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Prostate cancer (PCa) causes significant mortality and morbidity, with advanced metastasis. WNT signaling is a promising therapeutic target for metastatic PCa. GIPC2 is a GIPC1 paralog involved in WNT signaling pathways associated with tumor progression, but its role in PCa metastasis remains unclear. Herein, we demonstrated that high GIPC2 expression in PCa tissues was significantly associated with distant metastasis and poor prognosis. Functional studies demonstrated that high GIPC2 expression due to CpG-island demethylation promoted increased metastatic capabilities of PCa cells. Conversely, silencing GIPC2 expression significantly inhibited PCa metastasis in vitro and in vivo. Furthermore, GIPC2 directly bound the WNT co-receptor Fzd7 through its PDZ domain, which enabled activation of WNT-β-catenin cascades, thereby stimulating PCa metastasis. Interestingly, GIPC2 protein was also identified as a component of exosomes and that it robustly stimulated PCa adhesion, invasion, and migration. The presence of GIPC2 in tumor-derived exosomes and ability to impact the behavior of tumor cells suggest that GIPC2 is a novel epigenetic oncogene involved in PCa metastasis. Our findings identified GIPC2 as a novel exosomal molecule associated with WNT signaling and may represent a potential therapeutic target and biomarker for metastatic PCa.

The global distribution and temporal trend of age-related hearing loss (ARHL) are unknown, and we aimed to investigate magnitudes and temporal trends of ARHL burden and its influencing factors at the national, regional, and global levels. Based on the information of Global Burden of Disease Study 2019, we calculated the estimated annual percentage change to quantify the global, regional, and national temporal trends of age-standardized rates (ASRs) of ARHL by gender, age, and severity. The number of prevalent cases and disability-adjusted life years (DALYs) of ARHL increased from 751.50 million and 22.01 million in 1990 to 1456.66 million and 40.24 million in 2019, respectively. Except for a few countries such as Niger and Burkina Faso, the age-standardized prevalence rate and age-standardized DALYs rate showed a downward trend in most countries and regions. Mild ARHL accounted for the largest proportion in all ARHL, and only mild ARHL showed an upward trend in ASRs. In most regions, the proportion of ARHL disease burden attributable to occupational noise showed a downward trend in the past 30 years. In 2019, ARHL disease burden attributable to occupational noise declined with the increase of socio-demographic index in countries. Although the ASR of ARHL in most parts of the world is declining, the absolute disease burden of ARHL is still heavy. Understanding the real-time disease burden of ARHL and its temporal trend is of great significance for formulating more effective preventive measures and reducing the ARHL burden.

Background: The latest global melanoma disease burden and changes are rarely reported, which is important for developing potential strategies to reduce the melanoma-related burden. The aim of this study was to examine the variations and trends in the burden of melanoma between 1990 and 2019. Methods: We extracted detailed data about melanoma from the 2019 Global Burden of Disease study in 204 countries and territories. Detailed data includes the number of melanoma incident cases, deaths, DALYs, and age-standardized rates. We calculated the estimated annual percentage change (EAPC) to quantify the temporal trends of the age-standardized rates of melanoma, and analyzed the influential factors of EAPCs by Spearman correlation. Findings: From 1990 to 2019, the incidence of melanoma cases increased by 170% to 289 950, death increased by 90% to 62 840, and DALYs increased by 67% to 1 707 800 globally. The age-standardized incidence rate (ASIR) of melanoma increased globally by an average of 1 · 13 (95% CI, 0·93-1·32) while the ASRs of mortality and DALYs both declined with the EAPC of -0·27(95% CI, -0·36 to -0·19) and -0·49(95% CI, -0·57 to -0·41), respectively. In 2019, the highest burden of melanoma was observed in high SDI regions , especially Australasia (ASIR=43·36/100 000) and High-income North America regions (ASIR=16·62/100 000). The increasing trend in ASIR was observed in most countries (159/204) , with the highest increase in South Korea, followed by Belarus and Guatemala. However, decreasing or stable trends in ASRs of mortality and DALYs were detected in almost half of countries (102/204; 117/204) except for the low-middle SDI regions such as Guatemala. Interpretation: The variations and trends of melanoma burde n differed greatly across the world. Albeit the overall ASRs of mortality and DALYs declined, the ASIR of melanoma incrementally rose in most countries, which implies more targeted strategies should be taken for areas and groups with relatively higher burden. Funding Information: This work was supported by the National Key Research and Development program of China (grant number: 2017YFC0907003), the National Natural Science Foundation of China (grant numbers: 81973116 and 81573229), and the Shandong Provincial Natural Science Foundation (grant number: ZR2020QH302). Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: Ethics approval was exempted by the Ethics Committee of Qilu Hospital of Shandong University, because the GBD 2019 study is a publicly available database and all data were anonymous. My study does not involve human subjects.

