Has the core outcome (domain) set for vitiligo been implemented? An updated systematic review on outcomes and outcome measures in vitiligo randomized clinical trials.

BACKGROUND: In 2015, a major achievement in vitiligo research was the development of an internationally agreed upon core outcome domain set for randomized clinical trials (RCTs). Three outcomes were identified as being essential: repigmentation, side-effects/harms and maintenance of gained repigmentation. Four items were further recommended for inclusion. The following recommendations then followed: repigmentation should be assessed by measuring the percentage of repigmentation in quartiles (0-25%, 26-50%, 51-79%, 80-100%) and cosmetic acceptability of the results should be assessed using the Vitiligo Noticeability Scale. OBJECTIVES: The primary objective of this study was to assess uptake of the core outcome domain set for RCTs in vitiligo. Secondary objectives were to update the systematic review on outcomes reported in vitiligo RCTs, and to assess whether repigmentation and cosmetic acceptability of the results were measured using the above-mentioned recommended scales. METHODS: We searched PubMed, Cochrane Library (CENTRAL and Systematic Reviews) and ClinicalTrials.gov for vitiligo RCTs between November 2009 and March 2021. Screening and data extraction were independently performed on title and summary by two researchers. All outcomes and outcome measures reported in eligible RCTs were retrieved and collated. RESULTS: In total, 174 RCTs were identified: 62 were published between 2009 and 2015, and 112 were published between 2016 and 2021.Thirty-eight different outcomes were reported. Repigmentation was the primary outcome in 89% of trials (150 of 169). Forty-nine different tools were used to measure repigmentation. Side-effects and harms were reported in 78% of trials (136 of 174). Maintenance of gained repigmentation was reported in only 11% of trials (20 of 174) and duration of follow-up varied greatly from 1 to 14 months. Cosmetic acceptability of the results and cessation of disease activity were assessed in only 2% of trials (four of 174). Quality of life of patients with vitiligo was assessed in 13% of trials (22 of 174). Finally, only 11 of 112 RCTs (10%) published between 2016 and 2021 reported all three essential core outcome domains (repigmentation, side-effects and maintenance of gained repigmentation) and none of the trials reported both essential and recommended core outcome domains. CONCLUSIONS: Efforts are still needed to close the gap between set recommendations and RCT outcome reporting.

Organ-Specific Differentiation of Human Adipose-Derived Stem Cells in Various Organs of Xenotransplanted Rats: A Pilot Study.

Adipose-derived stem cells (ADSCs) are potential therapeutics considering their self-renewal capacity and ability to differentiate into all somatic cell types in vitro. The ideal ADSC-based therapy is a direct injection into the relevant organs. The objective of this study was to investigate the viability and safety of intra-organ human ADSC (h-ADSC) xenotransplants in vivo. Subcutaneous adipose tissue from the abdominal area of 10 patients was sampled. h-ADSCs were isolated from adipose tissue samples and identified using immunofluorescence antibodies. Multi-differentiation potential assays for adipocytes, osteocytes, and chondrocytes were performed. Cultured h-ADSCs at passage 4 were transplanted into multiple organs of 17 rats, including the skin, subcutaneous layer, liver, kidney, pancreas, and spleen. The h-ADSC-injected organs excised after 100 days were examined, and the survival of h-ADSCs was measured by quantitative real-time polymerase chain reaction (qRT-PCR) using specific human and rat target genes. h-ADSCs confirmed by stem cell phenotyping were induced to differentiate into adipogenic, osteogenic, and chondrogenic lineages in vitro. All rats were healthy and exhibited no side effects during the study; the transplanted h-ADSCs did not cause inflammation and were indiscernible from the native organ cells. The presence of transplanted h-ADSCs was confirmed using qRT-PCR. However, the engrafted survival rates varied as follows: subcutaneous fat (70.6%), followed by the liver (52.9%), pancreas (50.0%), kidney (29.4%), skin (29.4%), and spleen (12.5%). h-ADSCs were successfully transplanted into a rat model, with different survival rates depending on the organ.

Development of candidate reference method for accurate determination of four polycyclic aromatic hydrocarbons in olive oil via gas chromatography/high-resolution mass spectrometry using 13C-labeled internal standards.

