Causal relationship between air pollution, lung function, gastroesophageal reflux disease, and non-alcoholic fatty liver disease: univariate and multivariate Mendelian randomization study.

Background: The association between air pollution, lung function, gastroesophageal reflux disease, and Non-alcoholic fatty liver disease (NAFLD) remains inconclusive. Previous studies were not convincing due to confounding factors and reverse causality. We aim to investigate the causal relationship between air pollution, lung function, gastroesophageal reflux disease, and NAFLD using Mendelian randomization analysis. Methods: In this study, univariate Mendelian randomization analysis was conducted first. Subsequently, Steiger testing was performed to exclude the possibility of reverse association. Finally, significant risk factors identified from the univariate Mendelian analysis, as well as important factors affecting NAFLD from previous observational studies (type 2 diabetes and body mass index), were included in the multivariable Mendelian randomization analysis. Results: The results of the univariable Mendelian randomization analysis showed a positive correlation between particulate matter 2.5, gastroesophageal reflux disease, and NAFLD. There was a negative correlation between forced expiratory volume in 1 s, forced vital capacity, and NAFLD. The multivariable Mendelian randomization analysis indicated a direct causal relationship between gastroesophageal reflux disease (OR = 1.537, p = 0.011), type 2 diabetes (OR = 1.261, p < 0.001), and NAFLD. Conclusion: This Mendelian randomization study confirmed the causal relationships between air pollution, lung function, gastroesophageal reflux, and NAFLD. Furthermore, gastroesophageal reflux and type 2 diabetes were identified as independent risk factors for NAFLD, having a direct causal connection with the occurrence of NAFLD.

Comparison of carcinosarcoma and adenocarcinoma of the gallbladder: a study based on SEER population for propensity matching and nomogram analysis.

BACKGROUND: Carcinosarcoma of the gallbladder (CSGB) is an uncommon malignancy, and limited literature is available on its clinicopathological features, prognosis, and treatment options. METHODS: Using the SEER database, we selected 7634 gallbladder adenocarcinoma patients (diagnosed from 2004 to 2015) and 58 carcinosarcoma of the gallbladder patients (diagnosed from 1988 to 2019) based on predetermined criteria. We compared the overall survival (OS) and cancer-specific survival (CSS) before and after propensity score matching in two groups. Cox univariate and multivariate analyses were performed, and a nomogram was further generated to investigate the impact of clinical and pathological variables on the survival of patients with CSGB. Finally, we evaluated the effect of different treatment modalities on the overall survival of CSGB patients. RESULTS: Notably, CSGB patients had larger tumors and underwent surgery more frequently than gallbladder adenocarcinoma patients, with lower rates of deeper tumor infiltrates, and lymph node infiltrates. Conversely, gallbladder adenocarcinoma patients had a higher proportion of AJCC staging (III-IV). Despite these differences, no significant differences were found in OS and CSS between the two groups before and after propensity score matching. For CSGB patients, AJCC staging, surgery and tumor size were significant prognostic factors, while treatment modalities such as surgery combined with chemotherapy, or combined radiochemotherapy, as well as radical resection, did not significantly prolong patient survival. CONCLUSION: No significant difference was found in survival rates between CSGB and gallbladder adenocarcinoma patients, while radical surgery and different combined treatment modalities did not provide significant survival benefits.

Neuropilin 1 regulates bone marrow vascular regeneration and hematopoietic reconstitution.

Ionizing radiation and chemotherapy deplete hematopoietic stem cells and damage the vascular niche wherein hematopoietic stem cells reside. Hematopoietic stem cell regeneration requires signaling from an intact bone marrow (BM) vascular niche, but the mechanisms that control BM vascular niche regeneration are poorly understood. We report that BM vascular endothelial cells secrete semaphorin 3 A (SEMA3A) in response to myeloablation and SEMA3A induces p53 - mediated apoptosis in BM endothelial cells via signaling through its receptor, Neuropilin 1 (NRP1), and activation of cyclin dependent kinase 5. Endothelial cell - specific deletion of Nrp1 or Sema3a or administration of anti-NRP1 antibody suppresses BM endothelial cell apoptosis, accelerates BM vascular regeneration and concordantly drives hematopoietic reconstitution in irradiated mice. In response to NRP1 inhibition, BM endothelial cells increase expression and secretion of the Wnt signal amplifying protein, R spondin 2. Systemic administration of anti - R spondin 2 blocks HSC regeneration and hematopoietic reconstitution which otherwise occurrs in response to NRP1 inhibition. SEMA3A - NRP1 signaling promotes BM vascular regression following myelosuppression and therapeutic blockade of SEMA3A - NRP1 signaling in BM endothelial cells accelerates vascular and hematopoietic regeneration in vivo.

