Fetal bisphenol and phthalate exposure and early childhood growth in a New York City birth cohort.

BACKGROUND: Exposure to endocrine-disrupting chemicals such as bisphenols and phthalates during pregnancy may disrupt fetal developmental programming and influence early-life growth. We hypothesized that prenatal bisphenol and phthalate exposure was associated with alterations in adiposity through 4 years. This associations might change over time. METHODS: Among 1091 mother-child pairs in a New York City birth cohort study, we measured maternal urinary concentrations of bisphenols and phthalates at three time points in pregnancy and child weight, height, and triceps and subscapular skinfold thickness at ages 1, 2, 3, and 4 years. We used linear mixed models to assess associations of prenatal individual and grouped bisphenols and phthalates with overall and time-point-specific adiposity outcomes from birth to 4 years. RESULTS: We observed associations of higher maternal urinary second trimester total bisphenol and bisphenol A concentrations in pregnancy and overall child weight between birth and 4 years only (Beta 0.10 (95 % confidence interval 0.04, 0.16) and 0.07 (0.02, 0.12) standard deviation score (SDS) change in weight per natural log increase in exposure), We reported an interaction of the exposures with time, and analysis showed associations of higher pregnancy-averaged mono-(2-carboxymethyl) phthalate with higher child weight at 3 years (0.14 (0.06, 0.22)), and of higher high-molecular-weight phthalate, di-2-ethylhexyl phthalate, mono-(2-ethyl-5-carboxypentyl) phthalate, mono-(2-carboxymethyl) phthalate, and mono-(2-ethylhexyl) phthalate with higher child weight at 4 years (0.16 (0.04, 0.28), 0.15 (0.03, 0.27), 0.19 (0.07, 0.31), 0.16 (0.07, 0.24), 0.11 (0.03, 0.19)). Higher pregnancy-averaged high-molecular-weight phthalate, di-2-ethylhexyl phthalate, mono-(2-ethyl-5-carboxypentyl) phthalate, mono-(2-ethyl-5-hydroxyhexyl) phthalate, and mono-2(ethyl-5-oxohexyl) phthalate concentrations were associated with higher child BMI at 4 years (0.20 (0.05, 0.35), 0.20 (0.05, 0.35), 0.22 (0.06, 0.37), 0.20 (0.05, 0.34), 0.20 (0.05, 0.34)). For skinfold thicknesses, we observed no associations. DISCUSSION: This study contributes to the evidence suggesting associations of prenatal exposure to bisphenols and high-molecular-weight phthalates on childhood weight and BMI.

Prostate cancer-associated transcript 6 (PCAT6) promotes epithelial-mesenchymal transition and stemness and worsens prognosis in patients with colorectal cancer.

Approximately 20% of colorectal cancer (CRC) patients are first diagnosed with metastatic colorectal cancer (mCRC) because they develop symptoms at an advanced stage. Despite advancements in treatment, patients with metastatic disease still experience inferior survival rates. Our objective is to investigate the association between long noncoding RNAs (lncRNAs) and prognosis and to explore their role in mCRC. In this study, we find that elevated expression of PCAT6 is independently linked to unfavourable survival outcomes in The Cancer Genome Atlas (TCGA) data, and this finding is further confirmed in CRC samples obtained from Fudan University Shanghai Cancer Center. Cell lines and xenograft mouse models are used to examine the impact of PCAT6 on tumor metastasis. Knockdown of PCAT6 is observed to impede the metastatic phenotype of CRC, as evidenced by functional assays, demonstrating the suppression of epithelial-mesenchymal transition (EMT) and stemness. Our findings show the significance of PCAT6 in mCRC and its potential use as a prognostic biomarker.

Partial-linear single-index transformation models with censored data.

