Effects of concurrent chemoradiotherapy with or without Endostar on the regression of retropharyngeal lymph node and prognosis of patients with locally advanced nasopharyngeal carcinoma: a retrospective study.

BACKGROUND AND PURPOSE: To investigate the effect of combining Endostar with concurrent chemoradiotherapy (ECCRT) compared to concurrent chemoradiotherapy (CCRT) on the regression rate of retropharyngeal lymph nodes (RLNs) and the relationship between regression rate of RLNs and prognosis of patients with locally advanced nasopharyngeal carcinoma (LANPC). METHODS: A total of 122 LANPC patients with RLNs metastasis were included. Metastatic RLNs were delineated both before and after treatment slice by slice on the magnetic resonance images cross-section. The regression rate of RLNs, adverse effects (AE) were evaluated. The median regression rate of RLNs was taken as the cut-off value, and the patients were furtherly divided into high regression rate (HRR) group and low regression rate (LRR) group, then survival times were evaluated. RESULTS: The median regression rates of RLNs in the ECCRT and CCRT groups were 81% and 50%, respectively (P < 0.001). There was no statistically significant difference in the incidence of grade 3/4 AEs between the two groups, except for oral mucositis (ECCRT 26.23% vs. CCRT 44.26%, P = 0.037). The 3-year overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS) and locoregional failure-free survival (LRFFS) rates in the HRR and LRR groups were 85.48% and 86.67% (P = 0.983), 80.65% and 68.33% (P = 0.037), 83.87% and 85% (P = 0.704), 93.55% and 81.67% (P = 0.033), respectively. CONCLUSIONS: Patients in the ECCRT group had higher regression rates of RLNs and lower incidence of severe oral mucositis. Furthermore, patients in the HRR group had a better 3-year PFS and LRFFS rate than those in the LRR group.

Melanin-mediated accumulation of polycyclic aromatic hydrocarbons in human hair: Insights from biomonitoring and cell exposure studies.

While human hair is widely used to monitor micro-organic contaminants (MOCs), their incorporation mechanisms are poorly understood. Melanin, known to facilitate the accumulation of drugs in hair, hasn't been studied in the field of MOCs. Here, polycyclic aromatic hydrocarbons (PAHs), a class of priority MOCs, were investigated through hair biomonitoring as well as cell exposure experiments. PAH concentrations and melanin contents were measured in black and white hairs from the same individual. The results showed that five dominant PAHs (phenanthrene, fluoranthene, pyrene, benzo[a]anthracene and chrysene) in black hair (0.66 ng/g - 35.1 ng/g) were significantly higher than those in white hair (0.52 ng/g - 29.6 ng/g). Melanin contents in black hair (14.9 - 48.9 ng/g) were markedly higher than in white hair (0.35 - 2.15 ng/g) and were correlated to PAH concentrations, hinting melanin-mediated accumulation of PAHs in hair. The in vitro experiment using murine melanoma cells demonstrates that PAH levels in cells were affected by melanin, suggesting the affinity of melanin to PAHs. Both biomonitoring and cell exposure experiment implicate the pivotal role of melanin in PAH accumulation in hair. Therefore, to ensure the accuracy of hair biomonitoring for MOCs, attention must be paid to the melanin content uniformity.

Poor outcome of pediatric B-cell acute lymphoblastic leukemia associated with high level of CRLF2 gene expression in distinct molecular subtypes.