Epidermal growth factor receptor-dependent DNA repair promotes murine and human hematopoietic regeneration.

Chemotherapy and irradiation cause DNA damage to hematopoietic stem cells (HSCs), leading to HSC depletion and dysfunction and the risk of malignant transformation over time. Extrinsic regulation of HSC DNA repair is not well understood, and therapies to augment HSC DNA repair following myelosuppression remain undeveloped. We report that epidermal growth factor receptor (EGFR) regulates DNA repair in HSCs following irradiation via activation of the DNA-dependent protein kinase-catalytic subunit (DNA-PKcs) and nonhomologous end joining (NHEJ). We show that hematopoietic regeneration in vivo following total body irradiation is dependent upon EGFR-mediated repair of DNA damage via activation of DNA-PKcs. Conditional deletion of EGFR in hematopoietic stem and progenitor cells (HSPCs) significantly decreased DNA-PKcs activity following irradiation, causing increased HSC DNA damage and depressed HSC recovery over time. Systemic administration of epidermal growth factor (EGF) promoted HSC DNA repair and rapid hematologic recovery in chemotherapy-treated mice and had no effect on acute myeloid leukemia growth in vivo. Further, EGF treatment drove the recovery of human HSCs capable of multilineage in vivo repopulation following radiation injury. Whole-genome sequencing analysis revealed no increase in coding region mutations in HSPCs from EGF-treated mice, but increased intergenic copy number variant mutations were detected. These studies demonstrate that EGF promotes HSC DNA repair and hematopoietic regeneration in vivo via augmentation of NHEJ. EGF has therapeutic potential to promote human hematopoietic regeneration, and further studies are warranted to assess long-term hematopoietic effects.

Chronic myeloid leukemia stem cells require cell-autonomous pleiotrophin signaling.

Tyrosine kinase inhibitors (TKIs) induce molecular remission in the majority of patients with chronic myelogenous leukemia (CML), but the persistence of CML stem cells hinders cure and necessitates indefinite TKI therapy. We report that CML stem cells upregulate the expression of pleiotrophin (PTN) and require cell-autonomous PTN signaling for CML pathogenesis in BCR/ABL+ mice. Constitutive PTN deletion substantially reduced the numbers of CML stem cells capable of initiating CML in vivo. Hematopoietic cell-specific deletion of PTN suppressed CML development in BCR/ABL+ mice, suggesting that cell-autonomous PTN signaling was necessary for CML disease evolution. Mechanistically, PTN promoted CML stem cell survival and TKI resistance via induction of Jun and the unfolded protein response. Human CML cells were also dependent on cell-autonomous PTN signaling, and anti-PTN antibody suppressed human CML colony formation and CML repopulation in vivo. Our results suggest that targeted inhibition of PTN has therapeutic potential to eradicate CML stem cells.

PTPσ inhibitors promote hematopoietic stem cell regeneration.

Receptor type protein tyrosine phosphatase-sigma (PTPσ) is primarily expressed by adult neurons and regulates neural regeneration. We recently discovered that PTPσ is also expressed by hematopoietic stem cells (HSCs). Here, we describe small molecule inhibitors of PTPσ that promote HSC regeneration in vivo. Systemic administration of the PTPσ inhibitor, DJ001, or its analog, to irradiated mice promotes HSC regeneration, accelerates hematologic recovery, and improves survival. Similarly, DJ001 administration accelerates hematologic recovery in mice treated with 5-fluorouracil chemotherapy. DJ001 displays high specificity for PTPσ and antagonizes PTPσ via unique non-competitive, allosteric binding. Mechanistically, DJ001 suppresses radiation-induced HSC apoptosis via activation of the RhoGTPase, RAC1, and induction of BCL-XL. Furthermore, treatment of irradiated human HSCs with DJ001 promotes the regeneration of human HSCs capable of multilineage in vivo repopulation. These studies demonstrate the therapeutic potential of selective, small-molecule PTPσ inhibitors for human hematopoietic regeneration.

Wild-type Kras expands and exhausts hematopoietic stem cells.

