Nov 18.

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA.

T-cell depletion of an HLA-haploidentical (haplo) graft is often used to reduce the risk of graft-versus-host disease (GVHD), but the lack of donor T cells in the infused product may lead to graft failure, slow T-cell reconstitution, infections, and relapse. More selective T-cell depletion targeting CD45RA can effectively deplete naive T cells but preserve large numbers of memory T cells leading to robust engraftment of diverse T-cell populations and reduction of viremia in the early posttransplant period. Herein, we report the outcome of 143 pediatric and young adult hematologic malignancy patients receiving a first allogeneic hematopoietic cell transplantation (HCT) on six consecutive ex vivo T-cell depleted haploHCT protocols over the past 15 years at a single institution-including the first 50 patients on an active CD45RA-depleted haploHCT study in which patients also received NK-cells and pharmacological GvHD prophylaxis post transplant. Our data demonstrated an increase in the 3-year overall survival and event-free survival in nonchemorefractory recipients receiving CD45RA-depleted grafts (78.9% and 77.7%, respectively) compared with historic T-cell depleted haploHCT cohorts (46.7% and 42.7%, respectively, p = 0.004, and 0.003). This improvement was primarily due to a reduction in transplant related mortality without significant increase in the rates of GVHD.
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http://dx.doi.org/10.1038/s41409-019-0750-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202974PMC
May 2020

Docking protein-1 promotes inflammatory macrophage signaling in gastric cancer.

Oncoimmunology 2019;8(11):e1649961. Epub 2019 Aug 21.

Dept. of Medicine II, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Docking protein-1 (DOK1) is a tumor suppressor frequently lost in malignant cells, however, it retains the ability to control activities of immune receptors in adjacent stroma cells of the tumor microenvironment. We therefore hypothesized that addressing DOK1 may be useful for cancer immunotherapy. mRNA and DOK1 protein expression were downregulated in tumor cells of gastric cancer patients (n = 249). Conversely, its expression was up-regulated in cases positive for Epstein Barr Virus (EBV+) together with genes related to macrophage biology and targets of clinical immunotherapy such as programmed-cell-death-ligand-1 (PD-L1). Notably, high DOK1 positivity in stroma cells conferred poor prognosis in patients and correlated with high levels of inducible nitric oxide synthase in CD68+ tumor-associated macrophages. In macrophages derived from human monocytic leukemia cell lines, DOK1 (i) was inducible by agonists of the anti-diabetic transcription factor peroxisome proliferator-activated receptor-gamma (PPARγ), (ii) increased polarization towards an inflammatory phenotype, (iii) augmented nuclear factor-κB-dependent transcription of pro-inflammatory cytokines and (iv) reduced PD-L1 expression. These properties empowered DOK1+ macrophages to decrease the viability of human gastric cancer cells in contact-dependent co-cultures. DOK1 also reduced PD-L1 expression in human primary blood monocytes. Our data propose that the drugability of DOK1 may be exploited to reprogram myeloid cells and enforce the innate immune response against EBV+ human gastric cancer.
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http://dx.doi.org/10.1080/2162402X.2019.1649961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791443PMC
August 2019