Background: Overexpression of the cytokine receptor-like factor 2 (CRLF2) gene is the most common feature in the Philadelphia chromosome (Ph)-like subtype of B-cell acute lymphoblastic leukemia (B-ALL). However, the predictive value of CRLF2 overexpression for the prognosis of pediatric B-ALL patients remain controversial. The molecular mechanisms that upregulate CRLF2 expression level in patients has not been fully elucidated. Methods: In this study, the prognostic impact of CRLF2 expression level on molecular types of B-ALL in pediatric patients from Zhujiang Hospital (n = 111) was retrospectively analyzed. Youden index analysis was used to categorize CRLF2 expression into 3 groups, and these categories more precisely described the differences in the prognosis of patients with varying expression levels of CRLF2 in both the Zhujiang Hospital cohort and the TARGET cohort. Results: We used the Zhujiang Hospital cohort as a discovery cohort to determine the cutoff value of CRLF2 expression. CRLF2-high patients accounted for approximately 6%. In addition, the percentage of bone marrow blast cells and initial white blood cell count in CRLF2-high patients were higher than those in CRLF2-low patients, and MRD turned negative slower. The results were validated in the TARGET cohort and indicated that CRLF2 overexpression could be subdivided by CRLF2 expression levels into 2 categories: CRLF2-high with a poor survival and CRLF2-medium with a good OS and EFS. Such heterogeneity was attributed to the different molecular mechanisms leading to CLRF2 upregulation, where the CRLF2 overexpression level was high in Ph-like B-ALL and medium in high hyperdiploid B-ALL. Conclusion: This study highlights the importance of the molecular mechanisms of the upregulation of CRLF2 expression in predicting the prognosis of pediatric B-ALL patients.

Pertinence of glioma and single nucleotide polymorphism of TERT, CCDC26, CDKN2A/B and RTEL1 genes in glioma: a meta-analysis.

Background: Previous genetic-epidemiological studies considered TERT (rs2736100), CCDC26 (rs4295627), CDKN2A/B (rs4977756) and RTEL1 (rs6010620) gene polymorphisms as the risk factors specific to glioma. However, the data samples of previous genetic-epidemiological studies are modest to determine whether they have definite association with glioma. Method: The study paid attention to systematically searching databases of PubMed, Embase, Web of Science (WoS), Scopus, Cochrane Library and Google Scholars. Meta-analysis under 5 genetic models, namely recessive model (RM), over-dominant model (O-DM), allele model (AM), co-dominant model (C-DM) and dominant model (DM) was conducted for generating odds ratios (ORs) and 95% confidence intervals (CIs). That was accompanied by subgroup analyses according to various racial groups. The software STATA 17.0 MP was implemented in the study. Result: 21 articles were collected. According to data analysis results, in four genetic models (AM, RM, DM and C-DM) TERT gene rs2736100 polymorphism, CCDC26 gene rs4295627 polymorphism, CDKN2A/B gene rs4977756 polymorphism and RTEL1 gene rs6010620 polymorphisms increased the risk of glioma in Caucasians to different degrees. In Asian populations, the CCDC26 gene rs4295627 polymorphism and CDKN2A/B gene rs4977756 polymorphism did not exhibit a relevance to the risk of glioma. It is suggested to cautiously explain these results as the sample size is small. Conclusion: The current meta-analysis suggested that the SNP of TERT (rs2736100), CCDC26 (rs4295627), CDKN2A/B (rs4977756) and RTEL1 (rs6010620) genes in glioma might increase risk of glioma, but there are ethnic differences. Further studies evaluating these polymorphisms and glioma risk are warranted.

Interaction and Metabolic Function of Microbiota during the Washed Processing of Coffea arabica.

Coffee fermentation is crucial for flavor and aroma, as microorganisms degrade mucilage and produce metabolites. This study aimed to provide a basis for understanding the impact of microorganisms on Coffea arabica from Yunnan, China, during washed processing. The microbial community structure and differentially changed metabolites (DCMs) of C. arabica beans during washed processing were analyzed. The results indicated that the top five predominant microorganisms at the genera level were Achromobacter, Tatumella, Weissella, Streptococcus, and Trichocoleus for bacteria and Cystofilobasidium, Hanseniaspora, Lachancea, Wickerhamomyces, and Aspergillus for fungi. Meanwhile, the relative content of 115 DCMs in 36 h samples decreased significantly, compared to non-fermentation coffee samples (VIP > 1, p < 0.05, FC < 0.65), and the relative content of 28 DCMs increased significantly (VIP > 1, p < 0.05, FC > 1.5). Furthermore, 17 DCMs showed a strong positive correlation with microorganisms, and 5 DCMs had a strong negative correlation (p < 0.05, |r| > 0.6). Therefore, the interaction and metabolic function of microbiota play a key role in the formation of coffee flavor, and these results help in clarifying the fermentation mechanisms of C. arabica and in controlling and improving the quality of coffee flavor.

