Exposure to outdoor ambient air toxics and risk of breast cancer: The multiethnic cohort.

BACKGROUND: A growing literature has reported associations between traffic-related air pollution and breast cancer, however there are fewer investigations into specific ambient agents and any putative risk of breast cancer development, particularly studies occurring in populations residing in higher pollution areas such as Los Angeles. OBJECTIVES: To estimate breast cancer risks related to ambient air toxics exposure at residential addresses. METHODS: We examined the relationships between ambient air toxics and breast cancer risk in the Multiethnic Cohort among 48,665 California female participants followed for cancer from 2003 through 2013. We obtained exposure data on chemicals acting as endocrine disruptors or mammary gland carcinogens from the National-Scale Air Toxics Assessment. Cox proportional hazards models were used to estimate breast cancer risk per one interquartile range (IQR) increase in air toxics exposure lagged by 5-years. Stratified analyses were conducted by race, ethnicity, and hormone receptor types. RESULTS: Among all women, increased risks of invasive breast cancer were observed with toxicants related to industries [1,1,2,2-tetrachloroethane (hazard ratio [HR] = 4.22, 95% confidence interval [95% CI] 3.18-5.60), ethylene dichloride (HR = 2.81, 95% CI 2.20-3.59), and vinyl chloride (HR = 2.27, 95% CI 1.81, 2.85); these 3 agents were correlated (r2 = 0.45-0.77)]. Agents related to gasoline production or combustion were related to increased breast cancer risk [benzene (HR = 1.32, 95% CI 1.24, 1.41), ethylbenzene (HR = 1.20, 95% CI 1.13-1.28), toluene (HR = 1.29, 95% CI 1.20-1.38), naphthalene (HR = 1.11, 95% CI 1.02-2.22), acrolein (HR = 2.26, 95% CI 1.92, 2.65)]. Higher hazard ratios were observed in African Americans and Whites compared to other racial and ethnic groups (p-heterogeneity <0.05 for traffic-related air toxics, acrolein, and vinyl acetate). CONCLUSIONS: Our findings suggest that specific toxic air pollutants may be associated with increase breast cancer risk.

Linkage of cell division cycle 42 with clinical features, treatment response and survival in adult Philadelphia chromosome negative acute lymphoblastic leukemia.

Cell division cycle 42 (CDC42) regulates the progression of leukemia via mediating proliferation and immune evasion of malignant cells. The study aimed to investigate the correlation of CDC42 with clinical features, treatment response, event-free survival (EFS) and overall survival (OS) in adult Philadelphia chromosome negative acute lymphoblastic leukemia (Ph- ALL) patients. CDC42 expression in bone marrow mononuclear cells was detected in 78 adult Ph- ALL patients and 10 donors using real-time reverse transcriptase-polymerase chain reaction. CDC42 was increased in adult Ph- ALL patients compared with donors (p < .001). Besides, elevated CDC42 was linked with pro-B ALL or early-T ALL (p = .038) and white blood cell (WBC) elevation at diagnosis (p = .025). Fifty (64.1%) and 23 (29.5%) patients had complete remission (CR) at 1 month and minimal residual disease (MRD) after CR, respectively. CDC42 was inversely associated with CR at 1 month (p = .034), but not MRD after CR (p = .066). Concerning survival, patients with CDC42 ≥ 3.310 (cut by median value in patients) showed a shortened EFS (p = .006) and OS (p = .036) compared to those with CDC42 < 3.310. In detail, patients with CDC42 ≥ 3.310 and CDC42 < 3.310 had 5-year EFS rate of 29.9% and 45.4%, and 5-year OS rate of 39.4% and 63.6%, correspondingly. Further multivariate Cox's regression analyses revealed that CDC42 ≥ 3.310 was independently related to shorter EFS (hazard ratio = 2.933, p = .005). Elevated CDC42 is related with pro-B ALL or early-T ALL, WBC elevation at diagnosis, unfavorable treatment response and worse survival in adult Ph- ALL patients.

The persistence of SARS-CoV-2 in tissues and its association with long COVID symptoms: a cross-sectional cohort study in China.