Background Nearly half of the cases of esophageal cancer in the world were in China, but the corresponding burden in China has not been estimated for the past decades or for the near future. Methods Data on the incidence, mortality, and disability‐adjusted life years (DALYs) rates owing to esophageal cancer in China from 1990 to 2017 were extracted from the Global Burden of Disease Study 2017. To reflect the trend in the disease burden, we calculated the estimated annual percentage change (EAPC) in the age‐standardized rates of these three outcomes in China from 1990 to 2017. Results The age‐standardized incidence rate (ASIR) for esophageal cancer decreased from 19.38/100,000 in 1990 to 12.23/100,000 in 2017, with an EAPC of −2.53 (95%CI: −2.90, −2.16), but the number of cases of esophageal cancer increased from 164,473 to 234,624. The age‐standardized rates of esophageal cancer in females were always lower than they were in males during the study period, and there was a downward trend that was more pronounced among females than males. The most common risk factors for males were smoking and alcohol consumption, while the most common risk factors for females were a diet low in fruits and a high body mass index (BMI). New cases of, and deaths from esophageal cancer are predicted to increase by about 1.5 times in the coming 25 years. Conclusion Although the age‐standardized burden of esophageal cancer has been declining, the number of new cases of, and deaths from esophageal cancer have increased in China over the past 30 years, and they will continue to increase in the near future. Hence, national policies should be adopted to promote the prevention and management of known risk factors for it, especially smoking and excessive caloric intake., Although the age‐standardized burden of esophageal cancer has been declining, the number of new cases of, and deaths from esophageal cancer have increased in China over the past 30 years, and they will continue to increase in the near future. Hence, national policies should be adopted to promote the prevention and management of known risk factors for it, especially smoking and excessive caloric intake.

Background Selection of high-risk subjects for endoscopic screening of esophageal squamous cell carcinoma (ESCC) lacks individual predictive tools based on environmental risk factors. Methods We performed a large population-based case-control study of 1418 ESCC cases and 1992 controls in a high-risk area of China. Information on potential risk factors was collected via face-to-face interview using an electronic structured questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models, and predictive nomograms were established accordingly. A weighted analysis was further conducted to introduce age into predictive nomograms due to frequency matching study design. Results Most cases were usually exposed to 4 to 6 risk factors, but most controls were usually exposed to 3 to 5 risk factors. The AUCs of male and female predictive nomograms were 0.75 (95%CI: 0.72, 0.77) and 0.76 (95%CI: 0.73, 0.79), respectively. The weighted analysis adding age in the predictive model improved the AUC in both men and women (0.81 (95%CI: 0.79, 0.84) and 0.88 (95%CI: 0.85, 0.90), respectively). Conclusions An easy-to-use preclinical predictive tool is provided to select candidate population with high ESCC risk for endoscopic screening. Its usefulness needs to be further evaluated in future screening practice.

Objectives Understanding the global trend of lung cancer deaths attributable to smoking is crucial for prioritizing global lung cancer prevention, as well as tobacco control. We assessed patterns of smoking-induced lung cancer deaths at global, regional, and national levels from 1990 to 2017. Materials and methods We extracted detailed data on lung cancer deaths attributable to smoking from the Global Burden of Disease 2017 Study. The estimated annual percentage change (EAPC) was used to quantify temporal trends in the age-standardized mortality rate (ASMR) of smoking-induced lung cancer. Results In 2017, estimated 1.19 million lung cancer deaths were attributable to smoking, accounting for 63.17 % of all lung cancer deaths. The corresponding ASMR decreased by 13.36 % from 17.29/100,000 in 1990 to 14.98/100,000 in 2017, with an EAPC of −0.59 (95 % confidence interval: −0.66, −0.53). The ASMR of lung cancer in most geographic regions has significantly decreased since 1990; however, the EAPC of ASMR in 20 countries exceeded 1 during the same period. The reductions in the ASMR were pronounced in areas with high Socio-demographic Index and high disease burden, and kept pace with the decrease of smoking prevalence at least 10 years ago. Conclusion Despite the decline in lung cancer ASMR attributable to smoking over the past 28 years, the corresponding number of lung cancer deaths increased steadily due to population aging and growth. Tobacco prevention needs to be strengthened, especially in countries with high smoking prevalence and countries where the ASMR of smoking-induced lung cancer is increasing.

Aims Autism spectrum disorder (ASD) is a neurodevelopmental condition, with symptoms appearing in the early developmental period. Little is known about its current burden at the global, regional and national levels. This systematic analysis aims to summarise the latest magnitudes and temporal trends of ASD burden, which is essential to facilitate more detailed development of prevention and intervention strategies. Methods The data on ASD incidence, prevalence, disability-adjusted life years (DALYs) in 204 countries and territories between 1990 and 2019 came from the Global Burden of Disease Study 2019. The average annual percentage change was calculated to quantify the secular trends in age-standardised rates (ASRs) of ASD burden by region, sex and age. Results In 2019, there were an estimated 60.38 × 104 [95% uncertainty interval (UI) 50.17–72.01] incident cases of ASD, 283.25 × 105 (95% UI 235.01–338.11) prevalent cases and 43.07 × 105 (95% UI 28.22–62.32) DALYs globally. The ASR of incidence slightly increased by around 0.06% annually over the past three decades, while the ASRs of prevalence and DALYs both remained stable over the past three decades. In 2019, the highest burden of ASD was observed in high-income regions, especially in high-income North America, high-income Asia Pacific and Western Europe, where a significant growth in ASRs was also observed. The ASR of ASD burden in males was around three times that of females, but the gender difference was shrunk with the pronounced increase among females. Of note, among the population aged over 65 years, the burden of ASD presented increasing trends globally. Conclusions The global burden of ASD continues to increase and remains a major mental health concern. These substantial heterogeneities in ASD burden worldwide highlight the need for making suitable mental-related policies and providing special social and health services.

