Dynamic changes in the circulation of respiratory pathogens in children during and after the containment of the 2019 coronavirus disease pandemic in Kunming, China.

PURPOSE: We aimed to determine the changes in the frequency of respiratory pathogens and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during containment of the 2019 coronavirus disease pandemic and elucidate the epidemiological interference that may have occurred after lifting pandemic measures. METHODS: A total of 4,770 Nasopharyngeal swab samples were collected from children with ARTIs from the First People's Hospital of Yunnan Province between January 2022 and December 2023 and subjected to nucleic acid testing for 13 types of respiratory pathogens and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). RESULTS: The frequency of pathogens among children from 2020 to 2022 was in the following order: HRV > Mp > HADV > H3N2 > HMPV and HRV > HRSV > HPIV > H1N1 > H3N2. In weeks 1 to 3 of 2023, the frequency of pathogens significantly declined, and then H1N1 rebounded significantly in 2023. HRV, HRSV, and H3N2 showed a shift in the season of high frequency. Patterns of multi-pathogen infections were more complex in 2023 than in 2022, with HRV having a higher frequency and co-infection rate than other pathogens. These changes may have been associated with interference caused by the resurgence of SARS-CoV-2 prevalence, in addition to being influenced by changes in pandemic containment and lifting measures. CONCLUSIONS: The frequency rate of common respiratory pathogens among children was not significantly different and remained high. The study findings help elucidate the aforementioned unique historical period and effectively control respiratory tract infections to reduce the harm to pediatric health caused by respiratory pathogens.

Epidemiological changes in respiratory pathogen transmission among children with acute respiratory infections during the COVID-19 pandemic in Kunming, China.

BACKGROUND: Acute respiratory infections are a leading cause of morbidity and mortality in children. However, studies on the prevalence of respiratory viruses among children with acute respiratory infections in Kunming, China, are lacking. Therefore, we aimed to investigate the epidemiological characteristics of respiratory pathogens among children with acute respiratory infections in Kunming during the coronavirus disease 2019 pandemic. METHODS: Nasopharyngeal swab samples were collected from 4956 children with acute respiratory infections at Yunnan Provincial First People's Hospital between January 2020 and December 2022, patients with COVID-19 were excluded from the study. Multiplex reverse transcription polymerase chain reaction was used to detect respiratory pathogens. RESULTS: The frequency of respiratory pathogens among children was significantly lower in 2020 than in 2021 and 2022. The following pathogens had the highest prevalence rates (in descending order) from 2020 to 2022: HRV > RSV > PIV > ADV > MP; HRV > RSV > HADV > PIV > MP and HRV > Mp > HADV > H3N2 > HMPV. The overall frequency of respiratory pathogens exhibited an inverted U-shape with increasing age among the children. Human bocavirus, human parainfluenza virus, and human respiratory syncytial virus were the dominant respiratory viruses in children aged ≤ 3 years, whereas Mycoplasma pneumoniae was the dominant respiratory pathogen in children aged > 3 years. HRV has the highest prevalence and is the main pathogen of mixed infection. The prevalence of the influenza A virus has decreased significantly, whereas HRSV and Mp are found to be seasonal. CONCLUSIONS: Our findings offer an objective evaluation of transmission dynamics and epidemiological shifts in respiratory pathogens during the coronavirus disease 2019 pandemic in Kunming, serving as a basis for informed decision-making, prevention, and treatment strategies.

Identification of Urban Carbon Emission Peaks through Tree-Ring 14C.