BACKGROUND: Growing evidence suggests that symptoms associated with post-COVID-19 condition (also known as long COVID) can affect multiple organs and systems in the human body, but their association with viral persistence is not clear. The aim of this study was to investigate the persistence of SARS-CoV-2 in diverse tissues at three timepoints following recovery from mild COVID-19, as well as its association with long COVID symptoms. METHODS: This single-centre, cross-sectional cohort study was done at China-Japan Friendship Hospital in Beijing, China, following the omicron wave of COVID-19 in December, 2022. Individuals with mild COVID-19 confirmed by PCR or a lateral flow test scheduled to undergo gastroscopy, surgery, or chemotherapy, or scheduled for treatment in hospital for other reasons, at 1 month, 2 months, or 4 months after infection were enrolled in this study. Residual surgical samples, gastroscopy samples, and blood samples were collected approximately 1 month (18-33 days), 2 months (55-84 days), or 4 months (115-134 days) after infection. SARS-CoV-2 was detected by digital droplet PCR and further confirmed through RNA in-situ hybridisation, immunofluorescence, and immunohistochemistry. Telephone follow-up was done at 4 months post-infection to assess the association between the persistence of SARS-CoV-2 RNA and long COVID symptoms. FINDINGS: Between Jan 3 and April 28, 2023, 317 tissue samples were collected from 225 patients, including 201 residual surgical specimens, 59 gastroscopy samples, and 57 blood component samples. Viral RNA was detected in 16 (30%) of 53 solid tissue samples collected at 1 month, 38 (27%) of 141 collected at 2 months, and seven (11%) of 66 collected at 4 months. Viral RNA was distributed across ten different types of solid tissues, including liver, kidney, stomach, intestine, brain, blood vessel, lung, breast, skin, and thyroid. Additionally, subgenomic RNA was detected in 26 (43%) of 61 solid tissue samples tested for subgenomic RNA that also tested positive for viral RNA. At 2 months after infection, viral RNA was detected in the plasma of three (33%), granulocytes of one (11%), and peripheral blood mononuclear cells of two (22%) of nine patients who were immunocompromised, but in none of these blood compartments in ten patients who were immunocompetent. Among 213 patients who completed the telephone questionnaire, 72 (34%) reported at least one long COVID symptom, with fatigue (21%, 44 of 213) being the most frequent symptom. Detection of viral RNA in recovered patients was significantly associated with the development of long COVID symptoms (odds ratio 5·17, 95% CI 2·64-10·13, p<0·0001). Patients with higher virus copy numbers had a higher likelihood of developing long COVID symptoms. INTERPRETATION: Our findings suggest that residual SARS-CoV-2 can persist in patients who have recovered from mild COVID-19 and that there is a significant association between viral persistence and long COVID symptoms. Further research is needed to verify a mechanistic link and identify potential targets to improve long COVID symptoms. FUNDING: National Natural Science Foundation of China, National Key R&D Program of China, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and New Cornerstone Science Foundation. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Dysregulated N6-methyladenosine modification in peripheral immune cells contributes to the pathogenesis of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurogenerative disorder with uncertain origins. Emerging evidence implicates N6-methyladenosine (m6A) modification in ALS pathogenesis. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and liquid chromatography-mass spectrometry were utilized for m6A profiling in peripheral immune cells and serum proteome analysis, respectively, in patients with ALS (n = 16) and controls (n = 6). The single-cell transcriptomic dataset (GSE174332) of primary motor cortex was further analyzed to illuminate the biological implications of differentially methylated genes and cell communication changes. Analysis of peripheral immune cells revealed extensive RNA hypermethylation, highlighting candidate genes with differential m6A modification and expression, including C-X3-C motif chemokine receptor 1 (CX3CR1). In RAW264.7 macrophages, disrupted CX3CR1 signaling affected chemotaxis, potentially influencing immune cell migration in ALS. Serum proteome analysis demonstrated the role of dysregulated immune cell migration in ALS. Cell type-specific expression variations of these genes in the central nervous system (CNS), particularly microglia, were observed. Intercellular communication between neurons and glial cells was selectively altered in ALS CNS. This integrated approach underscores m6A dysregulation in immune cells as a potential ALS contributor.

Cycles of solar ultraviolet radiation favor periodic expansions of cyanobacterial blooms in global lakes.

