Asian Variant Research Articles

Analysis of genetic variation in human papillomavirus type 16 E1 and E2 in women with cervical infection in Xinjiang, China

BackgroundXinjiang is one of the regions with a high incidence of cervical cancer, and the genetic variation of human papillomavirus may increase its ability to infect the human body and enhance virus-mediated immune escape ability.MethodsSanger sequencing of the HPV16 genome from 165 samples positive for HPV16 infection and phylogenetic analysis of the E1 and E2 genes revealed the gene polymorphism of HPV16 in Xinjiang.ResultsThe results showed that there were 109 samples with variations in HPV16 E1, 48 sites with nucleotide variations (19 missense variations and 29 synonymous variations), and 91 samples with variations in HPV16 E2, 25 sites with nucleotide variations (20 missense variations and five synonymous variations).ConclusionsFrom the phylogenetic tree results, 149 samples were of the European variant and 16 samples were of the Asian variant. No African or North American/Asian variant types were found.

Ethnic-specific BRCA1/2 variation within Asia population: evidence from over 78 000 cancer and 40 000 non-cancer cases of Indian, Chinese, Korean and Japanese populations

BackgroundGermline mutation in BRCA1 and BRCA2 (BRCA) is genetic predisposition for breast and ovarian cancer. Identification of mutation carriers is a critical step to prevent and treat the cancer in...

Variant Aldehyde Dehydrogenase 2 (ALDH2*2) as a Risk Factor for Mechanical LA Substrate Formation and Atrial Fibrillation with Modest Alcohol Consumption in Ethnic Asians.

Aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism is a common genetic variant in Asians that is responsible for defective toxic aldehyde and lipid peroxidation metabolism after alcohol consumption. The extent to which low alcohol consumption may cause atrial substrates to trigger atrial fibrillation (AF) development in users with ALDH2 variants remains to be determined. We prospectively enrolled 249 ethnic Asians, including 56 non-drinkers and 193 habitual drinkers (135 (70%) as ALDH2 wild-type: GG, rs671; 58 (30%) as ALDH2 variants: G/A or A/A, rs671). Novel left atrial (LA) mechanical substrates with dynamic characteristics were assessed using a speckle-tracking algorithm and correlated to daily alcohol consumption and ALDH2 genotypes. Despite modest and comparable alcohol consumption by the habitual alcohol users (14.3 [8.3~28.6] and 12.3 [6.3~30.7] g/day for those without and with ALDH2 polymorphism, p = 0.31), there was a substantial and graded increase in the 4-HNE adduct and prolonged PR, and a reduction in novel LA mechanical parameters (including peak atrial longitudinal strain (PALS) and phasic strain rates (reservoir, conduit, and booster pump functions), p < 0.05), rather than an LA emptying fraction (LAEF) or LA volume index across non-drinkers, and in habitual drinkers without and with ALDH2 polymorphism (all p < 0.05). The presence of ALDH2 polymorphism worsened the association between increasing daily alcohol dose and LAEF, PALS, and phasic reservoir and booster functions (all Pinteraction: <0.05). Binge drinking superimposed on regular alcohol use exclusively further worsened LA booster pump function compared to regular drinking without binge use (1.66 ± 0.57 vs. 1.97 ± 0.56 1/s, p = 0.001). Impaired LA booster function further independently helped to predict AF after consideration of the CHARGE-AF score (adjusted 1.68 (95% CI: 1.06–2.67), p = 0.028, per 1 z-score increment). Habitual modest alcohol consumption led to mechanical LA substrate formation in an ethnic Asian population, which was more pronounced in subjects harboring ALDH2 variants. Impaired LA booster functions may serve as a useful predictor of AF in such populations.

The first wave of the COVID-19 epidemic in Spain was associated with early introductions and fast spread of a dominating genetic variant.