The blast crisis (BC) is the final deadly phase of chronic myeloid leukemia (CML), which remains a major challenge in clinical management. However, the underlying molecular mechanism driving blastic transformation remains unclear. Here, we show that ASF1A, an essential activator, enhanced the transformation to CML-BC by mediating cell differentiation arrest. ASF1A expression was aberrantly increased in bone marrow samples from CML-BC patients compared with newly diagnosed CML-chronic phase (CP) patients. ASF1A inhibited cell differentiation and promoted CML development in vivo. Mechanistically, we identified ASF1A as a coactivator of the Notch transcriptional complex that induces H3K56ac modification in the promoter regions of Notch target genes, and subsequently enhanced RBPJ binding to these promoter regions, thereby enhancing Notch signaling activation to mediate differentiation arrest in CML cells. Thus, our work suggests that targeting ASF1A might represent a promising therapeutic approach and a biomarker to detect disease progression in CML patients.

Background To assess the spatiotemporal variation in female breast cancer attributable to low physical activity (LPA) at a global scale from 1990 to 2019, which is essential to promote physical activity, as well as prevent and control breast cancer. Methods The number of deaths and disability-adjusted life years (DALYs), and the corresponding age-standardized rates (ASMR and ASDR) of LPA-related breast cancer in 204 countries and territories from 1990 to 2019 were retrieved from the Global Burden of Disease Study 2019 to measure the related breast cancer burden by age and region. The estimated annual percentage change (EAPC) was calculated to quantify the secular trend in breast cancer burden rates. Results From 1990 to 2019, globally, both breast cancer deaths and DALYs attributable to LPA nearly doubled, although the corresponding ASMR and ASDR decreased slightly, with EAPC of -0.46 (95% confidence interval: -0.52, -0.40) and -0.44 (95% confidence interval: -0.49, -0.39), respectively. The LPA-related breast cancer burden varied considerably across the world, with the highest-burden rates in Oceania, Tropical Latin America and Caribbean, and the fastest growth in North Africa and Middle East. The ASMR and ASDR showed a logarithmic association with the Socio-demographic Index, and a temporally upward trend in most of 204 countries regardless of the Socio-demographic Index or the ASMR in 1990. Conclusions Despite a decline in LPA-related breast cancer burden achieved in many countries during the last 3 decades like Bermuda, Myanmar, USA and China, an increase still occurred in most of 204 countries and territories, such as Solomon Islands, Equatorial Guinea, Japan and India. The findings can bring greater awareness to the importance of promoting physical activity for the local government to control the attributable breast cancer burden.

Uterine cancer is one of the most common female cancers worldwide, with huge heterogeneity in morbidity and mortality. Although a high body-mass index (BMI) has been linked to uterine cancer, systematic reports about the influence of high BMI and its temporal trends are scarce.The annual morbidity, mortality, and disability-adjusted life years (DALYs) of uterine cancer in 204 countries or territories were retrieved from the GBD 2019 study. To reflect trends in disease burden, we also calculated the estimated annual percentage change (EAPC) based on the age-standardized rates of uterine cancer from 1990 to 2019.The global incident cases of uterine cancer increased 2.3 times from 187,190 in 1990 to 435,040 in 2019. Although the age-standardized incidence rate (ASIR) of uterine cancer increased worldwide from 8.67/100,000 in 1990 to 9.99/100,000 in 2019, the age-standardized death rate (ASDR) and DALY rate decreased during the same period. High socio-demographic index (SDI) countries tended to have a higher ASIR than developing regions, and their increasing trend in ASIR was also more pronounced. The disease was rare before 40 years old, but its risk rose sharply among women aged 50-70. A high BMI was linked to more than one-third of deaths from uterine cancer in 2019.The incidence in developed areas was significantly higher than in developing areas and also increased much more rapidly. Elderly females, especially those with a high BMI, have a higher risk of uterine cancer. Therefore, more health resources may be needed to curb the rising burden in specific populations.

As an important environmental pollutant, lead exposure can result in idiopathic developmental intellectual disability (IDII). However, the latest spatiotemporal patterns across the world are unclear. Therefore, in this study, the global burden of lead exposure-related IDII was assessed using the Global Burden of Disease (GBD) study (2019). The data were downloaded from the Institute for Health Metrics and Evaluation (IHME), and the estimated annual percentage change (EAPC) was calculated to assess the changing trend of the age-standardized disability-adjusted life-years (DALYs) rates (ASDR) of global IDII attributed to lead exposure. In 2019, the number of global DALYs of IDII attributed to lead exposure was 2.72 million, the corresponding ASDR was 35.70 per 100,000. The ASDR was highest in children and adolescents, and low- and middle-income countries. From 1990 to 2019, the global number of DALYs of IDII attributable to lead exposure increased by 7.89%, while the ASDR of IDII decreased by 19.19% [EAPC = -0.78, 95% confidence interval (CI): (-0.90, -0.66)]. The downward trends were seen in most GBD regions and countries, especially in high-income countries, but 11 countries presented an upward trend. Therefore, it is important to continue to improve primary mental healthcare globally, especially in low- and middle-income countries. Meanwhile, the implementation of effective strategies to reduce lead exposure should be continually strengthened.

Understanding epidemiology trends and patterns of pancreatic cancer in China from 1990 to 2019 and predicting the burden to 2030 will provide foundations for future policies development.We collected incidence, mortality, and disability-adjusted life-years (DALYs) data of pancreatic cancer in China from 1990 to 2019 based on the Global Burden of Disease Study 2019. We calculated the estimated annual percentage change (EAPC) to depict the trends of pancreatic cancer burden and predicted the incidence and mortality in the next decade by using a Bayesian age-period-cohort analysis.The number of incident cases sharply increased from 26.77 thousand in 1990 to 114.96 thousand in 2019, the age-standardized incidence rate (ASIR) nearly doubled from 3.17 per 100,000 in 1990 to 5.78 per 100,000 in 2019, with an EAPC of 2.32 (95% confidence interval [CI]: 2.12, 2.51). The mortality and DALYs presented a similar pattern with incidence. The dominant risk factor for pancreatic cancer was smoking, but the contribution of high body-mass index increased from 1990 to 2019. We projected that the incident cases and deaths of pancreatic cancer would increase to 218.79 thousand and 222.97 thousand, respectively, in 2030 with around 2 times growth.During the past three decades, the incidence, mortality and DALYs of pancreatic cancer gradually increased in China, and the absolute number and rate of pancreatic cancer burden would continue to rise over the next decade. Comprehensive policies and strategies need to be implemented to reduce the incidence and mortality.