GNAQ R183Q somatic mutation contributes to aberrant arteriovenous specification in Sturge-Weber syndrome through Notch signaling.

Episcleral vasculature malformation is a significant feature of Sturge-Weber syndrome (SWS) secondary glaucoma, the density and diameter of which are correlated with increased intraocular pressure. We previously reported that the GNAQ R183Q somatic mutation was located in the SWS episclera. However, the mechanism by which GNAQ R183Q leads to episcleral vascular malformation remains poorly understood. In this study, we investigated the correlation between GNAQ R183Q and episcleral vascular malformation via surgical specimens, human umbilical vein endothelial cells (HUVECs), and the HUVEC cell line EA.hy926. Our findings demonstrated a positive correlation between episcleral vessel diameter and the frequency of the GNAQ R183Q variant. Furthermore, the upregulation of genes from the Notch signaling pathway and abnormal coexpression of the arterial marker EphrinB2 and venous marker EphB4 were demonstrated in the scleral vasculature of SWS. Analysis of HUVECs overexpressing GNAQ R183Q in vitro confirmed the upregulation of Notch signaling and arterial markers. In addition, knocking down of Notch1 diminished the upregulation of arterial markers induced by GNAQ R183Q. Our findings strongly suggest that GNAQ R183Q leads to malformed episcleral vasculatures through Notch-induced aberrant arteriovenous specification. These insights into the molecular basis of episcleral vascular malformation will provide new pathways for the development of effective treatments for SWS secondary glaucoma.

Combined Trabeculotomy-Non-Penetrating Deep Sclerectomy for Glaucoma in Sturge-Weber Syndrome.

INTRODUCTION: The aim of the study was to evaluate the efficacy and safety of combined trabeculotomy-non-penetrating deep sclerectomy (CTNS) in the treatment of Sturge-Weber syndrome (SWS) secondary glaucoma. METHODS: This retrospective study reviewed cases that underwent CTNS as initial surgery for SWS secondary glaucoma at our Ophthalmology Department center from April 2019 to August 2020. Surgical success was defined as an intraocular pressure (IOP) ≤ 21 mm Hg with (qualified success) or without (complete success) the use of anti-glaucoma medications. IOP >21 mm Hg or <5 mm Hg despite 3 or more applications of anti-glaucoma medications on 2 consecutive follow-up visits or at the last follow-up, performance of additional glaucoma (IOP-lowering) surgery, or with vision-threatening complications were classified as failure. RESULTS: A total of 22 eyes of 21 patients were included. Twenty-one eyes were of early-onset type and 1 eye was of adulthood onset. For Kaplan-Meier survival analysis, the overall success rates at 1st and 2nd years were 95.2% and 84.9%, while the complete success rates at 1st and 2nd years were 42.9% and 36.7%. At the last follow-up (22.3 ± 4.0 months, range: 11.2∼31.2), overall success was achieved in 19 (85.7%) eyes and complete success in 12 (52.4%) eyes. Postoperative complications included transient hyphema (11/22, 50.0%) and transient Ⅰ degree shallow anterior chamber (1/22, 4.5%), and retinal detachment (1/22, 4.5%). No other severe com plications were detected during the follow-up. CONCLUSION: CTNS significantly reduces IOP in SWS secondary glaucoma patients who have serious episcleral vascular malformation. CTNS in SWS secondary glaucoma patients is safe and effective for short and medium periods. A randomized controlled study comparing the long-term prognosis of SWS early-onset and late-onset glaucoma underwent CTNS is worth conducting.

