Genetic susceptibility to breast cancer increases the risk of neutropenia and agranulocytosis: insights from Mendelian randomization.

PURPOSE: The causal relationship between breast cancer and its estrogen receptor (ER) subtypes and neutropenia and agranulocytosis is unclear. METHODS: In two-sample Mendelian randomization (MR), we used inverse variance weighting (IVW), Bayesian weighted MR (BWMR), MR-Egger, weighted median, simple mode, and weighted mode methods to analyze causality for ER-positive breast cancer, ER-negative breast cancer, overall breast cancer, and drug-induced neutropenia and agranulocytosis. To validate the results, we performed the analysis again using GWAS data on neutropenia from different databases. In multivariable MR (MVMR), we assessed the independent effects of ER-positive and ER-negative breast cancer on causality. RESULTS: Two-sample MR analysis showed a causal relationship between ER-positive breast cancer (IVW odds ratio (OR) = 1.319, P = 7.580 × 10-10), ER-negative breast cancer (OR = 1.285, P = 1.263 × 10-4), overall breast cancer (OR = 1.418, P = 2.123 × 10-13), and drug-induced neutropenia and a causal relationship between ER-positive breast cancer (OR = 1.349, P = 1.402 × 10-7), ER-negative breast cancer (OR = 1.235, P = 7.615 × 10-3), overall breast cancer (OR = 1.429, P = 9.111 × 10-10), and neutropenia. Similarly, ER-positive breast cancer (OR = 1.213, P = 5.350 × 10-8), ER-negative breast cancer (OR = 1.179, P = 1.300 × 10-3), and overall breast cancer (OR = 1.275, P = 8.642 × 10-11) also had a causal relationship with agranulocytosis. MVMR analysis showed that ER-positive breast cancer remained causally associated with drug-induced neutropenia (OR = 1.233, P = 4.188 × 10-4), neutropenia (OR = 1.283, P = 6.363 × 10-4), and agranulocytosis (OR = 1.142, P = 4.549 × 10-3). Heterogeneity analysis and pleiotropy test showed that our results were reliable. CONCLUSION: Our study provides genetic evidence for a causal association between breast cancer and its estrogen receptor subtypes and neutropenia. In clinical practice, in addition to focusing on therapeutic factors, additional attention should be given to breast cancer patients to avoid severe neutropenia.

Association between body roundness index (BRI) and gallstones: results of the 2017-2020 national health and nutrition examination survey (NHANES).

BACKGROUND: Gallstones are associated with obesity, and the BRI is a new obesity index that more accurately reflects body fat and visceral fat levels. The relationship between BRI and gallstone risk is currently unknown, and we aimed to explore the relationship between BRI and gallstone prevalence. METHODS: A cross-sectional study was conducted utilizing data from the 2017-2020 NHANES involving a total of 5297 participants. To assess the association between BRI and gallstones, we used logistic regression analysis, subgroup analysis, and interaction terms. In addition, we performed restricted cubic spline (RCS) analysis and threshold effects analysis to characterize nonlinear relationships. We assessed the ability of BRI and Body mass index (BMI) to identify gallstones using receiver operating curve (ROC) analysis and area under the curve (AUC), and compared them using the Delong test. RESULTS: Of the 5297 participants aged 20 years and older included in the study, 575 had gallstones. In fully adjusted models, a positive association between BRI and gallstone prevalence was observed (OR = 1.16, 95% CI: 1.12-1.20, P < 0.0001). Individuals in the highest quartile of BRI had a 204% increased risk of gallstones compared with those in the lowest quartile (OR = 3.04, 95% CI: 2.19-4.22, P < 0.0001). The correlation between BRI and gallstones persisted in subgroup analyses. RCS analyses showed a nonlinear relationship between BRI and gallstones. The inflection point was further found to be 3.96, and the correlation between BRI and gallstones was found both before and after the inflection point. ROC analysis showed that BRI (AUC = 0.667) was a stronger predictor of gallstones than BMI (AUC = 0.634). CONCLUSIONS: Elevated BRI is associated with an increased risk of gallstones in the U.S. population, and BRI is a stronger predictor of gallstones than BMI. Maintaining an appropriate BRI is recommended to reduce the incidence of gallstones.

Assessment of Key Factors Impacting Variability in AAV Vector Genome Titration by Digital PCR.