In studies with time-to-event outcomes, multiple, inter-correlated, and time-varying covariates are commonly observed. It is of great interest to model their joint effects by allowing a flexible functional form and to delineate their relative contributions to survival risk. A class of semiparametric transformation (ST) models offers flexible specifications of the intensity function and can be a general framework to accommodate nonlinear covariate effects. In this paper, we propose a partial-linear single-index (PLSI) transformation model that reduces the dimensionality of multiple covariates into a single index and provides interpretable estimates of the covariate effects. We develop an iterative algorithm using the regression spline technique to model the nonparametric single-index function for possibly nonlinear joint effects, followed by nonparametric maximum likelihood estimation. We also propose a nonparametric testing procedure to formally examine the linearity of covariate effects. We conduct Monte Carlo simulation studies to compare the PLSI transformation model with the standard ST model and apply it to NYU Langone Health de-identified electronic health record data on COVID-19 hospitalized patients' mortality and a Veteran's Administration lung cancer trial.

Immediate effect of kinesiology taping on muscle strength, static balance and proprioception after eccentric muscle fatigue on ankle: a randomized cross-over trial.

BACKGROUND: Kinesiology Taping(KT) is commonly used as a physical therapy to prevent exercise-induced fatigue. This study aims to evaluate the immediate effects of KT on muscle strength, static balance, and proprioception after eccentric muscle fatigue on ankle. METHODS: Twenty healthy male university students were recruited. The experimental protocol was structured into four sessions, each separated by a one-week washout period to prevent carryover effects. Participants were randomly allocated to one of four intervention conditions in each session, ensuring no participant received the same intervention twice. These conditions were: no taping(NT),sham taping(ST),athletic taping(AT),and kinesiology taping(KT).Taping was applied immediately following an eccentric muscle fatigue protocol targeting the ankle, and assessments were conducted in the order of proprioception, muscle strength and static balance. Isometric muscle strength and proprioception were evaluated using the Biodex isokinetic system. Static balance was measured using the TecnoBody balance platform. RESULTS: KT had a significantly higher plantarflexion/dorsiflexion peak torque, dorsiflexion average peak torque, and plantarflexion/dorsiflexion average power at 60°/s compared with NT and ST in terms of isometric muscle strength (p < 0.05).Furthermore, the plantarflexion peak torque of KT was significantly greater than AT at 60°/s[p = 0.005,95% confidence interval(CI) = 3.39 to 18.20] and 180°/s[p = 0.006,95%CI(2.62,21.98)]. In terms of proprioception, KT showed a lower absolute error in 25° plantarflexion and 10° dorsiflexion compared to NT, ST and AT. For static balance with eyes-open and eyes-closed conditions, AT and KT had a lower total sway area than NT and ST (p < 0.05). Additionally, a significant difference in total sway length with eyes-open condition was observed between AT and KT[p < 0.001,95%CI(-431.81,-168.25)];total sway area and the center of pressure(COP) velocity in the mediolateral(ML) and anteroposterior(AP) directions with eyes-closed condition were significantly lower in AT compared to KT. CONCLUSION: This study suggests that KT is more effective than other taping conditions in improving muscle strength and proprioception after eccentric muscle fatigue on ankle. However, AT is more helpful in increasing static postural control ability after ankle muscle fatigue than KT. TRIAL REGISTRATION: This study was registered with www.chictr.org.cn (registration number: ChiCTR2300068278) on 13/2/2023.

ScRNA-seq of gastric cancer tissues reveals differences in the immune microenvironment of primary tumors and metastases.

Gastric carcinoma (GC) is regarded as one of the deadliest cancer characterized by diversity and haste metastasis and suffers limited understanding of the spatial variation between primary and metastatic GC tumors. In this project, transcriptome analysis on 46 primary tumorous, adjacent non-tumorous, and metastatic GC tissues was performed. The results demonstrated that metastatic tumorous tissues had diminished CD8+ T cells compared to primary tumors, which is mechanistically attributed to being due to innate immunity differences represented by marked differences in macrophages between metastatic and primary tumors, particularly those expressing ApoE, where their abundance is linked to unfavorable prognoses. Examining variations in gene expression and interactions indicated possible strategies of immune evasion hindering the growth of CD8+ T cells in metastatic tumor tissues. More insights could be gained into the immune evasion mechanisms by portraying information about the GC ecosystem.