Independent identification of carbon emission peaks determined from fuel inventories is a challenging goal. Because of the complete depletion of radiocarbon (14C) in fossil fuel sources, the measurement of atmospheric 14CO2 has proven to offer a means of achieving this goal. Here, we present a study identifying peak carbon emissions from two Chinese cities using urban tree-ring Δ14C time series during 2000-2019. After subtracting background atmospheric Δ14C from urban tree-ring Δ14C to isolate local Δ14C (Δ14Clocal), we find a minimum in 2010 (-51.1 ± 4.5‰) in Beijing and in 2013 in Xi'an (-52.5 ± 0.5‰). These levels correspond to an urban carbon emission peak in 2010 and in 2013 in the two respective cities. The urban carbon emission peaks are further identified by the declines of the mean absolute interannual rate of decrease of tree-ring Δ14C during a period, with the respective values of 3.6 and 6.4 ‰/yr after and before a turning point in Beijing and 3.0 and 6.0 ‰/yr after and before a turning point in Xi'an. This study provides an observation method to identify carbon emission peaks in basin cities.

Comprehensive analysis of the role of ICOS ( CD278 ) in pan-cancer prognosis and immunotherapy.

BACKGROUND: The immunological checkpoint known as Inducible T Cell Costimulatory Factor (ICOS, Cluster of Differentiation, CD278) is activated and expressed on T cells. Both somatic cells and antigen-presenting cells expressed its ligand, ICOSL (including tumor cells in the tumor microenvironment).It is important for immunosuppression. Uncertainty surrounds the function of ICOS in tumor immunity. METHODS: Several bioinformatics techniques were employed by us to thoroughly examine the expression and prognostic value of ICOS in 33 cancers based on data collected from TCGA and GTEx. In addition, ICOS was explored with pathological stage, tumor-infiltrating cells, immune checkpoint genes, mismatch repair (MMR) genes, DNA methyltransferases (DNMTs), microsatellite instability (MSI),and tumor mutation burden (TMB).In addition,To ascertain the level of ICOS expression in various cells, qRT-PCR was employed. RESULTS: The findings revealed that ICOS expression was up regulation in most cancer types. The high expression of ICOS in tumor samples was related to the poor prognosis of UVM and LGG; The positive prognosis was boosted by the strong expression of ICOS in OV, SARC, SKCM, THYM, UCEC, and HNSC. The result is that the expression of malignancy was revealed by the immune cells' invasion.profile of ICOS in different types of cancer. Different ways that ICOS expression is connected to immune cell infiltration account for variations in patient survival. Additionally, the TMB, MSI, MMR, and DNMT genes as well as ICOS expression are linked in many cancer types.The results of PCR showed that it is highly expressed in gastric, breast, liver and renal cell carcinoma cell lines compared with normal cells. CONCLUSION: This study suggests that ICOS may be a potential tumor immunotherapy target and prognostic marker.

Clinical, epidemiological, and genotypic characteristics of rotavirus infection in hospitalized infants and young children in Yunnan Province.

Rotaviruses are the most important pathogenic cause of non-bacterial diarrhea in infants and children. Approximately 60% of hospital admissions for acute diarrhea worldwide are caused by rotavirus infection. Rotavirus infection and hospitalization among children in China are a social burden, resulting in economic loss. The prevalence and geographical distribution of rotavirus genotypes is variable, partially due to population migration. Due to the unique geographical conditions and climate in Yunnan Province, several viruses with new genotypes have emerged, and multiple genotypes have become co-epidemic. In this study, rotavirus infection screening and genetic characterization of epidemic strains were performed in 149,492 infants and children admitted to hospitals in six representative prefectures in Yunnan Province between 2019 and 2021. The prevalence of rotavirus infection was 13.39% and was highest in January and lowest in September. G9P[8] was the main epidemic rotavirus genotype. Other epidemic genotypes included G2P[4], G8P[8], G9P[4], G2P[8], G3P[8], G4P[8], G3P[4], and G4P[6]. Phylogenetic analysis revealed that locally epidemic strains were influenced by importation of strains from neighboring provinces and other Asian countries. These findings provide a scientific basis for rotavirus prevention and control and lay a foundation for preliminary studies to establish a rotavirus surveillance network in Yunnan Province.

Altered H3K27 trimethylation contributes to flowering time variations in polyploid Arabidopsis thaliana ecotypes.