The coronavirus disease 2019 (COVID-19) pandemic has affected the world radically since 2020. Spain was one of the European countries with the highest incidence during the first wave. As a part of a consortium to monitor and study the evolution of the epidemic, we sequenced 2,170 samples, diagnosed mostly before lockdown measures. Here, we identified at least 500 introductions from multiple international sources and documented the early rise of two dominant Spanish epidemic clades (SECs), probably amplified by superspreading events. Both SECs were related closely to the initial Asian variants of SARS-CoV-2 and spread widely across Spain. We inferred a substantial reduction in the effective reproductive number of both SECs due to public-health interventions (Re < 1), also reflected in the replacement of SECs by a new variant over the summer of 2020. In summary, we reveal a notable difference in the initial genetic makeup of SARS-CoV-2 in Spain compared with other European countries and show evidence to support the effectiveness of lockdown measures in controlling virus spread, even for the most successful genetic variants.

Imaging Features and Prognostic Value of FDG PET/CT in Patients with Intravascular Large B-Cell Lymphoma.

PurposeThe clinical value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in intravascular large B-cell lymphoma (IVLBCL) is unknown. This study investigated the association between PET/CT features and prognosis in IVLBCL patients.Patients and MethodsSubjects were 30 newly diagnosed Asian variant IVLBCL patients at a single institution. Baseline PET/CT was analyzed for the distribution and intensity of FDG lesions, and PET/CT pattern groups were compared for the outcome.ResultsEight patients had hypermetabolic lymph node (LN) lesions (Nodal group). The remaining 22 patients with extranodal (EN) involvement were categorized into Deauville score 3–4 (EN/DS3-4; n = 14) and DS5 groups (EN/DS5; n = 8). First-line therapy resulted in a complete or partial response in 75.0%, 64.3%, and 100% of the respective groups. Treatment-related deaths occurred in one nodal group and three EN/DS3-4 group cases, but none among the EN/DS5 group. During 56 months of follow-up, disease progression or relapse occurred in five, four, and one case of respective groups. Cancer-related death occurred more frequently in the Nodal (n = 6) and EN/DS3-4 groups (n = 7) than the EN/DS5 group (n = 1; P = 0.041). Nodal and EN/DS3-4 groups had worse 5-year event-free survival (EFS; 25.0% and 49.0%, respectively, P = 0.010 and 0.076) and overall survival (OS; 33.3% and 48.2%, P = 0.010 and 0.068) compared to the EN/DS5 group (87.5% EFS and 87.5% OS).ConclusionIn patients with Asian variant IVLBCL, the distribution and intensity of FDG uptake lesions on PET/CT can be useful for predicting treatment outcomes and survival.

Prognostic significance of human papillomavirus 16 viral load level in patients with oropharyngeal cancer.

Human papillomavirus (HPV) infection in patients with oropharyngeal squamous cell carcinoma (OPSCC) is a major determinant for better prognosis. However, there remain HPV‐positive patients who have poor outcomes. The stratification strategy for detecting high‐risk patients among those with HPV‐positive OPSCC has not been well delineated, especially for Asian patients. We undertook a retrospective cohort study on the survival rate of 89 Japanese patients diagnosed with primary OPSCC. The tumors were concurrently analyzed for the presence of HPV E6 DNA/mRNA, viral DNA load, p16 expression, viral physical status, and viral variant lineage. Human papillomavirus 16 viral DNA was found in 45 (51%) OPSCCs. Human papillomavirus 16 DNA‐positive OPSCCs with higher viral load (classified as HPV16 DNA‐medium/high OPSCCs) showed significantly favorable overall survival and progression‐free survival compared with HPV16 DNA‐positive OPSCCs with lower viral load (<10 copies/cell; HPV16 DNA‐low OPSCCs) and HPV16 DNA‐negative OPSCCs. E6 mRNA expression was observed in all HPV16 DNA‐medium/high OPSCCs but not in HPV16 DNA‐low OPSCCs. Notably, p16‐positive and HPV16 DNA‐negative/low OPSCCs showed significantly worse survival than p16‐positive and HPV16 DNA‐medium/high OPSCCs and resembled HPV‐unrelated OPSCCs with regard to survival and risk factor profile. Although not significant, a trend toward shorter survival was observed for HPV16‐integrated OPSCCs. Phylogenetic analysis revealed two major types of HPV16 variants termed Asian (A4) and European (A1/A2/A3) variants, but no difference in survival between these variants was observed. Altogether, these findings suggest that HPV viral load is a potentially informative factor for more accurate risk stratification of patients with OPSCC.