Recombinant adeno-associated virus (rAAV) has emerged as a prominent vector for in vivo gene therapy, owing to its distinct advantages. Accurate determination of the rAAV genome titer is crucial for ensuring the safe and effective administration of clinical doses. The evolution of the rAAV genome titer assay from quantitative PCR (qPCR) to digital PCR (dPCR) has enhanced accuracy and precision, yet practical challenges persist. This study systematically investigated the impact of various operational factors on genome titration in a single-factor manner, aiming to address potential sources of variability in the quantitative determination process. Our findings revealed that a pretreatment procedure without genome extraction exhibits superior precision compared with titration with genome extraction. Additionally, notable variations in titration results across different brands of dPCR instruments were documented, with relative standard deviation (RSD) reaching 23.47% for AAV5 and 11.57% for AAV8. Notably, optimal operations about DNase I digestion were identified; we thought treatment time exceeding 30 min was necessary, and there was no need for thermal inactivation after digestion. And we highlighted that thermal capsid disruption before serial dilution substantially affected AAV genome titers, causing a greater than ten-fold decrease. Conversely, this study found that additive components of dilution buffer are not significant contributors to titration variations. Furthermore, we found that repeated freeze-thaw cycles significantly compromised AAV genome titers. In conclusion, a comprehensive dPCR titration protocol, incorporating insights from these impact factors, was proposed and successfully tested across multiple serotypes of AAV. The results demonstrate acceptable variations, with the RSD consistently below 5.00% for all tested AAV samples. This study provides valuable insights to reduce variability and improve the reproducibility of AAV genome titration using dPCR.

Body mass index and risk of inflammatory breast disease: a Mendelianrandomization study / Índice de masa corporal y riesgo de mastitis: un estudio de aleatorización mendeliana

Introduction: in previous studies, obesity was identified as a risk factor for inflammatory breast disease, but its causality is uncertain. In thepresent study, we performed a two-sample Mendelian randomization (TSMR) analysis to investigate the causal relationship between obesity andinflammatory breast disease.Methods: we use body mass index (BMI) as a measure of obesity. Data for single nucleotide polymorphisms (SNPs) associated with BMI wereobtained from UK Biobank. Data for single nucleotide polymorphisms (SNPs) associated with mastitis were obtained from FinnGen Biobank. We usedseveral MR analysis methods, such as inverse-variance weighting (IVW), MR-Egger, weighted median, simple mode and weighted mode to makeour results more convincing. We also performed MR-PRESSO test, MR-Egger test, heterogeneity test, pleiotropy test and leave-one-out analysisto make our analysis results more robust and credible. We used odds ratio (OR) to evaluate the causal relationship between BMI and mastitis.Results: based on the IVW random effects model, we found that a one-standard deviation (SD) increase in BMI increased the risk of mastitis by62.1 % (OR = 1.621, 95 % CI: 1.262-2.083, p = 1.59E-4), which is almost consistent with the results of several other methods.Conclusions: in European individuals, an increase in the number of BMI increases the risk of inflammatory breast disease. People with high BMIneed to control their weight to reduce the incidence of inflammatory breast disease.(AU)

Introducción: en estudios previos, la obesidad se identificó como un factor de riesgo para la enfermedad inflamatoria de mama, pero su cau-salidad es incierta. En el presente estudio, se realizó un análisis de aleatorización mendeliana de dos muestras (TSMR) para investigar la relacióncausal entre la obesidad y la enfermedad inflamatoria de mama.Métodos: se empleó el índice de masa corporal (IMC) como medida de obesidad. Los datos de los polimorfismos de nucleótido único (SNP)asociados con el IMC se obtuvieron del Biobank de Reino Unido y los datos de los polimorfismos de nucleótido único (SNP) asociados con lamastitis se obtuvieron de FinnGen Biobank. Se utilizaron varios métodos de análisis de RM, como la ponderación inversa de la varianza (IVW),RM-Egger, mediana ponderada, modo simple y modo ponderado para que nuestros resultados fueran más convincentes. También se realizaronla prueba MR-PRESSO, la prueba MR-Egger, la prueba de heterogeneidad, el test de pleiotropía y la validación dejando uno fuera (en inglés,leave-one-out) para que los resultados de nuestro análisis fueran más sólidos y creíbles. Se utilizó la odds ratio (OR) para evaluar la relacióncausal entre el IMC y la mastitis.Resultados: basándonos en el modelo de efectos aleatorios IVW, se halló que un aumento de una desviación estándar (DE) en el IMC aumentabael riesgo de mastitis en un 62,1 % (OR = 1,621, IC 95 %: 1,262-2,083, p = 1,59E-4), que es casi consistente con los resultados de otrosdiversos métodos.Conclusiones: en los individuos europeos, un aumento del número de IMC aumenta el riesgo de enfermedad inflamatoria mamaria. Las personascon un IMC elevado deben controlar su peso para reducir la incidencia de enfermedad inflamatoria de la mama.(AU)

Alterations in the gut microbiota of toddlers with cow milk protein allergy treated with a partially hydrolyzed formula containing synbiotics: A nonrandomized controlled interventional study.