Oncogenic Kras expression specifically in hematopoietic stem cells (HSCs) induces a rapidly fatal myeloproliferative neoplasm in mice, suggesting that Kras signaling plays a dominant role in normal hematopoiesis. However, such a conclusion is based on expression of an oncogenic version of Kras. Hence, we sought to determine the effect of simply increasing the amount of endogenous wild-type Kras on HSC fate. To this end, we utilized a codon-optimized version of the murine Kras gene (Krasex3op) that we developed, in which silent mutations in exon 3 render the encoded mRNA more efficiently translated, leading to increased protein expression without disruption to the normal gene architecture. We found that Kras protein levels were significantly increased in bone marrow (BM) HSCs in Krasex3op/ex3op mice, demonstrating that the translation of Kras in HSCs is normally constrained by rare codons. Krasex3op/ex3op mice displayed expansion of BM HSCs, progenitor cells, and B lymphocytes, but no evidence of myeloproliferative disease or leukemia in mice followed for 12 months. BM HSCs from Krasex3op/ex3op mice demonstrated increased multilineage repopulating capacity in primary competitive transplantation assays, but secondary competitive transplants revealed exhaustion of long-term HSCs. Following total body irradiation, Krasex3op/ex3op mice displayed accelerated hematologic recovery and increased survival. Mechanistically, HSCs from Krasex3op/ex3op mice demonstrated increased proliferation at baseline, with a corresponding increase in Erk1/2 phosphorylation and cyclin-dependent kinase 4 and 6 (Cdk4/6) activation. Furthermore, both the enhanced colony-forming capacity and in vivo repopulating capacity of HSCs from Krasex3op/ex3op mice were dependent on Cdk4/6 activation. Finally, BM transplantation studies revealed that augmented Kras expression produced expansion of HSCs, progenitor cells, and B cells in a hematopoietic cell-autonomous manner, independent from effects on the BM microenvironment. This study provides fundamental demonstration of codon usage in a mammal having a biological consequence, which may speak to the importance of codon usage in mammalian biology.

Deletion of the Imprinted Gene Grb10 Promotes Hematopoietic Stem Cell Self-Renewal and Regeneration.

Imprinted genes are differentially expressed by adult stem cells, but their functions in regulating adult stem cell fate are incompletely understood. Here we show that growth factor receptor-bound protein 10 (Grb10), an imprinted gene, regulates hematopoietic stem cell (HSC) self-renewal and regeneration. Deletion of the maternal allele of Grb10 in mice (Grb10m/+ mice) substantially increased HSC long-term repopulating capacity, as compared to that of Grb10+/+ mice. After total body irradiation (TBI), Grb10m/+ mice demonstrated accelerated HSC regeneration and hematopoietic reconstitution, as compared to Grb10+/+ mice. Grb10-deficient HSCs displayed increased proliferation after competitive transplantation or TBI, commensurate with upregulation of CDK4 and Cyclin E. Furthermore, the enhanced HSC regeneration observed in Grb10-deficient mice was dependent on activation of the Akt/mTORC1 pathway. This study reveals a function for the imprinted gene Grb10 in regulating HSC self-renewal and regeneration and suggests that the inhibition of Grb10 can promote hematopoietic regeneration in vivo.

Exposure to ambient heat and urolithiasis among outdoor workers in Guangzhou, China.

OBJECTIVES: To assess the impact of exposure to ambient heat on urolithiasis among outdoor workers in a subtropical city of China. METHODS: The 2003-2010 health check data of a shipbuilding company in Guangzhou, China were acquired. 190 cases and 760 matched controls were involved in this study. We assessed the relationship between exposure to ambient heat and urolithiasis for different occupations using conditional logistic regression. RESULTS: Spray painters were most likely to develop urolithiasis (OR=4.4; 95% CI: 1.7, 11.4), followed by smelter workers (OR=4.0; 95% CI: 1.8, 9.2), welders (OR=3.7; 95% CI: 1.9, 7.2), production security and quality inspectors (OR=2.7; 95% CI: 1.4, 3.0), and assemblers (OR=2.2; 95% CI: 1.1, 4.3). Overall, outdoor workers were more likely to present with urolithiasis compared with indoor employees (p<0.05). In addition, workers with longer cumulative exposure time (OR=1.5; 95% CI: 1.2, 1.8) and abnormal blood pressure (OR=1.6; 95% CI: 1.0, 2.5) had higher risk for urolithiasis. CONCLUSIONS: Our findings demonstrate a significant association between exposure to ambient heat and urolithiasis among outdoor working populations. Public health intervention strategies should be developed to specifically target outdoor occupations.

Nonfatal child pedestrian injury in two urban cities of Guangdong Province, China: results from a cross-sectional survey.