Abstract 807: Asian prevalent ABCB5 genetic variants rs2074000 and rs17143187 predicts overall survival and clinical outcomes in hepatocellular carcinoma patients

Abstract Background/Aims Incidence of HCC varies in diverse localities with differences on ethnicity and risk factors. The majority of HCC cases worldwide are from China, thus raising the concern on genetic susceptibility in addition to the prevalence of hepatitis virus infection. Drug transporter ABCB5 has been reported to be overexpressed in HCC and associated with poor survival. Recently a panel of SNPs and INDELs in ABCB5 gene have been reported to associate with HCC risk (Leung et al. 2020). We aim to further examine the ethnic differences on the ABCB5 genetic variations between local cohort and the data from The 1000 Genome Project. Subjects and Methods 300 HCC and 300 healthy blood samples were prospectively collected with informed consent. All patients had been diagnosed with primary HCC and underwent partial hepatectomy. Clinical information including sex, age, tumor stage and survival outcomes were collected prospectively. Genomic DNA were extracted from blood samples and SNPs were examined. SNP allele frequencies in different populations were obtained from The 1000 Genomes Browser by NCBI. Results Twelve ABCB5 genetic variants were within the coding regions, with one splicing variant, one stop codon change, while 2 were synonymous and 8 were non-synonymous changes. In particular, allele frequencies of rs2074000 observed in healthy local cohorts (C: 0.517 vs A: 0.483) were comparable to East Asian, while the genetic variation was absent in European in 1000 Genomes Project (CHB - C: 0.534 vs A: 0.466; CHS - C: 0.548 vs A: 0.452; GBR - C: 1.000 vs A: 0.000; CEU - C: 1.000 vs A: 0.000; P&amp;lt;0.001). Similarly, allele frequencies of rs17143187 in healthy local cohorts (G: 0.518 vs C: 0.482) were comparable to East Asian (CHB - G: 0.539 vs C: 0.461; CHS - G: 0.567 vs C: 0.433), while it was absent among European (GBR and CEU - G: 1.000 vs C: 0.000) (P&amp;lt;0.001). Data from our local HCC cohorts further demonstrated that rs2074000 and rs17143187 were independent protective factors in overall survival (Cox HR; rs2074000: 0.676, 95% CI: 0.49-0.93, P=0.017; rs17143187: 0.709, 95% CI: 0.51-0.98, P=0.038). These ABCB5 genetic variants were associated with early tumor stage (OR; rs2074000: 0.351, 95% CI: 0.21-0.59, P&amp;lt;0.001; rs17143187: 0.382, 95% CI: 0.22-0.65, P&amp;lt;0.001) and solitary tumor nodule (OR; rs2074000: 0.507, 95% CI: 0.30-0.86, P=0.012; rs17143187: 0.517, 95% CI: 0.30-0.88, P=0.015). Conclusions ABCB5 genetic variants rs2074000 and rs17143187 mainly prevalent in East Asian predicted better overall survival among HCC patients. ABCB5 is crucial in tumor-initiating cells in melanoma. ABCB5 rs2074000 (non-synonymous SNP, Gln to Lys, classified as damaging by SIFT score) and rs17143187 (splicing variant) both predicted to confer non-functional proteins, thus partly explain the protective effects. Further functional studies are warranted to comprehend the underlying mechanisms. Citation Format: Chun Philip Yeung, Ching Ning Charing Chong, Tan To Cheung, Kelvin Kwok Chai Ng, Paul Bo San Lai, Siu Tim Cheung. Asian prevalent ABCB5 genetic variants rs2074000 and rs17143187 predicts overall survival and clinical outcomes in hepatocellular carcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 807.

Effect and in silico characterization of genetic variants associated with severe spermatogenic disorders in a large Iberian cohort.