Global warming and eutrophication are known to increase the prevalence of cyanobacterial blooms, posing a severe threat to the ecological stability and sustainability of water bodies. The long-term (over an annual time frame) effect of UV radiation on cyanobacterial blooms in lakes are rarely discussed though the substantial effects of high-intensity UV radiation on the growth inhibition of marine phytoplankton were studied. Here, we employed the datasets on surface solar UV radiation, nitrogen and phosphorus concentrations, and the annual scales and frequencies of cyanobacterial blooms in lakes across long-term spatial scales to probe the relationship of UV radiation with cyanobacterial blooms. The results indicated that enhanced solar UV radiation may unintentionally stimulate cyanobacterial growth and favor the expansions of cyanobacterial blooms in lakes around the world. The fluctuating UV radiation significantly affects the annual scales of cyanobacterial blooms in both eutrophic and oligotrophic lakes. Solar UV radiation enhances the positive impact of rising phosphorus levels on cyanobacterial blooms because UV radiation prompts the synthesis of polyphosphate in cyanobacteria cells, which helps cyanobacteria to alleviate the stress of UV light. The scales of cyanobacterial blooms are significantly impacted by solar UV radiation intensities as opposed to the annual frequency of cyanobacterial blooms. Furthermore, solar UV radiation fluctuation with a 9-year period over a 14-year main cycles significantly affects the periodicities of cyanobacterial blooms in global lakes, which provides a basis for predicting the peak value of the scales of cyanobacterial blooms in lakes. These findings opened up new avenues of inquiry into the mechanism and management strategies of cyanobacterial blooms in lakes worldwide.

Alpha-1 antitrypsin deficiency and pregnancy complications and birth outcomes: A population-based cohort study in Denmark.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is related to developing lung and liver disease, but no large-scale studies examine its association with birth outcomes. OBJECTIVE: We investigated the risk of pregnancy complications and adverse birth outcomes in mothers and children with AATD. METHODS: Using a large cohort data of Danish mothers and children with AATD from 1973 to 2013 (n = 2,027,229), with 559 cases (305 mothers and 254 children). We conducted Poisson regression to examine associations between alpha-1 antitrypsin deficiency, adverse birth outcomes, and pregnancy complications in mothers and children. RESULTS: AATD was related to term low birth weight [<2500g; Risk Ratio(RR) = 2.04, 95% confidence interval (CI): 1.50-2.79], lowest quartile of abdominal circumference at birth in children of non-smoking mothers (RR = 1.55, 95% CI: 1.14-2.11), delivery via Cesarean-section (RR = 1.59, 95% CI: 1.05-2.40), preterm birth (RR = 1.54, 95% CI: 1.19-2.00) and preeclampsia (RR = 2.64, 95% CI: 1.76-3.94). CONCLUSIONS: This emphasizes the need for mothers with AATD to be monitored closely during pregnancy to reduce the risk of adverse birth outcomes. Routine screening for alpha-1 antitrypsin in pregnancy may be considered among mothers with a pulmonary and liver disease history.

A prediction model for classifying maternal pregnancy smoking using California state birth certificate information.

BACKGROUND: Systematically recorded smoking data are not always available in vital statistics records, and even when available it can underestimate true smoking rates. OBJECTIVE: To develop a prediction model for maternal tobacco smoking in late pregnancy based on birth certificate information using a combination of self- or provider-reported smoking and biomarkers (smoking metabolites) in neonatal blood spots as the alloyed gold standard. METHODS: We designed a case-control study where childhood cancer cases were identified from the California Cancer Registry and controls were from the California birth rolls between 1983 and 2011 who were cancer-free by the age of six. In this analysis, we included 894 control participants and performed high-resolution metabolomics analyses in their neonatal dried blood spots, where we extracted cotinine [mass-to-charge ratio (m/z) = 177.1023] and hydroxycotinine (m/z = 193.0973). Potential predictors of smoking were selected from California birth certificates. Logistic regression with stepwise backward selection was used to build a prediction model. Model performance was evaluated in a training sample, a bootstrapped sample, and an external validation sample. RESULTS: Out of seven predictor variables entered into the logistic model, five were selected by the stepwise procedure: maternal race/ethnicity, maternal education, child's birth year, parity, and child's birth weight. We calculated an overall discrimination accuracy of 0.72 and an area under the receiver operating characteristic curve (AUC) of 0.81 (95% confidence interval [CI] 0.77, 0.84) in the training set. Similar accuracies were achieved in the internal (AUC 0.81, 95% CI 0.77, 0.84) and external (AUC 0.69, 95% CI 0.64, 0.74) validation sets. CONCLUSIONS: This easy-to-apply model may benefit future birth registry-based studies when there is missing maternal smoking information; however, some smoking status misclassification remains a concern when only variables from the birth certificate are used to predict maternal smoking.