Organic Pollutant Exposure and CKD: A Chronic Renal Insufficiency Cohort Pilot Study.

Rationale & Objective: This study aimed to assess the effect of exposure to organic pollutants in adults with chronic kidney disease (CKD). Study Design: This was a cross-sectional and longitudinal analysis. Setting and Participants: Forty adults enrolled in the Chronic Renal Insufficiency Cohort (CRIC). Exposures: Exposure at baseline and longitudinally to various organic chemical pollutants. Outcomes: The outcomes were as follows: death; composite of congestive heart failure, myocardial infarction, and stroke; event-free survival from kidney failure or ≥50% decline in estimated glomerular filtration rate (eGFR); and longitudinal trajectory of eGFR. Analytical Approach: We used high-performance liquid chromatography with tandem mass spectrometry to measure urinary concentrations of bisphenols, phthalates, organophosphate pesticides, polycyclic aromatic hydrocarbons, melamine, and cyanuric acid at years 1, 3, and 5 after enrollment in the CRIC. Univariate and multivariable logistic regression were used to examine the association of individual compounds and classes of pollutants with the outcomes. The Cox proportional hazards model and Kaplan-Meier method were used to calculate hazard ratios and 95% CIs for each class of pollutants. Results: Median baseline eGFR and urinary protein-to-creatinine ratio were 33 mL/min/1.73 m2 and 0.58 mg/g, respectively. Of 52 compounds assayed, 30 were detectable in ≥50% of participants. Urinary chemical concentrations were comparable in patients with CKD and healthy individuals from contemporaneous National Health and Nutrition Examination Survey cohorts. Phthalates were the only class with a trend toward higher exposure in patients with CKD. There was an inverse relationship between exposure and the eGFR slopes for bisphenol F, mono-(3-carboxypropyl) phthalate, mono-benzyl phthalate, mono-[2-(carboxymethyl)hexyl] phthalate, and melamine. There were no associations between organic pollutant exposure and cardiovascular outcomes. Limitations: Small sample size, evaluation of single rather than combined exposures. Conclusions: Simultaneous measurement of multiple organic pollutants in adults with CKD is feasible. Exposure levels are comparable with healthy individuals. Select contaminants, especially in the phthalate class, may be associated with more rapid deterioration in kidney function.

The effect of exposure to organic pollutants has not been studied in adults with chronic kidney disease. (CKD). To fill this gap, we measured the exposure to a wide range of chemicals that are found in plastics, personal care products, and food preparation. Overall, the exposure was similar to that noted in the healthy population living in the United States. Only select compounds, mainly phthalates, demonstrated a trend with a more rapid decline in kidney function. These findings provide a useful reference for future studies that aim to evaluate organic pollutant exposure in patients with CKD. This is significant because these exposures represent a modifiable risk factor for disease progression through alterations in diet or lifestyle.

Sulfarotene Inhibits Colorectal Cancer via Mitigating Natural-Killer-Cell-Induced Stemness.

Tumor cell stemness stands out as a pivotal factor driving tumor recurrence or metastasis and significantly contributes to the mortality of patients with colorectal cancer (CRC). Recent research has unveiled a link between immune-active cells and the induction of tumor cell stemness, ultimately leading to heightened resistance to treatment. In this study, stemness in CRC cell lines was assessed after co-culture with natural killer (NK) cells, both with and without sulfarotene administration. Furthermore, a CRC xenograft model was utilized to scrutinize the in vivo efficacy of sulfarotene in overcoming stemness induced by NK cell activation. As a result, CRC cells exhibited significant stemness after NK cell co-culture, as evidenced by the upregulation of several stemness markers associated with cancer stem cells. Moreover, these cells demonstrated remarkable resistance to commonly used chemotherapy agents for CRC, such as oxaliplatin and irinotecan. Importantly, sulfarotene effectively reversed the altered stemness of CRC cells in both in vitro and in vivo assays. In conclusion, sulfarotene emerges as a promising therapeutic strategy for overcoming colorectal cancer resistance to NK cells by effectively inhibiting stemness remodeling. This study underscores the potential of sulfarotene in augmenting NK-cell-mediated immune surveillance, proposing a novel immunotherapeutic approach against colorectal cancer.