We developed an isotope-dilution gas chromatography/high-resolution mass spectrometry (ID-GC/HRMS) method for the accurate determination of four polycyclic aromatic hydrocarbons (PAHs) in olive oil. The clean-up steps were optimized to sufficiently remove co-extracted oil matrix using the EZ-POP NP dual-layer and NH2 solid-phase extraction (SPE) cartridges. However, the cleaned sample still contained some matrix residues, which caused a bias. When 13C-labeled PAHs were used as the internal standards instead of deuterated PAHs, the recovery results improved in both low- and high-resolution MS conditions. Furthermore, the HRMS analysis facilitated to obtain more accurate results. The accuracy and precision of the optimized ID-GC/HRMS method were validated using PAH-fortified (0.5, 3, and 6 µg/kg) olive oil. The recoveries and relative standard deviations obtained for all the PAHs/levels were 97.5-102% and ~1%, respectively. Measurement uncertainties were generally within 5% (with a 95% confidence level).

A cross-sectional study on the association between vitamin D levels and caries in the permanent dentition of Korean children.

BACKGROUND: A recent study in Canada reported that vitamin D deficiency is associated with dental caries. Because Koreans have been reported to be deficient in vitamin D, we investigated the relationship between dental caries and reduced serum vitamin D levels in Korean children. The purpose of this study was to analyze the relationships between blood vitamin D [25(OH)D] concentrations and dental caries in the permanent dentition of Korean children. METHODS: Data were collected from the Korea National Health and Nutrition Examination Survey performed in 2008-2013. A total of 1688 children (10-12 years of age) were enrolled. Vitamin D intake was measured through analysis of 25-hydroxy vitamin D [25(OH)D] levels. Caries experience in permanent dentition was assessed using the decay-missing-filled teeth (DMFT) index and decayed-missing-filled (DMF) rate. Statistical analyses included complex samples Chi-square tests, complex samples logistic regression analyses, and Pearson's correlations. RESULTS: The group with 25(OH) D levels lower than 50 nmol/L had a higher proportion of children with caries in the permanent dentition and permanent first molar than the group with 25(OH)D levels of 50 nmol/L or more. When external factors, such as sex, were controlled, 25(OH)D levels were not significantly correlated with caries, but were significantly correlated with first molar caries. Children with 25(OH)D levels lower than 50 nmol/L were 1.295 times more likely to have first molar caries than those with 25(OH)D levels of 50 nmol/L or more. Additionally, 25(OH)D levels and DMFT were negatively correlated; however, the degree of correlation was not strong. CONCLUSIONS: The association between 25(OH)D and dental caries is still not clear. However, our findings suggested that vitamin D insufficiency may be a risk factor for dental caries.

Integrated copy number and gene expression profiling analysis of Epstein-Barr virus-positive diffuse large B-cell lymphoma.

Viral oncogenes and host immunosenescence have been suggested as causes of Epstein-Barr virus-positive diffuse large B-cell lymphoma (EBV + DLBCL) of the elderly. To investigate the molecular genetic basis of immune evasion and tumor outgrowth, we analyzed copy number alterations (CNAs) and gene expression profiles in EBV + DLBCL samples compared with EBV - DLBCL. There were relatively few genomic alterations in EBV + DLBCL compared with those detected in EBV-negative DLBCL. The most frequent CNAs (>30%) in EBV + DLBCLs were gains at 1q23.2-23.3, 1q23.3, 1q32.1, 5p15.3, 8q22.3, 8q24.1-24.2, and 9p24.1; losses at 6q27, 7q11.2, and 7q36.2-36.3 were also recurrent. A gene expression profile analysis identified the host immune response as a key molecular signature in EBV + DLBCL. Antiviral response genes, proinflammatory cytokines, and chemokines associated with the innate immune response were overexpressed, indicating the presence of a virusinduced inflammatory microenvironment. Genes associated with the B-cell receptor signaling pathway were downregulated. An integrated analysis indicated that SLAMF1 and PDL2 were key targets of the gains detected at 1q23.2-23.3 and 9p24.1. The chromosomal gain at 9p24.1 was associated with poor overall survival. Taken together, our results led to the identification of recurrent copy number alterations and distinct gene expression associated with the host immune response in EBV + DLBCL. We suggest that the upregulation of PDL2 on 9p24.1 promotes immune evasion and is associated with poor prognosis in EBV + DLBCL.

CD79B and MYD88 mutations in diffuse large B-cell lymphoma.