Background Poor oral health may be a significant risk factor for gastric cancer (GC), however, previous results are not consistent. Here, we investigated the effect of oral health on GC and effect modification by other factors. Methods We conducted a population-based case-control study in Taixing, China. Participants aged between 40 and 85 years and who had lived in Taixing for at least 5 years were included. The GC cases were confirmed by endoscopy and pathological diagnosis, and the controls were randomly selected using the frequency-matching method. Unconditional logistic regression models were used to derive odds ratios (ORs) and 95% confidence intervals (CIs) of oral health for GC risk after adjusting for confounders and risk factors. Results Overall, 901 GC cases and 1972 controls were included. Tooth loss was not significantly associated with an increased risk of GC (yes vs. no, OR = 1.08, 95% CI 0.88-1.33). Compared with toothbrushing at least twice per day, toothbrushing once per day or less was associated with an increased risk of GC (OR = 2.39, 95% CI 1.94-2.94), and was more pronounced in esophagogastric junction cancer and intestinal-type GC. There was no significant interaction between the indicators of oral health and age, sex, tobacco smoking, alcohol drinking, and Helicobacter pylori seropositivity. Conclusion Poor oral hygiene behavior is associated with an increased risk of GC, and this positive association is consistent across all GC subgroups classified by anatomy and histology. Further studies are needed to explore the possible mechanisms behind this association. This article is protected by copyright. All rights reserved.

The relationship between risk of esophageal squamous cell carcinoma (ESCC) and adult height, changes in individual body mass index (BMI) and body shape is not established. We performed a large population‐based case‐control study, which enrolled a total of 1414 ESCC cases and 1989 controls in a high‐incidence area in China. Using face‐to‐face interview with a structured questionnaire, information on participants' heights, weights, and perceived body shapes at 20 years of age was collected. Additionally, data on weight and perceived body shape among the same participants 10 years prior to ascertainment were collected using the same method. Odd ratios (ORs) of ESCC risk in relation to BMI and body shape were estimated using unconditional logistic regression models. The adjusted results indicated that ESCC risk in adults rapidly rose as height increased, plateauing at 170 cm among men and 157 cm among women. Among participants who were underweight, normal weight, or thinner than body shape 4, body weight loss was associated with increased risk of ESCC, and body weight gain was associated with decreased incidence of ESCC (ORs ranging from 0.40 to 0.76). Notably, however, changes in body weight did not significantly affect ESCC risk among participants who were overweight, obese, or larger than body shape 3. Maintaining a fit body shape and a reasonable BMI is advisable and of vital importance to reduce the risk of ESCC, especially in high‐risk areas.

The dose-response relationship between folate and the risk of esophageal cancer (EC) is not clear. To further elucidate their relationships, we carried out a dose-response meta-analysis of folate intake, serum folate, and the risk of EC. PubMed, Embase, Web of Science, and China National Knowledge Infrastructure were searched for observational studies until September 2016. Then, we carried out a systematic review and dose-response meta-analysis using Stata 14.0 software. Subgroup analyses were further carried out according to study characteristics and adjustment confounders. A total of 23 studies with a total of 3886 patients were enrolled in this study. The pooled odds ratios for EC in the highest versus the lowest levels of folate intake and serum folate were 0.64 (0.54-0.76, P

Molecular mechanisms and observational studies have found that diet-derived antioxidants are associated with digestive system cancers, whereas there is a lack of causal evidence from randomized clinical trials. In this study, we aimed to assess the causality of these associations through a Mendelian randomization (MR) study. Single nucleotide polymorphisms of diet-derived circulating antioxidants (i.e., α- and γ-tocopherol, ascorbate, retinol, β-carotene, lycopene, and urate), accessed by absolute levels and relative metabolite concentrations, were used as genetic instruments. Summary statistics for digestive system cancers were obtained from the UK Biobank and FinnGen studies. Two-sample MR analyses were performed in each of the two outcome databases, followed by a meta-analysis. The inverse-variance weighted MR was adopted as the primary analysis. Five additional MR methods (likelihood-based MR, MR-Egger, weighted median, penalized weighted median, and MR-PRESSO) and replicate MR analyses for outcomes from different sources were used as sensitivity analyses. Genetically determined antioxidants were not significantly associated with five digestive system cancers, after correcting for multiple tests. However, we found suggestive evidence that absolute ascorbate levels were negatively associated with colon cancer in UK Biobank—the odds ratio (OR) per unit increase in ascorbate was 0.774 (95% confidence interval [CI] 0.608–0.985, p = 0.037), which was consistent with the results in FinnGen, and the combined OR was 0.764 (95% CI 0.623–0.936, p = 0.010). Likewise, higher absolute retinol levels suggestively reduced the pancreatic cancer risk in FinnGen—the OR per 10% unit increase in ln-transformed retinol was 0.705 (95% CI 0.529–0.940, p = 0.017), which was consistent with the results in UK Biobank and the combined OR was 0.747 (95% CI, 0.584–0.955, p = 0.020). Sensitivity analyses verified the above suggestive evidence. Our findings suggest that higher levels of antioxidants are unlikely to be a causal protective factor for most digestive system cancers, except for the suggestive protective effects of ascorbate on colon cancer and of retinol on pancreatic cancer.