Evaluation of Schlemm's canal with swept-source optical coherence tomography in primary angle-closure disease.

PURPOSE: To perform an in vivo evaluation of the changes in Schlemm's canal (SC) among patients with primary angle-closure disease (PACD) using swept-source optical coherence tomography (SS-OCT). METHODS: Patients diagnosed with PACD who had not undergone surgery were recruited. The SS-OCT quadrants scanned herein included the nasal and temporal sections at 3 and 9 o'clock, respectively. The diameter and cross-sectional area of the SC were measured. A linear mixed-effects model was performed to analyze the effects of parameters on the SC changes. The hypothesis of interest was related to the angle status (iridotrabecular contact, ITC/open angle, OPN), which was further explored with pairwise comparisons of the estimated marginal means (EMMs) of the SC diameter and SC area. In the ITC regions, the relationship between the trabecular-iris contact length (TICL) percentage and SC parameters was also studied by a mixed model. RESULTS: A total of 49 eyes of 35 patients were included for measurements and analysis. The percentage of observable SCs in the ITC regions was only 58.5% (24/41), whereas it was 86.0% (49/57) in the OPN regions (χ2 = 9.44, p = 0.002). ITC was significantly associated with a decreasing SC size. The EMMs for the diameter and cross-sectional area of SC at the ITC and OPN regions were 203.34 µm versus 261.41 µm (p = 0.006) and 3174.43 µm2 versus 5347.63 µm2 (p = 0.022), respectively. Sex, age, spherical equivalent refraction, intraocular pressure, axial length, extent of angle closure, history of acute attack and treatment with LPI were not significantly associated with SC parameters. In the ITC regions, a larger TICL percentage was significantly associated with a decrease in SC diameter and area (p = 0.003 and 0.019, respectively). CONCLUSIONS: The morphologies of SC could be affected by the angle status (ITC/OPN) in patients with PACD, and ITC was significantly associated with a decreasing SC size. These changes in SC as described by OCT scans might help to elucidate the progression mechanisms of PACD.

Prognostic factors of sepsis in children with acute leukemia admitted to the pediatric intensive care unit.

OBJECTIVE: To analyze the prognostic factors of sepsis in children with acute leukemia admitted to the pediatric intensive care unit (PICU) and to compare the efficacy of different scoring systems for predicting the outcome of children. METHODS: Patients with an acute leukemia diagnosis admitted to a tertiary care university hospital PICU due to sepsis during chemotherapy between May 2015 and August 2022 were retrospectively analyzed through an electronic medical record system. RESULTS: During this period, 693 children with acute leukemia initially diagnosed were admitted to the center, and 155 (22.3%) of them were transferred to PICU due to deterioration of the disease during treatment. Total 109 (70.3%) patients were transferred to PICU due to sepsis. Here, 17 patients was excluded (prior treatment from another hospital; referring from other hospitals; discontinued treatment; incomplete medical record). Of the 92 patients studied, the mortality rate was 35.9%. Multivariate analysis revealed that remission status, lactate level, invasive mechanical ventilation (IMV), and inotropic support within 48 hours after PICU transfer were independent risk factors for PICU mortality. The pediatric sequential organ failure assessment (PSOFA) score had the greatest predictive validity for hospital mortality (area under the receiver operating characteristic curve [AUROC]: 0.83, 95% confidence intervals [CI]: 0.74-0.92), followed by the pediatric early warning score (PEWS) (0.82, 0.73-0.91) and pediatric critical illness score (PCIS) (0.79, 0.69-0.88). CONCLUSION: The mortality rate among children with acute leukemia complicated with sepsis is high after being transferred to the PICU. Various scoring systems can be used to monitor the clinical status of patients, identify sepsis early, detect critical illness, and determine the optimal time for transfer to the PICU for supportive treatment, thereby improving the prognosis of these patients.