Formulas containing intact cow milk protein are appropriate alternatives when human milk (HM) is not feasible. However, for babies with a physician-diagnosed cow milk protein allergy (CMPA), hydrolyzed formulas are needed. We conducted a 3-month, open-label, nonrandomized concurrent controlled trial (ChiCTR2100046909) between June 2021 and October 2022 in Qingdao City, China. In this study, CMPA toddlers were fed with a partially hydrolyzed formula containing synbiotics (pHF, n = 43) and compared with healthy toddlers fed a regular intact protein formula (IF, n = 45) or HM (n = 21). The primary endpoint was weight gain; the secondary endpoints were changes in body length and head circumference of both CMPA and healthy toddlers after 3-month feeding; and the exploratory outcomes were changes in gut microbiota composition. After 3 months, there were no significant group differences for length-for-age, weight-for-age, or head circumference-for-age Z scores. In the gut microbiota, pHF feeding increased its richness and diversity, similar to those of IF-fed and HM-fed healthy toddlers. Compared with healthy toddlers, the toddlers with CMPA showed an increased abundance of phylum Bacteroidota, Firmicutes, class Clostridia, and Bacteroidia, and a decreased abundance of class Negativicutes, while pHF feeding partly eliminated these original differences. Moreover, pHF feeding increased the abundance of short-chain fatty acid producers. Our data suggested that this pHF partly simulated the beneficial effects of HM and shifted the gut microbiota of toddlers with CMPA toward that of healthy individuals. In conclusion, this synbiotic-containing pHF might be an appropriate alternative for toddlers with CMPA.

Microbial defluorination of TFA, PFOA, and HFPO-DA by a native microbial consortium under anoxic conditions.

In this study, the biodegradability of trifluoroacetate (TFA), perfluorooctanoic acid (PFOA), and perfluoro-2-methyl-3-oxahexanoic acid (HFPO-DA) by a native microbial community was evaluated over a 10-month incubation period. The observed microbial defluorination ratios and removal efficiency were 3.46 ( ± 2.73) % and 8.03 ( ± 3.03) %, 8.44 ( ± 1.88) % and 13.52 ( ± 4.96) %, 3.02 ( ± 0.62) % and 5.45 ( ± 2.99) % for TFA, PFOA and HFPO-DA, respectively. The biodegradation intermediate products, TFA and pentafluoropropionic acid (PFA), of PFOA and HFPO-DA were detected in their biodegradation treatment groups. Furthermore, the concentrations of the PFOA metabolites, perfluorohexanoic acid (PFHxA) and perfluoroheptanoic acid (PFHpA), in the aqueous solutions after incubation were quantified to be 0.21 and 4.14 µg/L. TFA, PFOA and HFPO-DA significantly reduced the microbial diversity and changed the structure of the community. The co-occurrence network analysis showed that low abundance species, such as Flexilinea flocculi, Bacteriovorax stolpii, and g_Sphingomonas, are positively correlated with the generation of fluoride ion, implying their potential collaborative functions contributing to the observed biodefluorination. The findings in this study can provide insights for the biodegradation of perfluoroalkyl carboxylic acids and their emerging alternatives by indigenous microorganisms in the environment.

Effect of radiation therapy on patients with stage T3 or T4 malignant phyllodes tumors: a retrospective observational study based on SEER.

PURPOSE: Among all primary breast tumors, malignant phyllodes tumor of the breast (MPTB) make up less than 1%. In the treatment of phyllode tumors, surgical procedures such as mastectomy and breast-conserving surgery are the mainstay. MPTB has, however, been controversial when it comes to treating it with RT. We aimed to explore the prognostic impact of RT and other clinicopathologic factors on long-term survival for patients with stage T3 or T4 malignant phyllodes tumors. METHODS: We select patients with stage T3 or T4 MPTB who qualified for the criteria between 2000 and 2018 via the Surveillance, Epidemiology, and End Results (SEER) database. We performed 1:1 propensity score matching (PSM) and Kaplan-Meier analysis to explore the role of RT in long-term survival of patients with stage T3 or T4 MPTB. A univariate and multivariate analysis of breast cancer-specific survival (BCSS) and overall survival (OS) risk factors was carried out using a Cox proportional hazards model. In addition, the nomogram graph of OS and BCSS was constructed. RESULTS: A total of 583 patients with stage T3 or T4 malignant phyllodes tumors were included in this study, of whom 154 (26.4%) received RT, and 429 (73.6%) were treated without RT. Before adjustment, between groups with and without RT, BCSS (p = 0.1) and OS (p = 0.212) indicated no significant difference respectively. Using of PSM, the two groups still did not differ significantly in BCSS (p = 0.552) and OS (p = 0.172). In multivariate analysis, age (p < 0.001), surgery of primary site (p < 0.001) and distant metastatic status (p < 0.001) were related to prognosis, while RT still did not affect BCSS (p = 0.877) and OS (p = 0.554). CONCLUSION: Based on the SEER database analysis, the study suggests that the patients with stage T3 or T4 MPTB treated with RT after surgery didn't have significant differences in BCSS or OS compared to those not treated with RT.