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML), which is characterized by the reciprocal t (15;17) (q24; q21) translocation, resulting in PML-RARA gene fusion. Therapy-related AML (t-AML) is a serious complication after cytotoxic and/or radiation therapy in many malignant diseases. In this report, MLL/KMT2A-MON2, with balanced chromosomal translocation t (11;12) (q23; q14), was identified as a novel fusion in a child transformed to t-AML after successful treatment of APL. This study emphasized that clinical monitoring with an integrated laboratory approach is essential for the diagnosis and treatment of t-AML.

To map the magnitudes and temporal trends of blindness and vision loss (BVL) due to common eye diseases along with its attributable risk factors at the national, regional, and global levels. The annual burden of BVL in 204 countries and territories was extracted from the Global Burden of Disease Study 2019. The estimated annual percentage change (EAPC) and causes composition change were calculated to quantify the temporal trends of BVL-related disease burden by sex, region, and eye disease. The global disability-adjusted life years (DALYs) of BVL increased from 12.44 million in 1990 to 22.56 million in 2019, with a slightly decreased rate from 3.03 to 2.78 per 1000 population (EAPC = -0.30). About 29.6% of BVL-related DALYs worldwide were caused by cataract, followed by refraction disorders (29.1%), near vision loss (21.7%), other vision loss (13.7%), glaucoma (3.3%), and age-related macular degeneration (2.5%) in 2019. The age-standardized DALYs rates due to each eye disease type in most regions were decreased, especially in countries with high burden and high-middle socio-demographic index. Moreover, the contribution of smoking and air pollution from solid fuels to BVL burden decreased, however, the age-standardized burden of BVL attributed to high body-mass index and high fasting plasma glucose elevated gradually across almost all regions. The temporal trend of BVL burden due to specific eye diseases varies remarkably by region, sex and age. Understanding the real-time patterns of BVL burden is crucial for formulating more effective and targeted prevention and healthcare strategies to decrease the BVL burden.

Adult acute lymphoblastic leukemia (ALL) is a malignant disorder of lymphoid progenitor cells that is associated with a high risk of relapse and poor prognosis. Thus, novel pathogenic mechanisms and therapeutic targets need to be explored. Histone methylation is one of the most significant chromatin post-translational modifications. Here, we show that the histone demethylase PHF8 is highly expressed in a large number of ALL clinical specimens and that PHF8 expression is associated with ALL progression. PHF8 knockdown inhibits proliferation and promotes the apoptosis of ALL cells in vitro as well as attenuates tumor growth in vivo. PHF8 transcriptionally upregulates MEK1, a key molecule in the MEK/ERK pathway, at least partially by directly binding to its promoter, thereby activating the MEK/ERK pathway. In addition, we found that an inhibitor of the MEK/ERK pathway, PD184352, subsequently suppresses PHF8 expression. Thus, PHF8 forms a positive feedback loop with the MEK/ERK pathway, and PHF8 knockdown enhances the lethality of PD184352 in ALL cells. In conclusion, this study identifies oncogenic functions of PHF8 in adult ALL and suggests a novel epigenetic strategy for disease intervention.

Objective: To investigate the effect of thalidomide in patients with thalassemia intermedia.Methods: We observed the effect of thalidomide in seven patients with thalassemia intermedia requiring blood transfusion. Four of the patients were transfusion-independent, and three patients were transfusion-dependent.Results: For the four transfusion-independent patients, hemoglobin concentration increased significantly (≥2 g/dl) in three and moderately (1–2 g/dl) in one. After 3 months of treatment, hemoglobin concentration increased 3.2 ± 1.2 g/dl compared to pretreatment. Among the three transfusion-dependent patients, transfusion was terminated after one month of treatment in one patient and decreased >50% in the other two patients, accompanied by an increase in the average hemoglobin concentration.Conclusion: Thalidomide had a significant effect in patients with thalassemia intermedia. Further studies of a larger scale and more rigorous design are warranted.

Background: Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors worldwide. Patients with poorly differentiated OSCC often have a poor prognosis. It is essential to search for promising diagnostic and prognostic biomarkers for OSCC. Methods: The differentially expressed genes (DEGs) were obtained using R language. Receiver operating characteristic curve analysis was performed to identify diagnostic markers for OSCC. AUNIP expression was analyzed in publicly available databases and clinical specimens. Bioinformatics analysis and in vitro experiments were conducted to explore biological functions and prognostic value of AUNIP in OSCC. Findings: The gene integration analysis revealed 90 upregulated DEGs. One candidate biomarker, AUNIP, for the diagnosis of OSCC was detected. Weighted gene co-expression network analysis and function enrichment analysis demonstrated that genes positively associated with AUNIP were enriched in cell cycle and the module eigengene was significantly correlated with the survival rate of OSCC patients. In gene set enrichment analysis, the correlation between AUNIP expression and human papillomavirus status in OSCC was verified. The suppression of AUNIP inhibited OSCC cell proliferation and resulted in G0/G1 phase arrest in OSCC cells. The survival analysis showed that AUNIP overexpression interrelated with the poor prognosis of OSCC patients. Interpretation: AUNIP could serve as a candidate diagnostic and prognostic biomarker for OSCC and suppression of AUNIP may be a potential approach to prevent and treat OSCC. Funding Statement: Taishan Scholars Project in Shandong Province (ts201511106) and the National Natural Science Foundation of China (Nos. 61603218). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: The samples were approved by Taizhou hospital Ethics Committee in Zhejiang province.