An updated meta-analysis of effectiveness and safety of mTOR inhibitors in the management of tuberous sclerosis complex patients.

PURPOSE: Tuberculous sclerosis complex (TSC) is an autosomal dominant multi-system disease. In TSC patients, the inhibition of mTOR pathway is weakened, which leads to the uncontrolled proliferation of normal resting cells. Therefore, mTOR inhibitors have many therapeutic potentials in the treatment of TSC. However, there is no consensus on the safety and efficacy of mTOR inhibitors so far. This article aimed to present new evidence for the efficacy and safety of mTOR inhibitors in the treatment of TSC by evaluating published clinical trials. METHODS: A systemic search of online databases, such as Cochrane Library, Embase, PubMed, and the US National Institutes of Health Clinical Trials Registry, was conducted. The researchers selected studies that met the following entry criteria: randomized, double-blinded or single-blinded, placebo-controlled, parallel-group studies with active and control arms receiving rapamycin or everolimus and matched placebo, respectively. The meta-analysis included seven studies. Tumor response or epilepsy seizure frequency response rates were considered efficacy outcomes. RESULTS: In seven studies involving 877 patients, using of mTOR inhibitors therapy showed an improvement in both tumor response and seizure frequency outcomes in TSC. In combination of AML (angiomyolipomas), SEGA (subependymal giant cell astrocytoma), epilepsy, and facial angiofibroma subjects, the RR is 3.01 (95% CI 2.03 to 4.45, p = 0.000) with observed heterogeneity (I-squared = 55.4%). The main side effect of mTOR inhibitors was stomatitis. CONCLUSION: The updated meta-analysis suggests that the use of mTOR inhibitors is an effective therapy for patients with TSC.

Gestational exposure to bisphenol AF causes endocrine disorder of corpus luteum by altering ovarian SIRT-1/Nrf2/NF-kB expressions and macrophage proangiogenic function in mice.

Bisphenol AF (BPAF) is extensively used in industrial production as an emerging substitute for the earlier-used bisphenol A (BPA). Studies have found that BPAF had stronger estrogenic activities than BPA. However, the effects of BPAF on the luteal function of pregnancy and its possible mechanisms are largely unknown. In this study, pregnant mice were orally administered 3.0 and 30 mg/kg/day of BPAF from gestational day (GD) 1 to 8, and samples were collected on GD 8 and GD 19. Results showed that maternal exposure to BPAF impaired embryo implantation and reduced ovarian weight, and interfered with steroid hormone secretion, and decreased the numbers and areas of corpus luteum. BPAF treatment significantly down-regulated expression levels of ovarian Star, Cyp11a, Hsd3b1, and Cyp19a1 mRNA and CYP19a1 and ERα proteins. BPAF also disrupted markers of redox/inflammation key, including silent information regulator of transcript-1 (SIRT-1), nuclear factor erythroid 2-related factor 2 (Nrf2), and nuclear factor kappa-B (NF-ĸB) expressions along with reduced ovarian antioxidant (CAT and SOD) capacity, enhanced oxidant (H2O2 and MDA) and inflammatory factor (Il6 and Tnfa) activities. Furthermore, BPAF exposure inhibited macrophages with a pro-angiogenic phenotype that specifically expressed TIE-2, accompanied by inhibition of angiogenic factors (HIF1a, VEGFA, and Angpt1) and promotion of anti-angiogenic factor Ang-2 to suppress luteal angiogenesis. In addition, BPAF administration also induced luteolysis and apoptosis by up-regulation of COX-2, BAX/BCL-2, and Cleaved-Caspase-3 protein. Collectively, our current data demonstrated that gestational exposure to BPAF caused luteal endocrine disorder by altering ovarian SIRT-1/Nrf2/NF-kB expressions and macrophage proangiogenic function in mice.