Current situation and influencing factors of disease uncertainty in parents of children with Sturge‒Weber syndrome: a retrospective study.

BACKGROUND: Sturge Weber syndrome (SWS), can cause extensive capillary malformations on the face, head, trunk, and other parts of the body, and the eyes can also suffer optic nerve injury. Secondary glaucoma can cause blindness, which has the characteristics of a relatively hidden onset and unclear pathogenesis. The treatment of SWS secondary glaucoma has always been difficult, and due to the characteristics of the disease, there is uncertainty about the long-term efficacy and safety of various treatment methods for such patients. METHODS: A total of 105 parents of children with SWS completed a self-designed general information questionnaire, a generalized anxiety questionnaire (GAD-7), a patient health questionnaire (PHQ-2), a stress perception scale (PSS-4), a simple coping scale (SCSQ) and a disease-uncertainty scale (PPUS). RESULTS: The total uncertainty score of parents of children with SWS was 79.07 ± 13.24, and the average item score was 2.82 ± 0.47. Multiple linear regression analysis revealed that anxiety and simple coping were the main influencing factors of disease uncertainty among parents of children with SWS (P < 0.05). CONCLUSIONS: Parents of children with SWS exhibit a high level of disease uncertainty. Medical staff should pay attention to the source of parents' disease uncertainty and provide targeted interventions, which are of great importance in reducing parents' disease uncertainty.

Association Between Genetic Risk, Adherence to Healthy Lifestyle Behavior, and Thyroid Cancer Risk.

Importance: Genetic and lifestyle factors are related to thyroid cancer (TC). Whether a healthy lifestyle is associated with TC and could attenuate the influence of genetic variants in TC remains equivocal. Objectives: To examine the associations between genetics and healthy lifestyle with incident TC and whether adherence to a healthy lifestyle modifies the association between genetic variants and TC. Design, Setting, and Participants: A prospective cohort study using UK Biobank data recruited 502 505 participants aged 40 to 69 years between March 13, 2006, and October 1, 2010. A total of 307 803 participants of European descent were recruited at baseline, and 264 956 participants were available for the present study. Data analysis was conducted from November 1, 2021, to April 22, 2022. Exposures: Lifestyle behaviors were determined by diet index, physical activity, weight, smoking, and alcohol consumption. Lifestyle was categorized as unfavorable (scores 0-1), intermediate (score 2), and favorable (scores 3-5). The polygenic risk score (PRS) was derived from a meta-genome-wide association study using 3 cohorts and categorized as low, intermediate, and high. Main Outcomes and Measures: Thyroid cancer was defined using the International Classification of Diseases, Ninth Revision (code 193), International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (code C73), and self-report (code 1065). Results: Of 264 956 participants, 137 665 were women (52%). The median age was 57 (IQR, 49-62) years. During a median follow-up of 11.1 (IQR, 10.33-11.75) years (2 885 046 person-years), 423 incident TCs were ascertained (14.66 per 100 000 person-years). Higher PRSs were associated with TC (hazard ratio [HR], 2.25; 95% CI, 1.91-2.64; P = 8.65 × 10-23). An unfavorable lifestyle was also associated with a higher risk of TC (HR, 1.93; 95% CI, 1.50-2.49; P < .001). When stratified by PRS, unfavorable lifestyle was associated with TC in the higher PRS group (favorable vs unfavorable HR, 0.52; 95% CI, 0.37-0.73; P < .001). Furthermore, participants with both a high PRS and unfavorable lifestyle had the highest risk of TC (HR, 4.89; 95% CI, 3.03-7.91; P < .001). Conclusions and Relevance: In this prospective cohort study, genetic and lifestyle factors were independently associated with incident TC, which suggests that a healthier lifestyle may attenuate the deleterious influence of genetics on the risk of TC in individuals of European descent.

Prognostic value of the cervical lymph node necrosis ratio in nasopharyngeal carcinoma.