Polyploidy is a widespread phenomenon in flowering plant species. Polyploid plants frequently exhibit considerable transcriptomic alterations after whole-genome duplication (WGD). It is known that the transcriptomic response to tetraploidization is ecotype-dependent in Arabidopsis; however, the biological significance and the underlying mechanisms are unknown. In this study, we found that 4x Col-0 presents a delayed flowering time whereas 4x Ler does not. The expression of FLOWERING LOCUS C (FLC), the major repressor of flowering, was significantly increased in 4x Col-0 but only a subtle change was present in 4x Ler. Moreover, the level of a repressive epigenetic mark, trimethylation of histone H3 at lysine 27 (H3K27me3), was significantly decreased in 4x Col-0 but not in 4x Ler, potentially leading to the differences in FLC transcription levels and flowering times. Hundreds of other genes in addition to FLC showed H3K27me3 alterations in 4x Col-0 and 4x Ler. LIKE HETEROCHROMATIN PROTEIN 1 (LHP1) and transcription factors required for H3K27me3 deposition presented transcriptional changes between the two ecotypes, potentially accounting for the different H3K27me3 alterations. We also found that the natural 4x Arabidopsis ecotype Wa-1 presented an early flowering time, which was associated with low expression of FLC. Taken together, our results demonstrate a role of H3K27me3 alterations in response to genome duplication in Arabidopsis autopolyploids, and that variation in flowering time potentially functions in autopolyploid speciation.

Rotavirus-related systemic diseases: clinical manifestation, evidence and pathogenesis.

Rotaviruses, double-stranded, non-enveloped RNA viruses, are a global health concern, associated with acute gastroenteritis and secretory-driven watery diarrhoea, especially in infants and young children. Conventionally, rotavirus is primarily viewed as a pathogen for intestinal enterocytes. This notion is challenged, however, by data from patients and animal models documenting extra-intestinal clinical manifestations and viral replication following rotavirus infection. In addition to acute gastroenteritis, rotavirus infection has been linked to various neurological disorders, hepatitis and cholestasis, type 1 diabetes, respiratory illness, myocarditis, renal failure and thrombocytopenia. Concomitantly, molecular studies have provided insight into potential mechanisms by which rotavirus can enter and replicate in non-enterocyte cell types and evade host immune responses. Nevertheless, it is fair to say that the extra-intestinal aspect of the rotavirus infectious process is largely being overlooked by biomedical professionals, and there are gaps in the understanding of mechanisms of pathogenesis. Thus with the aim of increasing public and professional awareness we here provide a description of our current understanding of rotavirus-related extra-intestinal clinical manifestations and associated molecular pathogenesis. Further understanding of the processes involved should prove exceedingly useful for future diagnosis, treatment and prevention of rotavirus-associated disease.

Expression of Leukocytic Syncytin-1 in B-Cell Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia Patients.

BACKGROUND: Syncytin-1 is improperly expressed in several cancers. However, its expression profile across leukocytes in leukemia patients has not yet been analyzed. METHODS: A total of 50 AML cases and 14 B-cell ALL patients were consecutively recruited. Bone marrow samples were subjected to flow cytometry. Statistical analysis was applied to compare syncytin-1 expression between B-cell ALL and AML across granulocytes, leukemia cells, and T-lymphocytes (including CD3+, CD4+, and CD8+ subsets thereof) and to correlate syncytin-1 expression to leukemia cells and lymphocytes with the T-cell subset percentages. RESULTS: The syncytin-1-expressing leukemia cell% in AML patients was significantly higher than that in B-cell ALL patients (p < 0.05). The CD8+ T-cell% in AML patients was significantly higher than that in B-cell ALL patients (p < 0.05). The syncytin-1 expression rate on leukemia cells was positively correlated with the CD8+ T-cell percentage (r = 0.289, p < 0.05), while the syncytin-1 expression rate on lymphocytes was negatively correlated with the CD3+, CD4+, and CD8+ T-cell percentages (r = -0.273, -0.450, and -0.307, respectively; p < 0.05). CONCLUSIONS: The percentage of syncytin-1-expressing leukemia cells in AML - due to its positive correlation with the CD8+ suppressor T-cell percentage - shows potential as an indicator of poorer long-term immunity in AML patients.