Noninvasive, MultiOmic, and Multicompartmental Biomarkers of Reflux Disease: A Systematic Review.

BACKGROUND AND AIMS: Gastroesophageal reflux disease (GERD) is a prevalent gastrointestinal disorder that may complicate conditions such as obstructive airway disease. Our group has identified predictive biomarkers of GERD in particulate exposed first responders with obstructive airway disease. In addition, GERD diagnosis and treatment is costly and invasive. In light of these clinical concerns, we aimed to systematically review studies identifying noninvasive, multiOmic, and multicompartmental biomarkers of GERD. METHODS: A systematic review of PubMed and Embase was performed using keywords focusing on reflux disease and biomarkers and registered with PROSPERO. We included original human studies in English, articles focusing on noninvasive biomarkers of GERD published after December 31, 2009. GERD subtypes (non-erosive reflux disease and erosive esophagitis) and related conditions (Barrett's Esophagus [BE] and Esophageal Adenocarcinoma). Predictive measures were synthesized and risk of bias assessed (Newcastle-Ottawa Scale). RESULTS: Initial search identified n = 238 studies andn 13 articles remained after applying inclusion/exclusion criteria. Salivary pepsin was the most studied biomarker with significant sensitivity and specificity for GERD. Serum assessment showed elevated levels of Tumor Necrosis Factor-alpha in both GERD and Barrett's. Exhaled breath volatile sulfur compounds and acetic acid were associated with GERD. Oral Microbiome: Models with Lautropia, Streptococcus, and Bacteroidetes showed the greatest discrimination between BE and controls vs Lautropia; ROCAUC 0.94 (95% confidence interval; 0.85-1.00). CONCLUSION: Prior studies identified significant multiOmic, multicompartmental noninvasive biomarker risks for GERD and BE. However, studies have a high risk of bias and the reliability and accuracy of the biomarkers identified are greatly limited, which further highlights the need to discover and validate clinically relevant noninvasive biomarkers of GERD.

Long-Term Exposure to Walkable Residential Neighborhoods and Risk of Obesity-Related Cancer in the New York University Women's Health Study (NYUWHS).

BACKGROUND: Living in neighborhoods with higher levels of walkability has been associated with a reduced risk of obesity and higher levels of physical activity. Obesity has been linked to increased risk of 13 cancers in women. However, long-term prospective studies of neighborhood walkability and risk for obesity-related cancer are scarce. OBJECTIVES: We evaluated the association between long-term average neighborhood walkability and obesity-related cancer risk in women. METHODS: The New York University Women's Health Study (NYUWHS) is a prospective cohort with 14,274 women recruited between 1985 and 1991 in New York City and followed over nearly three decades. We geocoded residential addresses for each participant throughout follow-up and calculated an average annual measure of neighborhood walkability across years of follow-up using data on population density and accessibility to destinations associated with geocoded residential addresses. We used ICD-9 codes to characterize first primary obesity-related cancers and employed Cox proportional hazards models to assess the association between average neighborhood walkability and risk of overall and site-specific obesity-related cancers. RESULTS: Residing in neighborhoods with a higher walkability level was associated with a reduced risk of overall and site-specific obesity-related cancers. The hazards ratios associated with a 1-standard deviation increase in average annual neighborhood walkability were 0.88 (95% CI: 0.85, 0.93) for overall obesity-related cancer, 0.89 (95% CI: 0.84, 0.95) for postmenopausal breast cancer, 0.82 (95% CI: 0.68, 0.99) for ovarian cancer, 0.87 (95% CI: 0.76, 0.99) for endometrial cancer, and 0.68 (95% CI: 0.49, 0.94) for multiple myeloma, adjusting for potential confounders at both the individual and neighborhood level. The association between neighborhood walkability and risk of overall obesity-related cancer was stronger among women living in neighborhoods with higher levels of poverty compared with women living in areas with lower poverty levels (pInteraction=0.006). DISCUSSION: Our study highlights a potential protective role of neighborhood walkability in preventing obesity-related cancers in women. https://doi.org/10.1289/EHP11538.

