ABSTRACT
Aging-elevated DNMT3A R882H-driven clonal hematopoiesis (CH) is a risk factor for myeloid malignancies remission and overall survival. Although some studies were conducted to investigate this phenomenon, the exact mechanism is still under debate. In this study, we observed that DNMT3A R878H bone marrow cells (human allele: DNMT3A R882H) displayed enhanced reconstitution capacity in aged bone marrow milieu and upon inflammatory insult. DNMT3A R878H protects hematopoietic stem and progenitor cells from the damage induced by chronic inflammation, especially TNFα insults. Mechanistically, we identified that RIPK1-RIPK3-MLKL-mediated necroptosis signaling was compromised in R878H cells in response to proliferation stress and TNFα insults. Briefly, we elucidated the molecular mechanism driving DNMT3A R878H-based clonal hematopoiesis, which raises clinical value for treating DNMT3A R882H-driven clonal hematopoiesis and myeloid malignancies with aging.
ABSTRACT
Objective To understand the prevalence of drug resistance in treatment-naive injecting drug users (IDUs) infected with HIV-1 in Guangzhou.Methods HIV-1 RNA were extracted from the serum specimens of the newly confirmed HIV-1 positive IDUs living in Guangzhou,being infected through injecting drug use and receiving no antiretroviral therapy at the time of confirmation during 2008-2015.Full sequence of pol protease (PR) gene and partial sequence of reverse transcriptase (RT) gene were amplified by nested reverse transcription polymerase chain reaction (nested-PCR) and sequenced.After that,data were submitted to the HIV resistance database of Stanford University for drug resistance analysis.Results Among the 518 HIV-1 infected IDUs,H1V-1 pol gene segments were successfully obtained from the serum samples of 407 HIV-1 infected IDUs (78.57％) aged 18-64 (37.44 ± 8.14) years.Among them,males accounted for 89.68％ (365/407),those of Han ethnic group accounted for 89.93％ (366/407),the unmarried accounted for 55.28％ (225/407),and those with education level of junior high school or below accounted for 83.78％ (341/407).The distribution of subtypes was predominated by CRF07_BC (47.18％,192/407),followed by CRF01_AE (23.83％,97/407),CRF08_BC (22.85％,93/407),and other subtypes (6.14％,25/407).The overall prevalence of drug resistance was 3.44％ (14/407).The prevalence of drug resistance to protease inhibitors,nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors were 1.47％(6/407),0.25％ (1/407) and 1.72％ (7/407) respectively.The mutation rate was 12.29％ (50/407).No major drug resistance mutation was detected in protease and nucleoside reverse transcriptase regions.Higher rate of V179E mutation in the non-nucleoside reverse transcriptase region was detected in other subtypes and subtype CRF07_BC.Mutation seemed to have occurred in all 8 cases of subtype CRF55_01B in other subtypes.The highest mutation rate of E138A was detected in subtype CRF08_BC (3.23％).Two cases were resistant to all four drugs of NNRTIs.Conclusions The prevalence of drug resistance in treatment-naive HIV-1 positive IDUs remained at a relatively low level during 2008-2015,in Guangzhou.Most infections were sensitive to existing antiviral drugs.However,drug resistance surveillance in IDUs infected with HIV should be strengthened to prevent the prevalence of multi-drug resistance and cross drug resistance.
ABSTRACT
Objective To understand the prevalence of drug resistance in treatment-naive injecting drug users (IDUs) infected with HIV-1 in Guangzhou.Methods HIV-1 RNA were extracted from the serum specimens of the newly confirmed HIV-1 positive IDUs living in Guangzhou,being infected through injecting drug use and receiving no antiretroviral therapy at the time of confirmation during 2008-2015.Full sequence of pol protease (PR) gene and partial sequence of reverse transcriptase (RT) gene were amplified by nested reverse transcription polymerase chain reaction (nested-PCR) and sequenced.After that,data were submitted to the HIV resistance database of Stanford University for drug resistance analysis.Results Among the 518 HIV-1 infected IDUs,H1V-1 pol gene segments were successfully obtained from the serum samples of 407 HIV-1 infected IDUs (78.57％) aged 18-64 (37.44 ± 8.14) years.Among them,males accounted for 89.68％ (365/407),those of Han ethnic group accounted for 89.93％ (366/407),the unmarried accounted for 55.28％ (225/407),and those with education level of junior high school or below accounted for 83.78％ (341/407).The distribution of subtypes was predominated by CRF07_BC (47.18％,192/407),followed by CRF01_AE (23.83％,97/407),CRF08_BC (22.85％,93/407),and other subtypes (6.14％,25/407).The overall prevalence of drug resistance was 3.44％ (14/407).The prevalence of drug resistance to protease inhibitors,nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors were 1.47％(6/407),0.25％ (1/407) and 1.72％ (7/407) respectively.The mutation rate was 12.29％ (50/407).No major drug resistance mutation was detected in protease and nucleoside reverse transcriptase regions.Higher rate of V179E mutation in the non-nucleoside reverse transcriptase region was detected in other subtypes and subtype CRF07_BC.Mutation seemed to have occurred in all 8 cases of subtype CRF55_01B in other subtypes.The highest mutation rate of E138A was detected in subtype CRF08_BC (3.23％).Two cases were resistant to all four drugs of NNRTIs.Conclusions The prevalence of drug resistance in treatment-naive HIV-1 positive IDUs remained at a relatively low level during 2008-2015,in Guangzhou.Most infections were sensitive to existing antiviral drugs.However,drug resistance surveillance in IDUs infected with HIV should be strengthened to prevent the prevalence of multi-drug resistance and cross drug resistance.
ABSTRACT
Objective To examine loss of heterozygosity (LOH) and microsatellite instability (MSI) of locus D8S532 on chromosome 8 and their influence on the expression of sFRP1 in the hepatocellular carcinoma (HCCs), which may provide an experimental evidence for clarifying the mechanism of sFRP1 gene and tumor development. Methods DNA was extracted from formalin-fixed paraffin-embedded tissues. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and ordinary silver stain were used to study LOH and MSI of locus D8S532. Envision immunohistochemistry, Leica-Qwin computerized imaging system and Image-Pro PluS (IPP) version 4.5 professional imaging analysis software were used to assess the expression of sFRP1. Results The detection rates of LOH and MSI of locus D8S532 in the 36 specimens of HCC were 11.11% and 8.33% respectively. The down-regulation of sFRP1 was observed in 31 of 36 HCCs (86.11%) compared with non-carcinoma liver tissues, and the positive rate of sFRP1 protein of the HCCs was 52.78%( 19/36 ). The frequency of LOH was lower in the cases with positive expression of sFRP1 protein than those negative (0 vs 23.53%, P <0.05). Conclusion It was a common phenomenon that expression of sFRP1 protein is negative or low in Chinese with HCCs. The genetic instability of sFRP1 gene was one of causes, which lead to HCCs. LOH may play a major role in negative expression of sFRP1.