Epigenetic disorders play a key role in tumorigenesis and development, among which histone methylation abnormalities are common. While patients living with chronic myeloid leukemia in the chronic phase (CML-CP) have a good response to TKI, blastic phase (CML-BP) patients demonstrate poor efficacy and high fatality rates. However, while the mechanism of blast crisis of chronic myeloid leukemia remains unclear, high expression and activation of BCR-ABL are usually related to CML blast crisis transition. We found that histone H3 lysine 4 (H3K4) demethylase RBP2 expression is negatively correlated with BCR-ABL expression, which suggests a regulatory link between these two genes. We also discovered that RBP2 mediates the dephosphorylation of BCR-ABL by directly downregulating PTEN expression, depending on histone demethylase activity, while PTEN targets protein phosphatase activity of BCR-ABL, a phosphatase which directly dephosphorylates BCR-ABL. In clinical specimens, the mRNA expression of RBP2 was found to be positively correlated with that of PTEN. These data suggest that the under-expression of RBP2 promotes blast crisis transition by activating an RBP2/PTEN/BCR-ABL cascade.

Thalidomide has been shown to reactivate fetal hemoglobin (HbF) production and reduce the need for blood transfusions in β-thalassemia patients. However, some patients show a minor response or no response to thalidomide. In view of its potential side effects, targeted prescription of thalidomide is imperative. We initially aimed to explore the relevance of HBG2 (rs7482144), BCL11A (rs11886868, rs4671393, rs766432 and rs1427407) and HBS1L-MYB (rs9399137, rs4895440 and rs4895441) single nucleotide polymorphisms (SNPs) in thalidomide response. Eight SNPs were investigated by PCR and DNA sequencing, and their roles in thalidomide response in Chinese β-thalassemia patients were assessed. Results demonstrated that minor alleles of four SNPs were associated with an increased main response risk (rs7482144: P = 0.015; rs9399137: OR = 4.911, P = 0.029; rs4895440: OR = 4.522, P = 0.040; and rs4895441: OR = 4.522, P = 0.040). For patients with non-transfusion-dependent thalassemia (NTDT), with an increase in the minor allele numbers of rs7482144 (P = 0.011), rs9399137 (P = 0.013), rs4895440 (P = 0.011) and rs4895441 (P = 0.011), Hb increments after treatment were increased significantly as well. The cumulative effects of patients carrying any combination of one or three significant minor alleles included a gradually increased main response risk compared to those without the significant minor alleles (P = 0.040–0.018, OR = 8.556–11.000). Furthermore, Hb increments after treatment correlated with cumulative numbers of minor alleles in the four significant SNPs among patients with NTDT (P = 0.001). It was demonstrated that SNPs in HBG2 and HBS1L-MYB contributed significantly to thalidomide response in Chinese patients with β-thalassemia and that the cumulative number of minor SNP alleles may serve as good predictors of treatment response in this population.

Background: Acute myeloid leukaemia (AML) is a malignant haematological tumour with high heterogeneity and mortality. A reliable prognostic assessment is critical for treatment strategies. However, the current prognostic evaluation system of AML is insufficient. Methods: Genome-wide univariate Cox regression analysis was performed on three independent AML datasets to screen for the prognostic-related genes. Kaplan–Meier survival analysis was employed to verify the efficacy of FHL1 in evaluating overall survival in 1298 de novo AML patients, 648 non-acute promyelocytic leukaemia AML patients and 407 cytogenetically normal AML patients; the data for some of these patients were also used for EFS and RFS validation. Multivariate Cox regression was performed to validate FHL1 as an independent prognostic indicator. WGCNA, GSEA, and gene correlation analysis were applied to explore the mechanism of FHL1 in AML. The synergistic cytocidal effect of FHL1 knockdown was verified in in vitro experiments. Findings: Comprehensive genome-wide analyses and large-sample validation showed that FHL1 is a powerful prognostic candidate for overall survival, event-free survival, and relapse-free survival in AML and is independent of prognosis-related clinical factors and genetic abnormalities. The molecular mechanism may occur through regulation of FHL1 in leukaemia stem cells, tumour-associated signalling pathways, and transmembrane transport of chemotherapeutic drugs. FHL1-targeted intervention enhances the sensitivity of AML cells to cytarabine. Interpretation: FHL1 may serve as an evaluation factor for clinical strategy selection, and its targeted intervention may be beneficial for chemotherapy in AML patients. Keywords: Acute myeloid leukaemia, Prognosis, FHL1, WGCNA, Cytarabine

Krüppel-like factor 1 (KLF1) regulates erythroid lineage commitment, globin switching, and the terminal maturation of red blood cells. Variants in human KLF1 have been identified as an important causative factor in a wide spectrum of phenotypes. This study investigated two unrelated male children in China who had refractory anemia associated with poikilocythemia. These were accompanied by an upregulation of biochemical markers of hemolysis, along with abnormal hemoglobin (Hb) level and elevated reticulocyte counts. Next-generation sequencing revealed that the patients were compound heterozygotes for a KLF1 frameshift mutation c.525_526insCGGCGCC (p.(Gly176ArgfsTer179)) and one of two missense variants, c.892 G>C (p.(Ala298Pro)) and c.1012C>T (p.(Pro338Ser)). The subjects had microcytic hypochromic anemia, and their healthy parents had single mutation. The two missense mutations affected a highly conserved codon in the zinc finger DNA-binding domain of KLF1, but the protein stability was unaffected in K-562 cells. A KLF1-targeted promoter–reporter assay showed that the two mutations reduce the expression of the HBB, BCL11A, and CD44 genes involved in erythropoiesis, with consequent dyserythropoiesis and an α/non-α chain imbalance. A systematic analysis was performed of the phenotypes associated with the KLF1 mutations in the two families, and the clinical characteristics and differential diagnoses of the disease are presented. This is the first report of an autosomal recessive anemia presenting with microcytic hypochromia, abnormal Hb profile, and other distinctive erythrocyte phenotypes, and provides insight into the multiple roles of KLF1 during erythropoiesis.