Correction: Podury et al. Severe Acute Respiratory Syndrome and Particulate Matter Exposure: A Systematic Review. Life 2023, 13, 538.

In the original publication [...].

Association Between Dietary and Serum Cholesterol and Cognitive Function Among the U.S. Elderly from NHANES 2011-2014.

BACKGROUND: The association between dietary or serum cholesterol and cognitive performance in older adults has not been well-established. OBJECTIVE: This study aimed to investigate the potential association between dietary or serum cholesterol and cognitive performance in the elderly population. METHODS: A cross-sectional analysis was conducted using data from the National Health and Nutrition Examination Survey (NHANES) 2011-2012 and 2013-2014. Diet and supplement cholesterol was estimated based on two non-consecutive 24-hour dietary recalls. Cognitive function was assessed using various statistical tests. Poor cognitive performance was defined as scores below the lowest quartile within age groups. Regression models were adjusted for demographic factors, and subgroup analyses were performed for non-Hispanic White (NHW) and non-Hispanic Black (NHB) individuals. RESULTS: Among 759 participants aged 60 years and above, dietary cholesterol was only associated with dietary saturated fatty acids and serum high-density lipoprotein cholesterol. There was no evidence of an association between dietary cholesterol and cognitive function, except for NHB individuals, where dietary cholesterol showed a positive correlation with cognitive function. In the overall sample and NHW participants, there were consistent positive associations between serum total cholesterol and cognitive performance across statistical tests, while such associations were rare among NHB individuals. Although not statistically significant, NHB individuals had higher dietary/supplementary/total cholesterol intake compared with NHW individuals. CONCLUSION: Within the normal range, increasing serum cholesterol may be a potential factor to prevent or relieve cognitive dysfunction. However, ethnic differences should be taken into account when considering the association between cholesterol and cognitive performance.

Role of small airway dysfunction in unexplained exertional dyspnoea.

Background: Isolated small airway abnormalities may be demonstrable at rest in patients with normal spirometry; however, the relationship of these abnormalities to exertional symptoms remains uncertain. This study uses an augmented cardiopulmonary exercise test (CPET) to include evaluation of small airway function during and following exercise to unmask abnormalities not evident with standard testing in individuals with dyspnoea and normal spirometry. Methods: Three groups of subjects were studied: 1) World Trade Center (WTC) dust exposure (n=20); 2) Clinical Referral (n=15); and Control (n=13). Baseline evaluation included respiratory oscillometry. Airway function during an incremental workload CPET was assessed by: 1) tidal flow versus volume curves during exercise to assess for dynamic hyperinflation and expiratory flow limitation; and 2) post-exercise spirometry and oscillometry to evaluate for airway hyperreactivity. Results: All subjects demonstrated normal baseline forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC). Dyspnoea was reproduced during CPET in WTC and Clinical Referral groups versus Control without abnormality in respiratory pattern and minute ventilation. Tidal flow-volume curves uncovered expiratory flow limitation and/or dynamic hyperinflation with increased prevalence in WTC and Clinical Referral versus Control (55%, 87% versus 15%; p<0.001). Post-exercise oscillometry uncovered small airway hyperreactivity with increased prevalence in WTC and Clinical Referral versus Control (40%, 47% versus 0%, p<0.05). Conclusions: We uncovered mechanisms for exertional dyspnoea in subject with normal spirometry that was attributable to either small airway dysfunction during exercise and/or small airway hyperreactivity following exercise. The similarity of findings in WTC environmentally exposed and clinically referred cohorts suggests broad relevance for these evaluations.