Severe spermatogenic failure (SpF) represents the most extreme manifestation of male infertility, as it decreases drastically the semen quality leading to either severe oligospermia (SO, <5 million spermatozoa/mL semen) or non-obstructive azoospermia (NOA, complete lack of spermatozoa in the ejaculate without obstructive causes). The main objective of the present study is to analyze in the Iberian population the effect of 6 single-nucleotide polymorphisms (SNPs) previously associated with NOA in Han Chinese through genome-wide association studies (GWAS) and to establish their possible functional relevance in the development of specific SpF patterns. We genotyped 674 Iberian infertile men (including 480 NOA and 194 SO patients) and 1058 matched unaffected controls for the GWAS-associated variants PRMT6-rs12097821, PEX10-rs2477686, CDC42BPA-rs3000811, IL17A-rs13206743, ABLIM1-rs7099208, and SOX5-rs10842262. Their association with SpF, SO, NOA, and different NOA phenotypes was evaluated by logistic regression models, and their functional relevance was defined by comprehensive interrogation of public resources. ABLIM1-rs7099208 was associated with SpF under both additive (OR=0.86, p=0.036) and dominant models (OR=0.78, p=0.026). The CDC42BPA-rs3000811 minor allele frequency was significantly increased in the subgroup of NOA patients showing maturation arrest (MA) of germ cells compared to the remaining NOA cases under the recessive model (OR=4.45, p=0.044). The PEX10-rs2477686 SNP was associated with a negative testicular sperm extraction (TESE) outcome under the additive model (OR=1.32, p=0.034). The analysis of functional annotations suggested that these variants affect the testis-specific expression of nearby genes and that lincRNA may play a role in SpF. Our data support the association of three previously reported NOA risk variants in Asians (ABLIM1-rs7099208, CDC42BPA-rs3000811, and PEX10-rs2477686) with different manifestations of SpF in Iberians of European descent, likely by influencing gene expression and lincRNA deregulation.

Discovery of the “Asian variant” of an intravascular large B-cell lymphoma in front of pseudo-septic symptoms

Discovery of the “Asian variant” of an intravascular large B-cell lymphoma in front of pseudo-septic symptoms

Prevalence of East Asian (East CagA) and Western variants of the cagA (Western cagA) gene of Helicobacter pylori in Yakutia

Prevalence of East Asian (East CagA) and Western variants of the cagA (Western cagA) gene of Helicobacter pylori in Yakutia

East Asian variant aldehyde dehydrogenase Type 2 genotype exacerbates myocardial ischemia/reperfusion injury in men among patients with ST-segment elevation myocardial infarction -sex differences-

Abstract Background Mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies toxic aldehydes including those generated during ischemia/reperfusion (I/R) injury in acute myocardial infarction. The deficient variant ALDH2 genotype (ALDH2*2) is prevalent among East Asians. We examined whether ALDH2*2 exacerbates I/R injury in Japanese patients with acute ST-segment elevation myocardial infarction (STEMI) utilizing Mendelian randomization. Methods and results The study subjects comprised 248 Japanese patients with STEMI (187 men and 61 women, mean age 67.1±11.5) who underwent successful primary percutaneous coronary intervention. Of these patients, 129 (52.0%) were the carriers of ALDH2*2 and 119 (48.0%) those of wild ALDH2*1/*1 on genotyping by direct application of the TaqMan polymerase chain system. There were no differences in clinical characteristics between the ALDH2*2 and ALDH2*1/*1 group except lower alcohol habit in the ALDH2*2 group. However, the peak plasma levels of creatine phosphokinase myocardial binding (CKMB), a marker of myocardial injury, were significantly higher (a median 234.0 vs 150.0 U/L, P&amp;lt;0.001 in the ALDH2*2 group. Furthermore, the peak CKMB levels were higher in ALDH2*2 group in men (a median 2 75.0 vs 144.9 U/L, P&amp;lt;0.001) but not in women (P=0.855) and there was a significant interaction between sex and ALDH2*2 on I/R injury (χ2=8.362, P=0.004). Conclusions The peak plasma levels of CKMB were higher in STEMI patients with ALDH2*2 than in those with ALDH2*1/*1 among men but not women. These findings identified deficient ALDH2 activity to be targeted for treatment of STEMI specifically in men with ALDH2*2. Visual overview Funding Acknowledgement Type of funding source: None

S2745 Thinking Outside the Box: Is This Really NASH?