Mutations in 2 upstream components of the nuclear factor κB (NF-κB) pathway, CD79B and MYD88, are important information for new target therapy in malignant lymphoma. We examined the prevalence and clinicopathologic characteristics of CD79B and MYD88 mutation in a cohort of Asian diffuse large B cell lymphoma (DLBCL) patients. CD79B and MYD88 mutations were analyzed by Sanger sequencing in 187 DLBCL tissue samples. CD79B immunoreceptor tyrosine-based activation motif spanning exon 5 and 6 and MYD88 TIR domain spanning exons 3, 4 and 5 were amplified and sequenced. The cell-of-origin was determined based on immunohistochemical stains for CD10, BCL-6 and MUM-1 by Hans' algorithm. CD79B was mutated in 16 cases (8.5%), mostly involving the first tyrosine (Y196) of immunoreceptor tyrosine-based activation motif. For MYD88, L265P mutation was found in 31 cases (out of 161, 19.3%). In 11 of these, a CD79B mutation coexisted, which constituted 69% of CD79B mutants and 36% of MYD88 L265P cases. Clinicopathologic comparison between the mutant and the wild-type group showed that the mean age was older for both CD79B (66 versus 58 years) and MYD88 L265P mutant groups (64 versus 58 years). Survival analyses showed that neither CD79B mutation nor MYD88 L265P was a significant prognostic indicator. In conclusion, CD79B and MYD88 mutations are associated with an older age at onset in DLBCL with a significant overlap, which did not affect the outcome of the disease.

Integrative analysis of copy number alteration and gene expression profiling in ovarian clear cell adenocarcinoma.

Ovarian clear cell adenocarcinoma (Ov-CCA) is a distinctive subtype of ovarian epithelial carcinoma. In this study, we performed array comparative genomic hybridization (aCGH) and paired gene expression microarray of 19 fresh-frozen samples and conducted integrative analysis. For the copy number alterations, significantly amplified regions (false discovery rate [FDR] q <0.05) were 1q21.3 and 8q24.3, and significantly deleted regions were 3p21.31, 4q12, 5q13.2, 5q23.2, 5q31.1, 7p22.1, 7q11.23, 8p12, 9p22.1, 11p15.1, 12p13.31, 15q11.2, 15q21.2, 18p11.31, and 22q11.21 using the Genomic Identification of Significant Targets in Cancer (GISTIC) analysis. Integrative analysis revealed 94 genes demonstrating frequent copy number alterations (>25% of samples) that correlated with gene expression (FDR <0.05). These genes were mainly located on 8p11.21, 8p21.2-p21.3, 8q22.1, 8q24.3, 17q23.2-q23.3, 19p13.3, and 19p13.11. Among the regions, 8q24.3 was found to contain the most genes (30 of 94 genes) including PTK2. The 8q24.3 region was indicated as the most significant region, as supported by copy number, GISTIC, and integrative analysis. Pathway analysis using differentially expressed genes on 8q24.3 revealed several major nodes, including PTK2. In conclusion, we identified a set of 94 candidate genes with frequent copy number alterations that correlated with gene expression. Specific chromosomal alterations, such as the 8q24.3 gain containing PTK2, could be a therapeutic target in a subset of Ov-CCAs.

Copy number analysis in EBV-positive nodal peripheral T cell lymphoma, unspecified.

Copy number alteration was investigated in three cases of EBV + nodal peripheral T cell lymphoma of cytotoxic phenotype using Agilent array comparative genomic hybridization platform. While no recurrent abnormality among three cases was identified, genomic abnormalities involving 9p23.3, 16p13.3, and 7q34 were overlapped with changes reported in other type of NK or T cell lymphomas previously. Chromosomal region 9p23.3 contains CDKN2A and CDKN2B which are frequently mutated or deleted in various types of cancer and may be a target to find genes associated with the pathogenesis of EBV-positive nodal peripheral T cell lymphoma.

Isolation of side population cells in B-cell non-Hodgkin's lymphomas.

BACKGROUND: Side population (SP) cells are characterized by the ability to exclude Hoechst 33342 dye due to high expression of the ATP-binding cassette transporter. This ability is associated with drug-resistant characteristics of cancer stem cells. METHODS: We analyzed SP cells from human B-cell non-Hodgkin's lymphoma cell lines and primary cells derived from patients and compared them with non-SP (NSP) cells. RESULTS: SP cells comprised a minor fraction of all cells ranging from 1.5 ± 1.8 to 8.3 ± 5.7% in cell lines and had higher ABCG2 expression than NSP cells. SP cells had better cell viability, colony-forming ability and drug resistance than NSP cells. The SP cells also showed stem cell-like characteristics, including elevated telomerase activity and higher expression of OCT4 and NANOG. A cDNA microarray demonstrated that SP cells had decreased expression of genes associated with apoptosis and cell death compared to NSP cells. CONCLUSIONS: The presence of SP cells might imply the possibility of lymphoma stem cells and be associated with a malignant potential of B-cell lymphoma.