Negative correlation between acetyl-CoA acyltransferase 2 and cetuximab resistance in colorectal cancer.

The emergence of anti-EGFR therapy has revolutionized the treatment of colorectal cancer (CRC). However, not all patients respond consistently well. Therefore, it is imperative to conduct further research to identify the molecular mechanisms underlying the development of cetuximab resistance in CRC. In this study, we find that the expressions of many metabolism-related genes are downregulated in cetuximab-resistant CRC cells compared to their sensitive counterparts. Specifically, acetyl-CoA acyltransferase 2 (ACAA2), a key enzyme in fatty acid metabolism, is downregulated during the development of cetuximab resistance. Silencing of ACAA2 promotes proliferation and increases cetuximab tolerance in CRC cells, while overexpression of ACAA2 exerts the opposite effect. RTK-Kras signaling might contribute to the downregulation of ACAA2 expression in CRC, and ACAA2 predicts CRC prognosis in patients with Kras mutations. Collectively, our data suggest that modulating ACAA2 expression contributes to secondary cetuximab resistance in Kras wild-type CRC patients. ACAA2 expression is related to Kras mutation and demonstrates a prognostic role in CRC patients with Kras mutation. Thus, ACAA2 is a potential target in CRC with Kras mutation.

JUNB mediates oxaliplatin resistance via the MAPK signaling pathway in gastric cancer by chromatin accessibility and transcriptomic analysis.

Currently, platinum-containing regimens are the most commonly used regimens for advanced gastric cancer patients, and chemotherapy resistance is one of the main reasons for treatment failure. Thus, it is important to reveal the mechanism of oxaliplatin resistance and to seek effective intervention strategies to improve chemotherapy sensitivity, thereby improving the survival and prognosis of gastric cancer patients. To understand the molecular mechanisms of oxaliplatin resistance, we generate an oxaliplatin-resistant gastric cancer cell line and conduct assay for transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) for both parental and oxaliplatin-resistant AGS cells. A total of 3232 genomic regions are identified to have higher accessibility in oxaliplatin-resistant cells, and DNA-binding motif analysis identifies JUNB as the core transcription factor in the regulatory network. JUNB is overexpressed in oxaliplatin-resistant gastric cancer cells, and its upregulation is associated with poor prognosis in gastric cancer patients, which is validated by our tissue microarray data. Moreover, chromatin immunoprecipitation sequencing (ChIP-seq) analysis reveals that JUNB binds to the transcriptional start site of key genes involved in the MAPK signaling pathway. Knockdown of JUNB inhibits the MAPK signaling pathway and restores sensitivity to oxaliplatin. Combined treatment with the ERK inhibitor piperlongumine or MEK inhibitor trametinib effectively overcomes oxaliplatin resistance. This study provides evidence that JUNB mediates oxaliplatin resistance in gastric cancer by activating the MAPK pathway. The combination of MAPK inhibitors with oxaliplatin overcomes resistance to oxaliplatin, providing a promising treatment opportunity for oxaliplatin-resistant gastric cancer patients.

BatMan: Mitigating Batch Effects Via Stratification for Survival Outcome Prediction.

Reproducible translation of transcriptomics data has been hampered by the ubiquitous presence of batch effects. Statistical methods for managing batch effects were initially developed in the setting of sample group comparison and later borrowed for other settings such as survival outcome prediction. The most notable such method is ComBat, which adjusts for batches by including it as a covariate alongside sample groups in a linear regression. In survival prediction, however, ComBat is used without definable groups for survival outcome and is done sequentially with survival regression for a potentially batch-confounded outcome. To address these issues, we propose a new method called BATch MitigAtion via stratificatioN (BatMan). It adjusts batches as strata in survival regression and uses variable selection methods such as the regularized regression to handle high dimensionality. We assess the performance of BatMan in comparison with ComBat, each used either alone or in conjunction with data normalization, in a resampling-based simulation study under various levels of predictive signal strength and patterns of batch-outcome association. Our simulations show that (1) BatMan outperforms ComBat in nearly all scenarios when there are batch effects in the data and (2) their performance can be worsened by the addition of data normalization. We further evaluate them using microRNA data for ovarian cancer from the Cancer Genome Atlas and find that BatMan outforms ComBat while the addition of data normalization worsens the prediction. Our study thus shows the advantage of BatMan and raises caution about the use of data normalization in the context of developing survival prediction models. The BatMan method and the simulation tool for performance assessment are implemented in R and publicly available at LXQin/PRECISION.survival-GitHub.