Increased incidence risks of cardiovascular disease among cancer patients: Evidence from a population-based cohort study in China.

BACKGROUND: Cardiovascular disease (CVD) is becoming a major concern among cancer patients, leading to the development of a new field named cardio-oncology. However, previous studies were mainly based on the western population and focused on CVD mortality. Evidence from the Chinese population is limited. Furthermore, few studies investigated the incidence risks of CVD among cancer patients. METHODS: 85,787 eligible cancer patients were included from Hangzhou city, China. Age-standardized standard incidence ratio (SIR) was used to reflect the incidence risks of CVD among cancer patients as compared with the standard population, which was defined as all residents in Hangzhou city during the same period. RESULTS: After three years of follow-up, cancer patients showed elevated incidence risks of CVD (SIR = 1.41, 95%CI: 1.35-1.47) as compared with the standard population. The elevated risks of CVD were highest in the first year after cancer diagnosis (SIR = 1.68, 95%CI: 1.58-1.78), then followed by the second (SIR = 1.21, 95%CI: 1.11-1.31) and the third (SIR = 1.18, 95%CI: 1.07-1.29) year. These results were consistent in males and females. Furthermore, different risks of CVD were observed among different cancer sites. Patients with pancreatic cancer showed the highest risks of CVD, then followed by liver cancer, lung cancer, kidney cancer, gastric cancer, bladder cancer, prostate cancer, and colorectal cancer. CONCLUSIONS: Cancer patients have increased incidence risks of CVD, especially in the first year after cancer diagnosis. The increased risks of CVD vary by different cancer sites. Our findings highlight the importance of paying close attention to the CVD risks among cancer patients.

In situ biosynthesized polyphosphate nanoparticles/reduced graphene oxide composite electrode for highly sensitive detection of heavy metal ions.

The development of an effective sensing platform is critical for the electrochemical detection of heavy metal ions (HMIs) in water. In this study, we fabricated a newly designed sensor through the in situ assembly of reduced graphene oxide (rGO) and polyphosphate nanoparticles (polyP NPs) on a carbon cloth electrode via microorganism-mediated green biochemical processes. The characterization results revealed that the rGO produced via microbial reduction had a three-dimensional porous structure, serving as an exceptional scaffold for hosting polyP NPs, and the polyP NPs were evenly distributed on the rGO network. In terms of detecting HMIs, the numerous functional groups of polyP NPs play a major role in the coordination with the cations. This electrochemical sensor, based on polyP NPs/rGO, enabled the individual and simultaneous determination of lead ion (Pb2+) and copper ion (Cu2+) with detection limits of 1.6 nM and 0.9 nM, respectively. Additionally, the electrode exhibited outstanding selectivity for the target analytes in the presence of multiple interfering metal ions. The fabricated sensor was successfully used to determine Pb2+/Cu2+ in water samples with satisfactory recovery rates ranging from 92.16% to 104.89%. This study establishes a facile, cost-effective, and environmentally friendly microbial approach for the synthesis of electrode materials and the detection of environmental pollutants.

The neonatal blood spot metabolome in retinoblastoma.

Background: Retinoblastoma is rare but nevertheless the most common pediatric eye cancer that occurs in children under age 5. High-resolution metabolomics (HRM) is a powerful analytical approach to profile metabolic features and pathways or identify metabolite biomarkers. To date, no studies have used pre-diagnosis blood samples from retinoblastoma cases and compared them to healthy controls to elucidate early perturbations in tumor pathways. Objectives: Here, we report on metabolic profiles of neonatal blood comparing cases later in childhood diagnosed with retinoblastoma and controls. Methods: We employed untargeted metabolomics analysis using neonatal dried blood spots for 1327 children (474 retinoblastoma cases and 853 healthy controls) born in California from 1983 to 2011. Cases were selected from the California Cancer Registry and controls, frequency matched to cases by birth year, from California birth rolls. We performed high-resolution metabolomics to extract metabolic features, partial least squares discriminant analysis (PLS-DA) and logistic regression to identify features associated with disease, and Mummichog pathway analysis to characterize enriched biological pathways. Results: PLS-DA identified 1917 discriminative features associated with retinoblastoma and Mummichog identified 14 retinoblastoma-related enriched pathways including linoleate metabolism, pentose phosphate pathway, pyrimidine metabolism, fructose and mannose metabolism, vitamin A metabolism, as well as fatty acid and lipid metabolism. Interpretation: Our findings linked a retinoblastoma diagnosis in early life to newborn blood metabolome perturbations indicating alterations in inflammatory pathways and energy metabolism. Neonatal blood spots may provide a venue for early detection for this or potentially other childhood cancers.