INTRODUCTION: Nonalcoholic steatohepatitis (NASH) is a diagnosis of exclusion and an alternative diagnosis should always be sought. We present a patient with features of portal hypertension and possible sepsis, concerning for decompensated NASH cirrhosis. He was eventually diagnosed with a hemophagocytic syndrome-associated variant of intravascular large B-cell lymphoma on autopsy. CASE DESCRIPTION/METHODS: A 64-year-old Caucasian male with metabolic syndrome presented with a 2-month history of fatigue, fevers, and 20-pound weight loss. Initial work-up was notable for an elevated AST (65 IU/L) and high total bilirubin (2 mg/mL; direct 1.3 mg/mL). Albumin was 3.2 g/dL, INR was 1.0 and platelets were 48,000 cells/mL. CT imaging showed mild hepatosplenomegaly with no ascites. He had no known history of liver disease or alcohol use. He was referred to the liver clinic for possible chronic liver disease and portal hypertension, thought to be from NASH. At the time of presentation, he was febrile (101.8 °F), tachycardic (105 bpm), and hypotensive. Besides hepatosplenomegaly, there were no other stigmata of chronic liver disease on exam. Admission labs were unchanged except an increase in total bilirubin (4 mg/mL) and a high ferritin (2400 ng/ml). Work-up for infectious etiologies, autoimmune liver serologies and drug toxin screen were unrevealing. He met 5 out of 8 criteria to diagnose hemophagocytic lymphohistiocytosis (HLH) including fever, splenomegaly, cytopenia, increased ferritin, and absent NK cell function. A PET scan showed uptake in the bone marrow, liver, spleen and lymph nodes. The patient rapidly declined clinically and died from respiratory failure. Autopsy showed diffuse involvement of the liver, spleen, bone marrow, lymph nodes and several other organs by intravascular large B-cell lymphoma (IVBCL). DISCUSSION: Our case emphasizes the importance of considering a broad differential in patients with thrombocytopenia and hepatosplenomegaly, even if typical risk factors for liver cirrhosis are present. Hematological malignancies should be strongly considered in the differential especially if patients present with B symptoms. Hemophagocytic syndrome-associated variant of IVBCL, the so-called ‘Asian variant’, is a rare and aggressive form of diffuse large B cell lymphoma. A prompt diagnosis is crucial, given its life-threatening potential and possibility of recovery with institution of therapy early in the course of the disease.Figure 1.: The cut sections of the liver looked relatively normal and did not show any gross evidence of cirrhosis.Figure 2.: Histology of the liver, which shows intravascular infiltration of tumor cells.

Saudization of English: A study of the Innovative Linguistic and Textual Strategies in the Academic and Multiple Discourses of Saudi Arabia

The research work attempts to investigate that in any geographical contact zone, where the diverse languages and cultures intersect, there would inevitably be linguistic and cultural integration and assimilation. In a similar vein, the worldwide dissemination of the English language has radically shaped the linguistic and textual devices installed by the Saudi English writers in their texts. Besides, the Saudi English writers have reconstructed L2 (English) on the linguistic pattern of L1(Arabic) to foreground their distinctive ideological and cultural norms. Also, the research work investigates, can Saudi English be considered an authentic linguistic instrument? The researcher also has focused and authenticated on the emergence of Saudi English regarding the innovative linguistic and textual tactics inducted by the Saudi writers in their texts. Besides, the research study has investigated the reconstruction of L2 (English) on the lexical, rhetorical, and grammatical patterns of L1(Arabic). The research work also has a great significance regarding the pedagogical, and theoretical linguistic debate about the emergence of the Asian and African variants of Englishes. Likewise, the researcher has chosen the appropriating linguistic theory, and multiple canons approach as a theoretical framework to analyze the selected Saudi English texts. The research work also has concluded that the Saudi English has emerged as a practical linguistic instrument like any other Asian variants of Englishes. Consequently, the researcher has suggested to the Saudi English writers to reconstruct L2 (English) as a functional instrument to disseminate their national, ideological, and cultural norms for global readers.

Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p< 5× 10-9, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count invivo and IL-7 secretion levels invitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

LRRK2 Mutations and Asian Disease-Associated Variants in the First Parkinson's Disease Cohort from Kazakhstan.