PURPOSE: Whether cervical lymph node necrosis (CNN) is an independent adverse prognostic factor in nasopharyngeal carcinoma (NPC) has not been determined. In this study, the CNN ratio was graded quantitatively to explore the prognostic value in NPC. PARTICIPANTS AND METHODS: We retrospectively reviewed a total of 648 pathologically confirmed as NPC. We outlined metastatic lymph nodes and necrotic area of lymph nodes slice by slice on the magneticresonanceimages (MRI) cross section, and calculated the corresponding CNN ratio. RESULTS: The median CNN ratio (17.37 %) was taken as the cut-off point, 256 (39.51 %) patients were divided into CNN1 group (<17.37 %, n = 128) and CNN2 group (≥17.37 %, n = 128), 392 (60.49 %) patients without lymph nodes necrosis were CNN0. Among the CNN0, CNN1 and CNN2 groups, five-year overall survival (OS) was 82.4 %, 76.6 % and 71.1 %, locoregional recurrence-free survival (LRRFS) was 91.3 %, 91.1 % and 90.5 %, distant metastasis-free survival (DMFS) was 83.7 %, 78.5 % and 68.7 %, progression-free survival (PFS) was 78.3 %, 71.7 % and 61.6 % respectively. By multivariate analysis, CNN was an independent prognostic factor for OS (P = 0.003), DMFS (P = 0.019) and PFS (P = 0.007). More than 3 cycles of chemotherapy significantly increased OS (P = 0.024) and DMFS (P = 0.015) in the CNN1 group. CONCLUSIONS: This study indicated that CNN is one of the factors with the negative prognosis of NPC. The CNN ratio might be used as one of the reference factors in the formulation of individualized treatment plan.

Population pharmacokinetics of posaconazole in Chinese pediatric patients with acute leukaemia: Effect of food on bioavailability and dose optimization.

This study aimed to investigate the effect of food on the pharmacokinetics of posaconazole suspension in pediatric patients with acute leukaemia and to recommend optimal dosing strategies. This single-site, prospective, open-label, observational study was conducted in 42 patients and included 186 plasma concentrations of posaconazole. Sparse data were analyzed using population pharmacokinetic modeling. Monte Carlo simulations were conducted to predict the morning trough concentrations at steady-state with the proposed dose of 2-7 mg/kg three times daily (tid) or four times daily (qid) for bodyweights of 10-36 kg. The target concentrations were 700 ng/mL for prophylaxis and 1000 ng/mL for treatment. Dosage regimens with percentage of target attainment (PTA) ≥70% were recommended. A one-compartment model with allometric scaling adequately described the pharmacokinetic profile. The apparent clearance was 9.05 L/h (95% confidence interval [CI] 7.14-11.09) and the apparent volume of distribution was 283 L (95% CI 168-491) for a typical individual of 17.5 kg. The relative bioavailability with high-fat diet was as high as 1.95-fold compared with regular food. Following the intake of regular meals, 4 mg/kg qid was adequate with a PTA ≥ 71.8% for prophylaxis. A dosage of 6 mg/kg qid under a regular diet reached a PTA ≥ 73.4% for treatment. The recommended dosage of posaconazole for prophylaxis and treatment could be predicted by the pharmacokinetic model based on bodyweight and diet type in pediatric patients.

Case Report: Reversible Hyperglycemia Following Rapamycin Treatment for Atypical Choroid Plexus Papilloma in an Infant.

In this study, atypical choroid plexus papilloma was treated with high-dose rapamycin for 17 days preoperatively in an infant. Rapamycin significantly reduced the blood supply to the tumor while reducing the tumor volume, and most of the tumor was resected successfully. However, the infant developed hyperglycemia related to the rapamycin dose, which was effectively controlled by adjusting the dose and applying insulin.

CFTR mRNAs with nonsense codons are degraded by the SMG6-mediated endonucleolytic decay pathway.