J-Aggregation induced NIR-II fluorescence: an aza-BODIPY luminogen for efficient phototheranostics.

The development of organic dyes with emission peaks in the second near-infrared window (NIR-II 1000-1700 nm) is highly desirable for in vivo imaging and imaging-guided phototheranostics. However, the lack of appropriate molecular frameworks and the challenges associated with complex synthesis critically hinder the development of new candidate fluorophores. J-Aggregation is considered as a smart and straightforward way to construct such a therapeutic agent with NIR-II fluorescence imaging properties. Here, we present the design and synthesis of an aza-BODIPY probe (TA). Upon encapsulation within the amphiphilic polymer DSPEG-PEG2000-NH2, TA underwent self-assembly and formed J-aggregates (TAJ NPs), which showed emission at 1020 nm. High spatial resolution and adequate signal-to-noise ratio of the TAJ NPs are demonstrated for noninvasive bioimaging of the vasculature, lymph nodes and bones of mice in the NIR-II region. Moreover, the TAJ NPs exhibited good tumor enrichment efficiency with reduced liver accumulation and significant imaging-guided phototherapy performance against lung cancer cells. Taken together, this work not only introduces a new NIR-II imaging and phototheranostic agent based on J-aggregates, but also provides insight into the development of versatile organic dyes for future clinical implementation.

CRY1/2 regulate rhythmic CYP2A5 in mouse liver through repression of E4BP4.

CYP2A5, an enzyme responsible for metabolism of diverse drugs, displays circadian rhythms in its expression and activity. However, the underlying mechanisms are not fully established. Here we aimed to investigate a potential role of CRY1/2 (circadian clock modulators) in circadian regulation of hepatic CYP2A5. Regulatory effects of CRY1/2 on CYP2A5 were determined using Cry1-null and Cry2-null mice, and validated using AML-12, Hepa1-6 and HepG2 cells. CYP2A5 activities both in vivo and in vitro were assessed using coumarin 7-hydroxylation as a probe reaction. mRNA and protein levels were detected by qPCR and western blotting, respectively. Regulatory mechanism was studied using a combination of luciferase reporter assays, chromatin immunoprecipitation (ChIP) and co-immunoprecipitation (Co-IP). We found that ablation of Cry1 or Cry2 in mice reduced hepatic CYP2A5 expression (at both mRNA and protein levels) and blunted its diurnal rhythms. Consistently, these knockouts showed decreased CYP2A5 activity (characterised by coumarin 7-hydroxylation) and a loss of its time-dependency, as well as exacerbated coumarin-induced hepatotoxicity. Cell-based assays confirmed that CRY1/2 positively regulated CYP2A5 expression and rhythms. Based on combined luciferase reporter, ChIP and Co-IP assays, we unraveled that CRY1/2 interacted with E4BP4 protein to repress its inhibitory effect on Cyp2a5 transcription and expression. In conclusion, CRY1/2 regulate rhythmic CYP2A5 in mouse liver through repression of E4BP4. These findings advance our understanding of circadian regulation of drug metabolism and pharmacokinetics.

Polyphosphate promotes oxidation resistance of ppk-expressing transgenic rice in low phosphorus culture.

Phosphorus (P) plays a crucial role in plant growth. Insufficient availability of inorganic phosphate (Pi) can significantly impact crop yields. To address this, we previously developed transgenic rice expressing the low polyphosphate kinase gene (ppk) - known as ETRS - to enhance the efficiency of P resource utilization. Previous studies have shown that ETRS thrives and presents high yields in the low P culture. ETRS and wild-type rice (WT) were cultivated to the heading stage at 15 µM of P in the low P (LP) culture and 300 µM of P in the normal culture (CK) to identify the molecular pathways behind low P tolerance. Our findings revealed that polyphosphate (polyP) significantly enhanced the growth performance of ETRS in the LP culture. This enhanced tolerance can be attributed to polyP's capacity to mitigate oxidative damage induced by LP. This was evidenced by the reduction in levels of superoxide radicals, hydrogen peroxide, and malondialdehyde. PolyP also improved the antioxidant capacity of ETRS under LP stress by regulating enzymatic antioxidants viz., superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), as well as non-enzymatic antioxidants such as ascorbate (AsA) and glutathione (GSH). In addition, transcriptomics analysis suggested that polyP synthesis positively promoted the expressions of SOD, POD, and CAT related genes and played an active role in regulating the expression of AsA-GSH cycle system related genes in ETRS in the LP culture. These results strongly support the notion that polyP within ETRS mitigates oxidative damage through enhancement of the antioxidant system, ultimately bolstering tolerance to LP conditions.