Background LRRK2 mutations have emerged as the most prevalent and potentially treatable determinants of Parkinson's disease (PD). Peculiar geographic distribution of these mutations has triggered an interest in genotyping PD cohorts of different ethnic backgrounds for LRRK. Objective Here, we report on the results of LRRK2 screening in the first Central Asian PD cohort. Methods 246 PD patients were consecutively recruited by movement disorder specialists from four medical centers in Kazakhstan, and clinicodemographic data and genomic DNA from blood were systematically obtained and shipped to the Institute of Neurology University College London together with DNAs from 200 healthy controls. The cohort was genotyped for five LRRK2 mutations (p.Gly2019Ser, p.Arg1441His, p.Tyr1699Cys, p.Ile2020Thr, and p.Asn1437His) and three East Asian disease-associated variants (p.Gly2385Arg, p.Ala419Val, and p.Arg1628Pro) via Kompetitive allele-specific polymerase chain reaction assay analysis. Results None of the study subjects carried LRRK2 mutations, whereas the following Asian variants were found with insignificant odds ratios (OR): p.Gly2385Arg (1.2%, minor allele frequency (MAF) 0.007, OR 1.25, p=0.8), p.Ala419Val (3.7%, MAF 0.02, OR 1.5, p=0.8), p.Ala419Val (3.7%, MAF 0.02, OR 1.5, Conclusions We showed that East Asian LRRK variants could be found in Central Asian populations but their pathogenicity remains to be elucidated in larger PD cohorts.

High prevalent human papillomavirus infections of the oral cavity of asymptomatic HIV-positive men

BackgroundIncidence of anal and oral infections with Human Papillomavirus (HPV) is increasing, particularly among Human Immunodeficiency Virus-positive (HIV+) men. HPV type 16 has exhibited the highest incidence and only limited data is available on other prevalent types, variants of HPV16, as well as associated factors. We were interested in identifying prevalent HPV types, variants of type 16, as well as factors associated with HPV16 infections in the oral cavity of HIV+ men who have sex with men (MSM).MethodsA cross-sectional study of oral cavity samples from HIV+ MSM, that in a previous study were identified as positive for HPV16 in the anal canal. Cells from the oral cavity (102 samples, paired with 102 from the anal canal of same patient) were used to extract DNA and detect HPV infections using INNO-LiPA HPV Genotyping Extra II, and PCR. From these, 80 samples (paired, 40 anal and 40 oral) were used to identify variants of type 16 by sequencing. Statistical differences were estimated by the X2 test, and p values equal to or less than 0.05 were considered significant. SPSS ver. Twenty-four statistical software (IBM Corp) was used.ResultsWe found a high prevalence of High-Risk HPV (HR-HPV) and Low-Risk HPV (LR-HPV). Patients were positive in the oral cavity for HR types; 16, 39 and 18 (80.4, 61.8 and 52.9% respectively) and LR types 11 and 6 (53.9 and 34.3% respectively). Surprisingly, only European variants of type 16 were found in the oral cavity, although American Asian (22.5%) and African (2.5%) variants were identified in the anal canal. The analysis showed that CD4 counts could be the most important risk factor associated with HR-HPV infections in the oral cavity, anal canal or both anatomical regions. The risk of infection of the oral cavity with type 18 increased in men diagnosed with HIV for more than 6 years.ConclusionsPrevalence of both HR and LR HPV’s in the oral cavity of Mexican HIV+ MSM is very high. The fact that only European variants of HPV16 were found in the oral cavity suggest a possible tropism not previously described.

Rituximab, cyclophosphamide, vincristine, and prednisolone with high-dose methotrexate as an effective regimen in a frail patient with intravascular large B-cell lymphoma

Intravascular large B-cell lymphoma (IVLBCL) is a rare non-Hodgkin lymphoma characterized by the presence of lymphoma cells within the lumina of small vessels. Membranous CD20 is universally expressed on IVLBCL cells in immunohistochemical staining. The outcome of IVLBCL was dismal in the prerituximab era; however, rituximab in combination with chemotherapy has been proposed to be an effective treatment for IVLBCL. Herein, we report a 68-year-old female with “Asian variant” IVLBCL diagnosed from a pleural biopsy. We administered rituximab, cyclophosphamide, vincristine, and prednisolone (R-CVP) with high-dose methotrexate as the initial treatment. The patient achieved a complete response after the treatment. Therefore, R-CVP with high-dose methotrexate can be considered as a treatment option for frail IVLBCL patients.

Asian variant of intravascular large B-cell lymphoma: a comparison of clinical features based on involvement of the central nervous system.