Hemoglobinopathies are among the most common autosomal-recessive disorders worldwide. A comprehensive next-generation sequencing (NGS) test would greatly facilitate screening and diagnosis of these disorders. An NGS panel targeting the coding regions of hemoglobin genes and four modifier genes was designed. We validated the assay by using 2522 subjects affected with hemoglobinopathies and applied it to carrier testing in a cohort of 10,111 couples who were also screened through traditional methods. In the clinical genotyping analysis of 1182 β-thalassemia subjects, we identified a group of additional variants that can be used for accurate diagnosis. In the molecular screening analysis of the 10,111 couples, we detected 4180 individuals in total who carried 4840 mutant alleles, and identified 186 couples at risk of having affected offspring. 12.1% of the pathogenic or likely pathogenic variants identified by our NGS assay, which were undetectable by traditional methods. Compared with the traditional methods, our assay identified an additional at-risk 35 couples. We describe a comprehensive NGS-based test that offers advantages over the traditional screening/molecular testing methods. To our knowledge, this is among the first large-scale population study to systematically evaluate the application of an NGS technique in carrier screening and molecular diagnosis of hemoglobinopathies., Highlights • In 10,111 couples in prevention programs for thalassemia, 186 at-risk couples were identified by NGS and 151 by traditional routine method. • NGS assay had better performance than traditional routine screening approach in carrier screening for hemoglobinopathies. • NGS assay can characterize patients with Thalassemia Major or Thalassemia Intermedia more accurately. Hemoglobinopathies represent a major cause of birth defects in China. Traditional carrier screening strategy is phenotype-based that is associated with risk of miss phenotype-negative carriers. In this study, we validated an effective method for molecular screening and clinical genotyping of hemoglobinopathies using NGS assay. Considering the broad mutation spectrum and high prevalence of hemoglobinopathy-causing mutations across ethnic groups, this technology could make it technically feasible to offer more effective preconception screening and diagnosis in large populations worldwide. Therefore, the current phenotype-based screening guideline might be modified to a better genotype-based screening guideline.

MicroRNA-mediated posttranscriptional regulation is an important epigenetic regulatory mechanism of gene expression, and its dysregulation is involved in the development and progression of a variety of malignancies, including chronic myeloid leukemia (CML). The BCR-ABL1 fusion gene is not only the initiating factor of CML, but it is also an important driving factor for blastic transformation. Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 tyrosine kinase activity, represented by imatinib, are currently the first-line treatment for CML. However, due to primary resistance or secondary resistance caused by mutations in the BCR-ABL1 kinase domain, TKIs cannot completely prevent the progression of CML; thus, the study of BCR-ABL1 gene expression regulation is of great significance. In this study, bioinformatics analysis and our results showed that miR-96 could directly bind to the 3'UTR region of BCR-ABL1 to regulate fusion protein expression, thereby regulating its downstream signaling pathway activity. We also found that miR-96 was downregulated during the progression from the chronic phase (CML-CP) to the blast crisis (CML-BC). Downregulation of miR-96 could promote the proliferation and participate in the cell differentiation of CML-BC cells. Additionally, we found that the novel histone deacetylase drug chidamide and the DNA methyltransferase inhibitor decitabine could restore the low expression of miR-96 in CML cells, and there were two abnormal hypermethylated sites in the promoter region of miR-96 in CML, suggesting that its low expression might be at least partially regulated by epigenetic mechanisms. In addition, re-expression of miR-96 could increase the sensitivity of CML-BC cells to imatinib. Thus, miR-96 functions as a tumor suppressor, and re-expression of this microRNA might have therapeutic benefits in CML blastic transformation.

The beta-lactamase (BLA) genes, the genes for aminoglycosides-modifying enzymes (AMEs), disinfectant-sulfanilamide resistance (qacEDelta1-sul1) genes, class 1 integrase (intl1) gene, and the qnr gene associated with plasmid-mediated quinolone resistance were analyzed using PCR and verified by DNA sequencing for 31 clinical isolates of multidrug-resistant Acinetobacter baumannii (MDRAB). The organism typing was performed by pulsed-field gel electrophoresis (PFGE). The positive rate of ADC, TEM, PER, and DHA of BLA genes were 100%, 61.3%, 19.4%, and 3.2%, respectively; however, the genes of SHV, OXA-23 group, OXA-24 group, GES, VIM, IMP, and qnr gene were negative. The positive rate of the genes of AMEs for aac (3)-I, aac (6')-I, ant (3")-I, ant (2")-I, aac (3)-II, and aac (6')-II were 67.7%, 45.2%, 29.0%, 22.6%, 12.9%, and 3.2%, respectively. The positive rate of qacEDelta1-sul1 and intl1 were 80.6% and 58.1%, respectively. Six different PFGE clones were found, of which two dominated. The findings show that clinical isolates of MDRAB harbor various kinds of resistance genes.