Positivity and incidence of human papillomavirus in women attending gynecological department of a major comprehensive hospital in Kunming, China 2012-2014.

HPV DNA testing is receiving increasing popularity in cervical cancer screening. There is a lack of universal guidelines on HPV testing. Our study aimed to assess age-specific and year-on-year trend of HPV positivity and incidence and HPV retesting among 26,457 individual women attending the gynecological department at the First People's Hospital of Yunnan Province (FPHY) who had an HPV testing between January 1, 2012 and December 31, 2014. HPV 16, HPV 52, and cp8304 ranked among top 5 with regard to positivity in each year and overall incidence. The positivity of various HPV types peaked among women aged 15-19 years, then sharply decreased with age, stabilized among women aged 25-49 years and then surged again among women aged 50 years and older. The positivity of high-risk (HR) HPV types, including HPV 16, 18, 31, 33, 56 and 58, were on the rise during the time period (P < 0.05 for all). HR HPV types tended to be more likely to persist than LR HPV types (P < 0.05). Additionally, the incidence rate for any HR HPV type was also significantly higher than that for any LR HPV type (42.8 vs. 12.6 per 100 person-years, P < 0.001). The majority (57.3-77.5%) of women detected with HR HPV types did not retest within 12 months. Clinical guidelines on HPV DNA testing are needed and education, and counseling about HPV infection and its implications for women detected with HPV at clinical settings, are warranted.

Upregulation of Leukocytic Syncytin-1 in Acute Myeloid Leukemia Patients.

BACKGROUND Syncytin-1, a cell membrane-localizing fusogen, is abnormally expressed in several cancers, including endometrial cancer, breast cancer, and leukemia. Although abnormal syncytin-1 expression has been detected in two-thirds of leukemia blood samples, its expression profile in acute leukemia patients has not yet been analyzed. MATERIAL AND METHODS Bone marrow samples from 50 acute myelogenous leukemia (AML) cases and 14 B-cell acute lymphocytic leukemia (B-cell ALL) patients were subjected to flow cytometry to assess leukocyte type distributions and leukocytic syncytin-1 surface expression. RT-PCR was applied to assess leukocytic syncytin-1 mRNA expression. Statistical analysis was applied to compare syncytin-1 expression between AML and B-cell ALL patients across blasts, granulocytes, lymphocytes, and monocytes as well as to determine clinical factors statistically associated with changes in syncytin-1 expression. RESULTS The leukocyte type distributions of the AML and B-cell ALL cohorts highly overlapped, with an observable difference in blast distribution between the 2 cohorts. The AML cohort displayed significantly greater syncytin-1 surface and mRNA expression (p<0.05). Syncytin-1 surface and mRNA expression was significantly increased across all 4 leukocyte types (p<0.05). The percentage of syncytin-1-expressing blasts was significantly greater in AML patients (p<0.05), with blasts showing the largest fold-change in syncytin-1 expression (p<0.05). M5, M5a, and M5b AML patients displayed significantly higher syncytin-1 surface expression relative to all other AML French-American-British (FAB) classifications (p<0.05). CONCLUSIONS These findings suggest leukocytic syncytin-1 expression may play a role in the development and/or maintenance of the AML phenotype and the acute monocytic leukemia phenotype in particular.

Comprehensive analysis of the effects of the cuprotosis-associated gene SLC31A1 on patient prognosis and tumor microenvironment in human cancer.