Approximately 10% of cystic fibrosis patients harbor nonsense mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene which can generate nonsense codons in the CFTR mRNA and subsequently activate the nonsense-mediated decay (NMD) pathway resulting in rapid mRNA degradation. However, it is not known which NMD branches govern the decay of CFTR mRNAs containing nonsense codons. Here we utilize antisense oligonucleotides targeting NMD factors to evaluate the regulation of nonsense codon-containing CFTR mRNAs by the NMD pathway. We observe that CFTR mRNAs with nonsense codons G542X, R1162X, and W1282X, but not Y122X, require UPF2 and UPF3 for NMD. Furthermore, we demonstrate that all evaluated CFTR mRNAs harboring nonsense codons are degraded by the SMG6-mediated endonucleolytic pathway rather than the SMG5-SMG7-mediated exonucleolytic pathway. Finally, we show that upregulation of all evaluated CFTR mRNAs with nonsense codons by NMD pathway inhibition improves outcomes of translational readthrough therapy.

Appraising the Effect of Potential Risk Factors on Thyroid Cancer: A Mendelian Randomization Study.

CONTEXT: Various risk factors have been associated with the risk of thyroid cancer in observational studies. However, the causality of the risk factors is not clear given the susceptibility of confounding and reverse causation. OBJECTIVE: A 2-sample Mendelian randomization approach was used to estimate the effect of potential risk factors on thyroid cancer risk. METHODS: Genetic instruments to proxy 55 risk factors were identified by genome-wide association studies (GWAS). Associations of these genetic variants with thyroid cancer risk were estimated in GWAS of the FinnGen Study (989 cases and 217 803 controls). A Bonferroni-corrected threshold of P = 9.09 × 10-4 was considered significant, and P < 0.05 was considered to be suggestive of an association. RESULTS: Telomere length was significantly associated with increased thyroid cancer risk after correction for multiple testing (OR 4.68; 95% CI, 2.35-9.31; P = 1.12 × 10-5). Suggestive associations with increased risk were noted for waist-to-hip ratio (OR 1.85; 95% CI, 1.02-3.35; P = 0.042) and diastolic blood pressure (OR 1.60; 95% CI, 1.08-2.38; P = 0.019). Suggestive associations were noted between hemoglobin A1c (HbA1c) (OR 0.20; 95% CI, 0.05-0.82; P = 0.025) and decreased risk of thyroid cancer. Risk of thyroid cancer was not associated with sex hormones and reproduction, developmental and growth, lipids, diet and lifestyle, or inflammatory factors (All P > 0.05). CONCLUSION: Our study identified several potential targets for primary prevention of thyroid cancer, including central obesity, diastolic blood pressure, HbA1c, and telomere length, which should inform public health policy.

Causal relationships between blood calcium, iron, magnesium, zinc, selenium, phosphorus, copper, and lead levels and multisystem disease outcomes in over 400,000 Caucasian participants.

BACKGROUND & AIMS: Metal elements have been associated with a wide range of clinical outcomes. The available epidemiological evidence for these associations is often inconsistent and suffers from confounding and reverse causation. We aimed to explore the broad clinical effects of varying blood metal element levels and possible underlying mechanisms. METHODS: We performed a two-sample Mendelian randomization (MR) analysis by using metal element-associated genetic loci as instrumental variable to evaluate the causal associations between blood metal element levels and 1050 disease outcomes in a UK Biobank cohort. A total of 408,910 White British participants were enrolled in the analysis. We further used the metal element-related genes and disease-related genes to construct a protein-protein interaction (PPI) network. RESULTS: Eight metal elements were associated with 63 diseases in total. Notably, we found nine pairs of suggestive evidence between two different metal elements for the same disease. Selenium and lead share some of the associated clinical outcomes, including diabetes mellitus, type 2 diabetes, lymphoid leukemia, and acute pharyngitis. Lead and zinc share the associated disease of acquired hypothyroidism. Iron and copper share the associated disease of arthropathies. Copper and zinc share the associated disease of occlusion of cerebral arteries. Calcium and zinc share the associated disease of arthropathies. In addition, the PPI network provided potential links between metal elements and disease outcomes at the genetic level. CONCLUSIONS: Our MR study of eight metal elements comprehensively characterized their shared and unique clinical effects, highlighting their potential causal roles in multiple diseases. Given the modifiable nature of blood metal elements and the potential for clinical interventions, these findings warrant further investigation.