Background/AimsThere are limited data about the influence of the central nervous system (CNS) involvement on the prognosis for patients with the Asian variant of intravascular large B-cell lymphoma (IVLBCL).MethodsWe analyzed 46 patients who were diagnosed with IVLBCL between 2001 and 2018. All patients were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).ResultsCNS involvement was diagnosed by cerebrospinal fluid analysis (n = 6) and brain imaging (n = 5) in 11 patients at diagnosis, and four cases with CNS relapse were found. Thus, 15 patients had CNS involvement (15/46, 33%). The clinical characteristics were not different between patients with and without CNS involvement, but all patients with CNS involvement belonged to the high-risk group of CNS-International Prognostic Index (IPI). Thirty-one patients achieved a complete response (67%, 31/46) whereas eight patients showed disease progression and six patients died after the first or second cycle of R-CHOP. CNS-directed therapy such as high-dose methotrexate was combined with R-CHOP for patients with CNS involvement, and five patients were alive without relapse. The median overall survival of all patients was 45.0 months, and overall survival was not different according to the involvement of CNS.ConclusionsThe treatment outcome of patients with the Asian variant of IVLBCL is still not satisfactory. The prediction of CNS involvement based on the clinical features including CNS-IPI score might not serve to identify patients at high risk of CNS involvement, either. Thus, more effective strategies for diagnosis and treatment should be developed.

Resistin expression in human monocytes is controlled by two linked promoter SNPs mediating NFKB p50/p50 binding and C-methylation

Resistin is a key cytokine associated with metabolic and inflammatory diseases. Especially in East Asian populations, the expression levels are strongly influenced by genetic polymorphisms. Mechanisms and functional implications of this genetic control are still unknown. By employing reporter assays, EMSA, inhibition studies, bisulphite sequencing, ChIP-Seq and gene-editing we show that the p50/p50 homodimer known to act as repressor for a number of pro-inflammatory genes plays a central role in the genetic regulation of resistin in monocytes along with promoter methylation. In the common RETN haplotype p50/p50 constitutively dampens the expression by binding to the promoter. In an Asian haplotype variant however this interaction is disrupted by the A allele of rs3219175. The SNP is in very close linkage to rs34861192, a CpG SNP, located 280 bp upstream which provides an allele-specific C-methylation site. rs34861192 is located in a 100 bp region found to be methylated in the common but not in the Asian haplotype, resulting in the latter having a higher basal expression, which also associates with elevated histone acetylation (H3K27ac). Genotype associations within cohort data of 200 East Asian individuals revealed significant associations between this haplotype and the plasma levels of factors such as TGF-b, S100B, sRAGE and IL-8 as well as with myeloid DC counts. Thus, the common RETN haplotype is tightly regulated by the epigenetic mechanism linked to p50/p50-binding. This control is lost in the Asian haplotype, which may have evolved to balance the antagonistic RETN effects on pathogen protection vs. metabolic and inflammatory disease induction.

Distribution of HPV 16 E6 gene variants in screening women and its associations with cervical lesions progression

The aim of this study is to investigate distribution of human papillomavirus (HPV) 16 variants in screening healthy women and the potential association between HPV 16 variants and progression of cervical lesions. For this study a total of 2000 healthy women in Tianjin urban area and 212 patients who were HPV 16 positive and underwent colposcopy were analyzed for HPV 16 variants by pyrosequencing. The results show that the HPV 16 was the most prevalent genotype in Tianjin healthy women and five HPV 16 variant types were detected. The HPV 16 variants were determined by sequencing parital E6 region and the detected variants were European prototype E-T350 (E-p), E-G350, E-C109 G, Asian (As) and Asian-American (AA), among which the E-p variant was the most prevalent (82.76%) followed by As variant. Interestingly, in patients with suspected cervical lesions the most prevalent variant was As variant (54.9%) by increasing significance with severity of cervical diseases (OR 4.337; 95% CI 1.248–15.067; P = 0.021), and followed by HPV 16 E-p variant while E-G350 variant only appeared in HSIL and cervical cancer. Our results show that HPV 16 E-p variant was more prevalent than As in Tianjin healthy screening women while As variant was the most frequently type in HSIL and cervical cancer. It is suggested that the mutation of HPV 16 Asian variants, comparing with HPV 16 E-p variants, might contribute to the transformation from HPV 16 persistent infection to cervical cancer.