Background: Solute carrier family 31 (copper transporter), member 1 (SLC31A1) is a key factor in maintaining intracellular copper concentration and an important factor affecting cancer energy metabolism. Therefore, exploring the potential biological function and value of SLC31A1 could provide a new direction for the targeted therapy of tumors. Methods: This study assessed gene expression levels, survival, clinicopathology, gene mutations, methylation levels, the tumor mutational burden (TMB), microsatellite instability (MSI), and the immune cell infiltration of SLC31A1 in pan-cancer using the Tumor Immune Estimation Resource 2.0 (TIMER2.0), Gene Expression Profiling Interactive Analysis (GEPIA), University of Alabama at Birmingham CANcer (UALCAN) data analysis portal, and cBioPortal databases. To further understand the potential biological mechanisms of SLC31A1 in different cancers, single-cell level sequencing and a Gene Ontology/Kyoto Encyclopedia of Genes and Genomes (GO/KEGG) enrichment analysis of SLC31A1 were also performed. Finally, real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB) were used to validate the expression of SLC31A1 in cancers, such as gastric cancer. Results: SLC31A1 was expressed in most cancer tissues. In kidney renal clear cell carcinoma (KIRC), the high expression of SLC31A1 was associated with good overall survival (OS), while in adrenocortical carcinoma (ACC), breast invasive carcinoma (BRCA), lower grade glioma (LGG), mesothelioma (MESO), and skin cutaneous melanoma (SKCM), the low expression of SLC31A1 was associated with good OS. The highest frequency of SLC31A1 amplification was observed in ACC. In addition, missense mutations accounted for a major portion of the mutation types. The truncation mutation S105Y may be a putative cancer driver. SLC31A1 affected methylation levels in cancer and was associated with the TMB, MSI, and the level of infiltration of various immune cells. Additionally, the single-cell sequencing results showed that SLC31A1 was associated with multiple biological functions in cancer. Finally, the SLC31A1 enrichment analysis revealed that the SLC31A1-related genes were mainly enriched in the mitochondrial matrix and envelope vesicles. The RT-qPCR and WB results were consistent with the predicted results. Conclusions: SLC31A1 may be a potential target related to cancer energy metabolism and may have prognostic value.

Association of Methylenetetrahydrofolate Reductase rs1801133 Gene Polymorphism with Cancer Risk and Septin 9 Methylation in Patients with Colorectal Cancer.

PURPOSE: Colorectal cancer (CRC) is one of the most common malignancies, with a high incidence and mortality worldwide. Methylated Septin 9 (mSEPT9) has been used clinically as an auxiliary tool for CRC screening. The aim of the present study was to investigate the association of the methylenetetrahydrofolate reductase (MTHFR) rs1801133 polymorphism with the risk of CRC and the methylation status of Septin 9 in CRC. METHODS: Information of 540 patients with a confirmed diagnosis of CRC and with a physical examination were utilized to assess the association of the MTHFR rs1801133 polymorphism with CRC and the methylation of SEPT9. MTHFR rs1801133 polymorphism was genotyped using polymerase chain reaction (PCR). The commercial Septin 9 Gene Methylation(mSEPT9) Detection Kit was used for plasma SEPT9 methylation analysis. RESULTS: Among 540 patients, 61.48% were men and the median age was 54.47 ± 13.14. 65.37% of all colorectal tumors developed in the rectum. 195 patients had negative mSEPT9 methylation, while 345 had positive results. 87 individuals with stage I, 90 with stage II, 287 with stage III, and 76 with stage IV colorectal cancer were included in the sample. The results demonstrated that the positivity rate and degree of methylation of mSEPT9 were remarkably higher in patients with more advanced TNM stages than in those with less advanced stages. The frequencies of the MTHFR rs1801133 CC genotype and allele C carriers in patients with CRC were significantly higher than those in healthy individuals (P = 0.006 and P = 0.001, respectively). The positivity rate of the mSEPT9 assay was significantly higher among the MTHFR rs1801133 TT genotype and allele T carriers than among the CC and allele C carriers respectively. The MTHFR rs1801133 TT genotype and allele T carriers were positively associated with the methylation of SEPT9 (OR = 3.320, 95% CI 1.485-7.424, P = 0.003 and OR = 1.783, 95% CI 1.056-3.010, P = 0.030, respectively). CONCLUSION: In conclusion, individuals harboring the MTHFR rs1801133 CC genotype had a higher risk of CRC and the MTHFR rs1801133 TT carriers were more susceptible to Septin 9 gene methylation.