Sensitive and discriminative detection of cysteine by a Nile red-based NIR fluorescence probe.

Cysteine (Cys) is a significant biological mercaptan that achieves key roles in several important physiological processes, such as reversible redox homeostasis in living organisms. Abnormal levels of Cys in the human body are directly related to many diseases. In this work, we constructed a sensitive sensor (Cys-NR) by connecting a Cys recognition group to a Nile red derivative. Due to photo-induced electron transfer (PET), the Cys-NR probe showed little fluorescence at 650 nm. With the addition of Cys to the assay solution, the chlorine unit of the probe was substituted by the thiol group of Cys. Further, the amino and sulfhydryl groups in cysteine underwent an intramolecular rearrangement, which led to the Cys-NR probe water solution turning from colorless to pink with an enhancement in fluorescence. The red fluorescence at 650 nm increased about 20 times. Based on the turn-on signal, a selective Cys detection method is developed. The probe signal is not affected by various potential interferences or other competing biothiols and the limit of detection (LOD) is determined to be 0.44 µM. In addition, the probe is further employed for imaging of Cys in live cells, revealing good biological imaging ability that could provide a new way of intracellular Cys detection.

PER2 integrates circadian disruption and pituitary tumorigenesis.

Rationale: The role of circadian clock in pituitary tumorigenesis remains elusive. Here we investigate whether and how circadian clock modulates the development of pituitary adenomas. Methods and Results: We found altered expression of pituitary clock genes in patients with pituitary adenomas. In particular, PER2 is prominently upregulated. Further, jetlagged mice with PER2 upregulation have accelerated growth of GH3 xenograft tumor. Conversely, loss of Per2 protects mice against developing estrogen-induced pituitary adenoma. Similar antitumor effect is observed for SR8278, a chemical that can decrease pituitary PER2 expression. RNA-seq analysis suggests involvement of cell cycle disturbance in PER2 regulation of pituitary adenoma. Subsequent in vivo and cell-based experiments validate that PER2 induces pituitary expression of Ccnb2, Cdc20 and Espl1 (three cell cycle genes) to facilitate cell cycle progression and inhibit apoptosis, thereby promoting pituitary tumorigenesis. Mechanistically, PER2 regulates the transcription of Ccnb2, Cdc20 and Espl1 through enhancing the transcriptional activity of HIF-1α. HIF-1α trans-activates Ccnb2, Cdc20 and Espl1 via direct binding to its specific response element in the gene promoters. Conclusion: PER2 integrates circadian disruption and pituitary tumorigenesis. These findings advance our understanding of crosstalk between circadian clock and pituitary adenomas and highlight the relevance of clock-based approaches in disease management.

Metabolite Stability in Archived Neonatal Dried Blood Spots Used for Epidemiologic Research.

Epidemiologic studies of low-frequency exposures or outcomes using metabolomics analyses of neonatal dried blood spots (DBS) often require assembly of samples with substantial differences in duration of storage. Independent assessment of stability of metabolites in archived DBS will enable improved design and interpretation of epidemiologic research utilizing DBS. Neonatal DBS routinely collected and stored as part of the California Genetic Disease Screening Program between 1983 and 2011 were used. The study population included 899 children without cancer before age 6 years, born in California. High-resolution metabolomics with liquid-chromatography mass spectrometry was performed, and the relative ion intensities of common metabolites and selected xenobiotic metabolites of nicotine (cotinine and hydroxycotinine) were evaluated. In total, we detected 26,235 mass spectral features across 2 separate chromatography methods (C18 hydrophobic reversed-phase chromatography and hydrophilic-interaction liquid chromatography). For most of the 39 metabolites related to nutrition and health status, we found no statistically significant annual trends across the years of storage. Nicotine metabolites were captured in the DBS with relatively stable intensities. This study supports the usefulness of DBS stored long-term for epidemiologic studies of the metabolome. -Omics-based information gained from DBS may also provide a valuable tool for assessing prenatal environmental exposures in child health research.