Goodness-of-fit two-phase sampling designs for time-to-event outcomes: a simulation study based on New York University Women's Health Study for breast cancer.

BACKGROUND: Sub-cohort sampling designs such as a case-cohort study play a key role in studying biomarker-disease associations due to their cost effectiveness. Time-to-event outcome is often the focus in cohort studies, and the research goal is to assess the association between the event risk and risk factors. In this paper, we propose a novel goodness-of-fit two-phase sampling design for time-to-event outcomes when some covariates (e.g., biomarkers) can only be measured on a subgroup of study subjects. METHODS: Assuming that an external model, which can be the well-established risk models such as the Gail model for breast cancer, Gleason score for prostate cancer, and Framingham risk models for heart diseases, or built from preliminary data, is available to relate the outcome and complete covariates, we propose to oversample subjects with worse goodness-of-fit (GOF) based on an external survival model and time-to-event. With the cases and controls sampled using the GOF two-phase design, the inverse sampling probability weighting method is used to estimate the log hazard ratio of both incomplete and complete covariates. We conducted extensive simulations to evaluate the efficiency gain of our proposed GOF two-phase sampling designs over case-cohort study designs. RESULTS: Through extensive simulations based on a dataset from the New York University Women's Health Study, we showed that the proposed GOF two-phase sampling designs were unbiased and generally had higher efficiency compared to the standard case-cohort study designs. CONCLUSION: In cohort studies with rare outcomes, an important design question is how to select informative subjects to reduce sampling costs while maintaining statistical efficiency. Our proposed goodness-of-fit two-phase design provides efficient alternatives to standard case-cohort designs for assessing the association between time-to-event outcome and risk factors. This method is conveniently implemented in standard software.

Maternal urinary bisphenols and phthalates in relation to estimated fetal weight across mid to late pregnancy.

BACKGROUND: Bisphenols and phthalates are high production volume chemicals used as additives in a variety of plastic consumer products leading to near ubiquitous human exposure. These chemicals have established endocrine disrupting properties and have been linked to a range of adverse reproductive and developmental outcomes. Here, we investigated exposure in relation to fetal growth. METHODS: Participants included 855 mother-fetal pairs enrolled in the population-based New York University Children's Health and Environment Study (NYU CHES). Bisphenols and phthalates were measured in maternal urine collected repeatedly during pregnancy. Analyses included 15 phthalate metabolites and 2 bisphenols that were detected in 50 % of participants or more. Fetal biometry data were extracted from electronic ultrasonography records and estimated fetal weight (EFW) was predicted for all fetuses at 20, 30, and 36 weeks gestation. We used quantile regression adjusted for covariates to model exposure-outcome relations across percentiles of fetal weight at each gestational timepoint. We examined sex differences using stratified models. RESULTS: Few statistically significant associations were observed across chemicals, gestational time periods, percentiles, and sexes. However, within gestational timepoints, we found that among females, the molar sums of the phthalates DiNP and DnOP were generally associated with decreases in EFW among smaller babies and increases in EFW among larger babies. Among males, the opposite trend was observed. However, confidence intervals were generally wide at the tails of the distribution. CONCLUSION: In this sample, exposure to bisphenols and phthalates was associated with small sex-specific shifts in fetal growth; however, few associations were observed at the median of fetal weight and confidence intervals in the tails were wide. Findings were strongest for DiNP and DnOP, which are increasingly used as replacements for DEHP, supporting the need for future research on these contaminants.