Causal Effect of Genetically Determined Blood Copper Concentrations on Multiple Diseases: A Mendelian Randomization and Phenome-Wide Association Study.

Exposures to copper have become a health concern. We aim to explore the broad clinical effects of blood copper concentrations. A total of 376,346 Caucasian subjects were enrolled. We performed a Mendelian randomization and phenome-wide association study (MR-PheWAS) to evaluate the causal association between copper and a wide range of outcomes in UK Biobank, and we constructed a protein-protein interaction network. We found association between blood copper concentrations and five diseases in the overall population and nine diseases in male. MR analysis implicated a causal role of blood copper in five diseases (overall population), including prostate cancer (OR = 0.87, 95% CI 0.77-0.98), malignant and unknown neoplasms of the brain and nervous system (OR = 0.58, 95% CI 0.38-0.89), and hypertension (OR = 0.94, 95% CI 0.90-0.98), essential hypertension (OR = 0.94, 95% CI 0.90-0.98) and cancer of brain and nervous system (OR = 0.63, 95% CI 0.41-0.98). For male, except for dysphagia being newly associated with blood copper (OR = 1.39, 95% CI 1.18-1.63), other MR results were consistent with the overall population. In addition, the PPI network showed possible relationship between blood copper and four outcomes, namely brain cancer, prostate cancer, hypertension, and dysphagia. Blood copper may have causal association with prostate cancer, malignant and unknown neoplasms of the brain and nervous system, hypertension, and dysphagia. Considering that copper is modifiable, exploring whether regulation of copper levels can be used to optimize health outcomes might have public health importance. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-022-00052-3.

Somatic GNAQ R183Q mutation is located within the sclera and episclera in patients with Sturge-Weber syndrome.

AIMS: To determine the correspondence between GNAQ R183Q (c.548G＞A) mutation in abnormal scleral tissue of patients with Sturge-Weber syndrome (SWS) secondary glaucoma and explore the role of GNAQ R183Q in glaucoma pathogenesis. METHODS: Episcleral tissues were obtained from 8 patients: SWS secondary glaucoma (n=5) and primary congenital glaucoma (PCG, n=3). Scleral tissues were obtained from 7 patients: SWS secondary glaucoma (n=2), PCG (n=1) and juvenile open-angle glaucoma (n=4). GNAQ R183Q mutation was detected in scleral tissue by droplet digital PCR. Tissue sections from SWS were examined by immunohistochemistry to determine the expression of p-ERK. RESULTS: The GNAQ R183Q mutation was present in 100% of the SWS abnormal sclera. Five cases were SWS patient-derived episcleral tissue, and the mutant allelic frequencies range from 6.9% to 12.5%. The other two were deep scleral tissues and the mutant frequencies were 1.5% and 5.3%. No mutations in GNAQ R183 codon were found in the sclera of PCG and juvenile open-angle glaucoma. Increased expression of p-ERK and p-JNK was detected in the endothelial cells of SWS abnormal scleral blood vessels. CONCLUSIONS: GNAQ R183Q occurred in all abnormal scleral tissue of SWS secondary glaucoma. Increased expression of p-ERK and p-JNK in endothelial cells of blood vessels was detected in the abnormal scleral tissue. This study suggests GNAQ R183Q may regulate episcleral vessels of patients with SWS through abnormal activation of ERK and JNK, providing new genetic evidence of pathogenesis of glaucoma in SWS, and the dysplasia of scleral tissue in anterior segment may be used as an early diagnostic method or treatment targets to prevent the development and progression of glaucoma in patients with SWS.