Maternal migraine and risk of pediatric cancers.

BACKGROUND: Maternal migraine has been linked to adverse birth outcomes including low birth weight and preterm birth, as well as congenital anomalies in offspring. It has been speculated that this may be due to the use of medications in pregnancy, but lifestyle, genetic, hormonal, and neurochemical factors could also play a role. There is evidence for varying cancer incidences among adults with migraine. Here, we utilized data from national registries in Denmark to examine associations between maternal diagnoses of migraine and risk for cancer in offspring. METHODS: We linked several national registries in Denmark to identify cases from the Cancer Registry among children less than 20 years (diagnoses 1996-2016) and controls from the Central Population Register, matched to cases by birth year and sex (25:1 matching rate). Migraine diagnoses were identified from the National Patient Register using International Classification of Diseases, versions 8 and 10 codes and migraine-specific acute or prophylactic treatment recorded in the National Pharmaceutical Register. We used logistic regression to estimate the risk of childhood cancers associated with maternal migraine. RESULTS: Maternal migraine was positively associated with risk for non-Hodgkin lymphoma (odds ratio [OR] = 1.70, 95% confidence interval [CI]: 1.01-2.86), central nervous system tumors ([OR = 1.31, 95% CI: 1.02-1.68], particularly glioma [OR = 1.64, 95% CI: 1.12-2.40]), neuroblastoma (OR = 1.75, 95% CI: 1.00-3.08), and osteosarcoma (OR = 2.60, 95% CI: 1.18-5.76). CONCLUSIONS: Associations with maternal migraine were observed for several childhood cancers, including neuronal tumors. Our findings raise questions about the role of lifestyle factors, sex hormones, genetic, and neurochemical factors in the relationship between migraine and childhood cancers.

Genomic mapping of metastatic organotropism in lung adenocarcinoma.

We analyzed 2,532 lung adenocarcinomas (LUAD) to identify the clinicopathological and genomic features associated with metastasis, metastatic burden, organotropism, and metastasis-free survival. Patients who develop metastasis are younger and male, with primary tumors enriched in micropapillary or solid histological subtypes and with a higher mutational burden, chromosomal instability, and fraction of genome doublings. Inactivation of TP53, SMARCA4, and CDKN2A are correlated with a site-specific shorter time to metastasis. The APOBEC mutational signature is more prevalent among metastases, particularly liver lesions. Analyses of matched specimens show that oncogenic and actionable alterations are frequently shared between primary tumors and metastases, whereas copy number alterations of unknown significance are more often private to metastases. Only 4% of metastases harbor therapeutically actionable alterations undetected in their matched primaries. Key clinicopathological and genomic alterations in our cohort were externally validated. In summary, our analysis highlights the complexity of clinicopathological features and tumor genomics in LUAD organotropism.

Radiogenomics study to predict the nuclear grade of renal clear cell carcinoma.

Purpose: To develop models based on radiomics and genomics for predicting the histopathologic nuclear grade with localized clear cell renal cell carcinoma (ccRCC) and to assess whether macro-radiomics models can predict the microscopic pathological changes. Method: In this multi-institutional retrospective study, a computerized tomography (CT) radiomic model for nuclear grade prediction was developed. Utilizing a genomics analysis cohort, nuclear grade-associated gene modules were identified, and a gene model was constructed based on top 30 hub mRNA to predict the nuclear grade. Using a radiogenomic development cohort, biological pathways were enriched by hub genes and a radiogenomic map was created. Results: The four-features-based SVM model predicted nuclear grade with an area under the curve (AUC) score of 0.94 in validation sets, while a five-gene-based model predicted nuclear grade with an AUC of 0.73 in the genomics analysis cohort. A total of five gene modules were identified to be associated with the nuclear grade. Radiomic features were only associated with 271 out of 603 genes in five gene modules and eight top 30 hub genes. Differences existed in the enrichment pathway between associated and un-associated with radiomic features, which were associated with two genes of five-gene signatures in the mRNA model. Conclusion: The CT radiomics models exhibited higher predictive performance than mRNA models. The association between radiomic features and mRNA related to nuclear grade is not universal.