The crosstalking of lactate-Histone lactylation and tumor.

Lactate was once considered to be a by-product of energy metabolism, but its unique biological value was only gradually explored with the advent of the Warburg effect. As an end product of glycolysis, lactate can act as a substrate for energy metabolism, a signal transduction molecule, a regulator of the tumor microenvironment and immune cells, and a regulator of the deubiquitination of specific enzymes, and is involved in various biological aspects of tumor regulation, including energy shuttling, growth and invasion, angiogenesis and immune escape. Furthermore, we describe a novel lactate-dependent epigenetic modification, namely histone lactylation modification, and review the progress of its study in tumors, mainly involving the reprogramming of tumor phenotypes, regulation of related gene expression, mediation of the glycolytic process in tumor stem cells (CSCs) and influence on the tumor immune microenvironment. The study of epigenetic regulation of tumor genes by histone modification is still in its infancy, and we expect that by summarizing the effects of lactate and histone modification on tumor and related gene regulation, we will clarify the scientific significance of future histone modification studies and the problems to be solved, and open up new fields for targeted tumor therapy.

Prevalence and Genotype Distribution of Human Papillomavirus Infection Among 40,613 Women: An Outpatient-Based Population Study in Kunming, Yunnan.

Human Papillomavirus (HPV) infection is one of the most common sexually transmitted infections worldwide. The current study aimed to investigate the prevalence and genotype distribution of HPV infection among outpatient-based populations. A total of 40,613 women were recruited from the First People's Hospital of the Yunnan Province. Our study retrospectively analyzed the results of cervical HPV screening among 40,613 women. The results of study showed the prevalence and genotype distribution of HPV infection was different among various outpatient-based populations, and the prevalence of HPV infection was the highest in the gynecological outpatients (26.59%), followed by reproductive gynecological outpatients (18.51%), and the prevalence of physically examined population was the lowest (8.15%). The outpatient-based population was facing a huge threat of HPV infection, especially women from the gynecology clinic. The three most common HPV genotypes were HPV-52 (4.79%), 16 (2.95%) and 58 (2.83%). However, the distribution of HPV genotype varied by populations, especially in physically examined population, the infection rate of HPV-81 ranked third among all infections with various genotypes. Two peaks of prevalence of HPV infection were observed among women under 25 years (31.93%) and over 55 years (28.55%), while the prevalence in women aged 46-55 years (20.18%) was the lowest. Our study on the prevalence and genotype distribution of HPV infection among various outpatient-based populations will provide scientific evidence for vaccination strategies of HPV and prevention and control plans of cervical cancer in Kunming area.

Prevalence and Genotypes of Human Papillomavirus among Men in Yunnan Province, China.

Human papillomavirus (HPV) infection is one of the most commonly reported sexually transmitted infections. Persistent infection is associated with the development of cervical cancer. Men may serve as a medium for HPV transmission among women, and much remains unknown about the prevalence and genotypes of HPV infection among men in Yunnan Province. This study was designed to investigate these parameters among men in this region. Clinical information was collected from January 2015 to May 2020, and 369 men who wished to undergo tests for HPV were included in this study. HPV screening was performed using the HPV GenoArray Test Kit, and the anatomical site of sample collection was the urethra. The mean age was 36.15 ± 9.08 years. Our results revealed that the prevalence of HPV infection among men was 23.85% in Yunnan Province, and there was no association between age and HPV prevalence in men. There were 72 (81.81%) individuals positive for a single HPV type, and 16 (18.19%) positive for multiple HPV types. The most prevalent oncogenic HPV types were found to be 52, 51, and 16. The most prevalent types of HPV infection were similar between men and women in this region, though the prevalence of HPV in men was relatively high.