Motivation: For many complex traits/diseases, it is believed that rare variants account for some of the missing heritability that cannot be explained by common variants. Sequencing a large number of samples through DNA pooling is a cost-effective strategy to discover rare variants and to investigate their associations with phenotypes. Overlapping pool designs provide further benefit because such approaches can potentially identify variant carriers, which is important for downstream applications of association analysis of rare variants. However, existing algorithms for analysing sequence data from overlapping pools are limited. Results: We propose a complete data analysis framework for overlapping pool designs, with novelties in all three major steps: variant pool and variant locus identification, variant allele frequency estimation and variant sample decoding. The framework can be used in combination with any design matrix. We have investigated its performance based on two different overlapping designs and have compared it with three state-of-the-art methods, by simulating targeted sequencing and by pooling real sequence data. Results on both datasets show that our algorithm has made significant improvements over existing ones. In conclusion, successful discovery of rare variants and identification of variant carriers using overlapping pool strategies critically depend on many steps, from generation of design matrixes to decoding algorithms. The proposed framework in combination with the design matrixes generated based on the Chinese remainder theorem achieves best overall results. Availability: Source code of the program, termed VIP for Variant Identification by Pooling, is available at http://cbc.case.edu/VIP. Contact: jingli@cwru.edu Supplementary information: Supplementary data are available at Bioinformatics online.

BACKGROUND: Innate immunity of which Toll-like receptor (TLR) 4 and CXCR1 are key elements plays a central role in the development of urinary tract infection (UTI). Although the relation between the genetics of TLR4 and CXCR1 and UTI is investigated partly, the polymorphisms and expression of TLR4 and CXCR1 in different types of UTI in adults are not extremely clear. METHODOLOGY/PRINCIPAL FINDINGS: This study investigates the presence of TLR4 A (896) G and CXCR1 G (2608) C polymorphisms in 129 UTI patients using RFLP-PCR. Gene and allelic prevalence were compared with 248 healthy controls. Flow cytometry was used to detect TLR4 and CXCR1 expression in the monocytes of UTI patients and healthy controls. TLR4 (896) AG genotype and TLR4 (896) G allele had higher prevalence in UTI (especially in acute cystitis and urethritis) patients, whereas CXCR1 (2608) GC genotype and CXCR1 (2608) C allele had lower prevalence in UTI patients than controls. TLR4 expression was significantly lower in chronic UTI patients than in acute pyelonephritis or healthy controls. CXCR1 expression was similar in both controls and patients. TLR4 expression in chronic UTI patients after astragalus treatment was higher than pre-treatment. CONCLUSIONS: The results indicate the relationship between the carrier status of TLR4 (896) G alleles and the development of UTI, especially acute cystitis and urethritis, in adults. TLR4 expression levels are correlated with chronic UTI.

The innate host defenses at mucosal surfaces are critical in the early stages of urinary tract bacterial infection. Recent studies have shown that uroepithelial cells aid innate immune cells in fighting off infection, although the exact mechanism by which the uroepithilium participates in immunity remains unclear. TLR4 has been implicated to possess antimicrobial activities specific for bladder epithelial cells (BECs). TLR4 promotes secretion of IL-6 and IL-8, mediates inhibition of bladder epithelial cell (BEC) bacterial invasion, and mediates expulsion of uropathogenic Escherichia coli from BECs. In this study, cultured 5637 cells and Balb/C mice were treated with Astragalus polysaccharides (APS) against invading E. coli. To determine the contribution of TLR4 upregulation to immune response, TLR4 expression and bacterial colony numbers were monitored. After 24 h incubation, only 5637 cells treated with 500 microg/ml APS expressed higher levels of TLR4 compared with the untreated group. However, after 48h, all 5637 cells treated by APS showed higher levels of TLR4 expression than the control cells. The TLR4 expression in the bladder and macrophages mice that received APS was higher than that in the controls. Bacterial colonization in 5637 cells and the bladders of mice treated with APS was significantly reduced compared with the controls. These results demonstrate that at certain concentrations, APS can induce increased TLR4 expression in vivo and in vitro. Further, TLR4 expression upregulation can enhance innate immunity during mucosal bacterial infection. The findings establish the use of APS to modulate the innate immune response of the urinary tract through TLR4 expression regulation as an alternative option for UTI treatment.

Respiratory syncytial virus (RSV) is the primary cause of serious lower respiratory tract illness in young children. We have engineered a recombinant candidate vaccine G1F/M2, consisting of a cytotoxic T lymphocyte (CTL) epitope of RSV-M2 protein and a domain of RSV-G protein. In this study, the long-term immunogenicity and protective effect were evaluated. In G1F/M2-immunized mice, special antibodies lasted for more than 19 weeks, and the IgG1/IgG2a ratio remained a balanced level till the end of the study, suggesting mixed Th1/Th2 type of responses. Concomitantly, G1F/M2 elicited long-lived RSV-specific CTL activity that was detectable at 12 weeks after the final immunization. Stronger CTL responses were induced with immunization once more at 13 weeks after the last immunization in G1F/M2-primed mice than those in F/M2-primed mice. These results suggest that G1F/M2-induced long-lasting balanced humoral and cellular immunity responses, and immunological memory in mice. Furthermore, following RSV challenge, long-term protective efficacy was observed. RSV replication in lungs of G1F/M2-primed mice elicited also mixed Th1/Th2 responses, a property that is considered advantageous for the safety of an RSV vaccine. Therefore, G1F/M2 is a promising RSV subunit vaccine.