OBJECTIVE: To describe the epidemiological characteristics of nonfatal child pedestrian injuries and provide information to help understand an important public-health problem. METHODS: This was a school-based, cross-sectional questionnaire survey. The sample (42 750 children) was obtained from two urban cities of Guangdong Province, China, using multi-stage randomized sampling. Information was collected by the respondents self-reporting in the classroom. RESULTS: The incidence rate of nonfatal child pedestrian injuries in the cities was 2.0%. Boys had a higher incidence rate (2.6%) than girls (1.4%). Compared to other children, those aged 10 years are at the highest risk. The primary places of occurrence were sidewalks, residential roads, and crosswalks. High-risk behavior of the children immediately prior to injury included mid-block crossings, playing on roads, and crossing on red lights. The major vehicles that caused pedestrian injuries were bicycles, car or vans, and motorcycles. Bruises, fractures, and injuries to the internal organs were the top three types of injuries. Almost 40% of victims were hospitalized, and nearly 30% of the victims suffered long-term disabilities. CONCLUSION: This study shows that nonfatal child pedestrian injuries are a very serious public-health problem in the urban cities of Guangdong. Based on the epidemiological characteristics, prevention strategies and further research should be carried out to reduce the occurrence of injuries.

Relationships between weight status and bullying victimization among school-aged adolescents in Guangdong Province of China.

OBJECTIVE: To examine relationships between weight status and different forms of bullying victimization among adolescents aged 11-18 years. METHODS: The relationships between weight status and bullying victimization (physical, verbal, and relational) were examined utilizing data from the Guangdong Provincial Youth Health Behavior Survey. Data on height, weight, and victimization behaviors were collected by self-reporting from 12 439 subjects. , test and logistic regression were used to analyze relationships between weight and bullying victimization. RESULTS: The incidence of victimization for adolescents aged 11-18 years was 8.6%, with higher rates for boys (12.4%) than for girls (4.7%). For children with normal, overweight and obese body mass index (BMI), the incidence rates of victimization were 8.2%, 17.3%, and 11.5%, respectively. Compared to normal weight, overweight was a risk factor for bullying victimization(OR = 1.60, 95% CI: 1.18-2.17), and it also increased children's risk of being teased in a hurtful way (OR = 2.13, 95% CI: 1.41-3.24) and being made fun of due to physical appearance (OR = 3.58, 95% CI: 2.27-5.67). Obesity only increased the risk for children of being made fun of due to physical appearance (OR = 2.45, 95% CI: 1.44-4.15). CONCLUSIONS: The victimization for children at school is common in Guangdong province, China. Overweight and obese children are more likely to be victims of bullying behaviors, especially verbal victimization.

[Study on the events of nonfatal drowning among primary and middle school students in a rural town of Guangdong province, 2006].

OBJECTIVE: To understand the incidence and characteristics of nonfatal drowning among primary and middle school students in rural area and to provide basic information for intervention. METHODS: A rural town was selected and all students from 3th-8th grades, 10th grade and 11th grade were studied. All data were collected, using a self-administrated questionnaires which was guided by investigator. RESULTS: The overall incidence rate of nonfatal drowning was 5.65% (549/9732) and were 7.69%, 5.80%, 2.39% for primary, secondary and high school students, respectively. Male students had a higher rate (7.14%) than that of females (4.03%). The incidence rates of non-treated, treated in emergency and under hospitalization were 4.52%, 0.77% and 0.35%. The major reasons of drowning were swimming (46.88%), falling into waters (15.67%), diving (13.79%) and rescuing others (6.24%). The proportion of drowning occurred in the afternoon, evening, at noon or in the morning were 59.94%, 15.64%, 14.77% and 9.65% respectively. The common sites of drowning were river/lake (42.48%), swimming pool (19.56%), reservoir (11.39%) and pond (4.38%). 66.76% of the drowning cases were witnessed by other person, and 17.86% were conscious when being removed from waters. CONCLUSION: The incidence of nonfatal drowning among students in rural areas was high, and the natural body of waters was the most common site causing drowning while swimming was the major reason of drowning. Intervention targeting on primary and middle school students in rural should be carried out to reduce the incidence.

Accessing men who have sex with men through long-chain referral recruitment, Guangzhou, China.

Men who have sex with men (MSM) may account for an increasing proportion of China's HIV epidemic, but remain difficult to access for epidemiological studies due to high stigma. We compare the composition of two samples of MSM obtained in Guangzhou, China. The first survey, conducted in 2004, recruited MSM through convenience sampling. The second survey in 2006 used long-chain referral recruitment in the context of respondent-driven sampling. Compared to convenience sampling, the long-chain referral method included higher proportions of subgroups of MSM thought to be at elevated risk for HIV infection and more difficult to reach, including internal migrants and those engaging in commercial sex. Long-chain referral also recruited more MSM who were under 25 years, unemployed, and had lower education. We conclude that long-chain referral recruitment will be more effective in tracking the leading edge of the epidemic among MSM in China than convenience sampling.