The Alternative 2/1 Schedule of Sunitinib is Superior to the Traditional 4/2 Schedule in Patients With Metastatic Renal Cell Carcinoma: A Meta-analysis.

Alternate sunitinib schedules attracted the interest of oncologists recently owing to their superior safety profile. This meta-analysis compared the tolerability and efficacy of a new alternative dosing schedule (2 weeks on/1 week off) of sunitinib with the traditional 4/2 schedule in patients with metastatic renal cell carcinoma (mRCC). Studies were retrieved from Medline, Cochrane Central, Scopus, Embase, and Web of Science databases. Data were extracted and pooled as hazard ratio (HR: survival data) or odds ratio (OR: dichotomous data) using Comprehensive Meta-analysis software. Based on data of 1173 patients, the progression-free survival (HR, 0.52; 95% confidence interval [CI], 0.39-0.95; P < .0001), overall survival (HR, 0.6; 95% CI, 0.43-0.85; P < .0001), and stable disease rates (OR, 0.38; 95% CI, 0.19-0.76; P = .006) were significantly improved on the alternative 2/1 schedule, compared with the traditional 4/2 schedule. However, the complete response (OR, 1.32; 95% CI, 0.34-5.22; P = .69) and partial response (OR, 1.34; 95% CI, 0.44-4.14; P = .61) rates were comparable between the 2 regimens. The tolerability of the alternative 2/1 schedule was superior to the traditional one as investigated adverse events like fatigue (OR, 2.91; 95% CI, 1.89-4.46; P < .0001), hypertension (OR, 2.08; 95% CI, 1.56-2.75; P < .0001), and diarrhea (OR, 2.18; 95% CI, 1.19-3.98; P = .012) were significantly less common. In conclusion, the alternative 2/1 sunitinib schedule provides improved tolerability and survival in patients with mRCC. Large randomized trials with long follow-up periods are required to validate and confirm these findings.

The endonuclease APE1 processes miR-92b formation, thereby regulating expression of the tumor suppressor LDLR in cervical cancer cells.

BACKGROUND: The molecular mechanisms underlying cervical cancer require elucidation to identify novel therapeutic targets. Apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) is a multifunctional apurinic/apyrimidinic (AP) endonuclease that influences the transcription of many cancer-related genes via microRNome regulation. Herein, we examine the role of miR-92b-3p (hereinafter miR-92b), whose processing may be regulated by APE1, in cervical cancer progression. METHODS: APE1's processing of miR-92b from its pri-miR form was measured by a quantitative reverse transcription polymerase chain reaction (qRT-PCR)-based ratio. APE1's endonuclease activity was measured with AP-site incision assays. APE1-DROSHA interaction was studied with immunofluorescence, confocal and proximity ligation analyses. The miR-92b's targeting of low-density lipoprotein receptor (LDLR) was investigated with luciferase reporter assays. The miR-92b mimics and shRNA-based miR-92b silencing, as well as LDLR overexpression and short interfering RNA (siRNA)-based LDLR silencing, were employed in CaSki and SiHa cervical cancer cells. Cell proliferation and chemosensitivity to paclitaxel and cisplatin were assayed. Cell-cycle progression and apoptosis were assessed by flow cytometry. Tumor growth was studied in a murine xenograft model. RESULTS: APE1's endonuclease activity, via association with the DROSHA-processing complex, is necessary for processing mature miR-92b, thereby regulating expression of miR-92b's direct target LDLR. The miR-92b promotes cell proliferation in vitro and in vivo, promotes cell-cycle progression, and reduces apoptosis and chemosensitivity. LDLR silencing recapitulated miR-92b's transformative effects, while LDLR overexpression rescued these effects. CONCLUSIONS: APE1 enhances miR-92b processing, thereby suppressing LDLR expression and enhancing cervical carcinoma progression. Our identification of the novel APE1-miR-92b-LDLR axis improves our understanding of the complex pathogenesis of cervical carcinoma and reveals a novel therapeutic strategy for combating this disease.