Peak Region Research Articles

Lipid Metabolism Pathway Genes and Lung Cancer: ACADSB rs12220683G>C Is Associated with Better Survival Outcome in Patients with Non-Small Cell Lung Cancer

Introduction: Altered lipid metabolism has been reported to be associated with prognosis in multiple cancers. This study aimed to investigate the association of polymorphisms in lipid metabolism pathway genes with survival outcomes in patients with surgically resected non-small cell lung cancer (NSCLC). Methods: In total, 744 patients with surgically resected NSCLC (380 in the discovery cohort and 364 in the validation cohort) were included in this study. The association between 176 polymorphisms of lipid metabolism pathway genes and the clinical outcomes of NSCLC patients was analyzed. Results: Among the polymorphisms investigated, ACADSB rs10902859G>A was associated with significantly better overall survival (OS) in the discovery, validation, and combined cohorts. ACADSB rs10902859G>A was located in the repressed region and had strong linkage disequilibrium (D′ = 1.00 and r2 = 0.94), with rs12220683G>C located in the H3K4me3 peak region, which indicates the presence of active promoters. ACADSB rs12220683G>C was also associated with better OS in the discovery, validation, and combined cohorts (in a dominant model; adjusted hazard ratio [aHR] = 0.53, 95% confidence interval [CI] = 0.30–0.94, p = 0.03; aHR = 0.37, 95% CI = 0.15–0.89, p = 0.03; and aHR = 0.47, 95% CI = 0.29–0.75, p = 0.002, respectively). In vitro luciferase assay demonstrated that the promoter activity of ACADSB was significantly increased in the rs12220683 variant C allele compared with that in the wild G allele (p = 3 × 10−5). Conclusion: These results suggest that ACADSB rs12220683G>C increases promoter activity and that increased ACADSB expression may result in better OS in patients with surgically resected NSCLC.

Linked candidate genes of different functions for white mold resistance in common bean (Phaseolus vulgaris L) are identified by multiple QTL mapping approaches.

White mold (WM) is a major disease in common bean (Phaseolus vulgaris L.), and its complex quantitative genetic control limits the development of WM resistant cultivars. WM2.2, one of the nine meta-QTL with a major effect on WM tolerance, explains up to 35% of the phenotypic variation and was previously mapped to a large genomic interval on Pv02. Our objective was to narrow the interval of this QTL using combined approach of classic QTL mapping and QTL-based bulk segregant analysis (BSA), and confirming those results with Khufu de novo QTL-seq. The phenotypic and genotypic data from two RIL populations, 'Raven'/I9365-31 (R31) and 'AN-37'/PS02-029C-20 (Z0726-9), were used to select resistant and susceptible lines to generate subpopulations for bulk DNA sequencing. The QTL physical interval was determined by considering overlapping interval of the identified QTL or peak region in both populations by three independent QTL mapping analyses. Our findings revealed that meta-QTL WM2.2 consists of three regions, WM2.2a (4.27-5.76 Mb; euchromatic), WM 2.2b (12.19 to 17.61 Mb; heterochromatic), and WM2.2c (23.01-25.74 Mb; heterochromatic) found in both populations. Gene models encoding for gibberellin 2-oxidase 8, pentatricopeptide repeat, and heat-shock proteins are the likely candidate genes associated with WM2.2a resistance. A TIR-NBS-LRR class of disease resistance protein (Phvul.002G09200) and LRR domain containing family proteins are potential candidate genes associated with WM2.2b resistance. Nine gene models encoding disease resistance protein [pathogenesis-related thaumatin superfamily protein and disease resistance-responsive (dirigent-like protein) family protein etc] found within the WM2.2c QTL interval are putative candidate genes. WM2.2a region is most likely associated with avoidance mechanisms while WM2.2b and WM2.2c regions trigger physiological resistance based on putative candidate genes.

The photon energy spectrum in B → Xsγ at N3LL′

We present predictions for the photon energy spectrum in inclusive B → Xsγ decays mediated by the electromagnetic penguin operator O7 to N3LL′. We use soft-collinear effective theory (SCET) to resum the singular contributions in the peak region at large photon energy. In the tail region the resummed predictions are matched to fixed order at N3LO, where we include the known fixed-order contributions for O7 up to mathcal{O} ( {alpha}_s^2 ). We develop a method to suitably parametrize the still unknown mathcal{O} ( {alpha}_s^3 ) nonsingular corrections in terms of theory nuisance parameters, whose variations provide an estimate of the associated theory uncertainty. In this context, we also study different ways to treat higher-order cross terms in the matching. Another important aspect of our analysis is the short-distance scheme used for the b-quark mass mb. We find that in the present context, the 1S mass scheme, which was previously used up to 2-loop order, fails to work at 3-loop order, because the mass scheme enters at a soft scale much smaller than mb here, for which the 1S scheme was not devised. Using instead the MSR mass scheme with R ~ 1 GeV, we obtain stable results with good perturbative convergence up to N3LL′.

Effect of Storage Time on the Physical, Chemical, and Rheological Properties of Blueberry Jam: Experimental Measurements and Artificial Neural Network Simulation.

Reversible data hiding (RDH) is crucial in modern data security, ensuring confidentiality and tamper-proofness in various industries like copyright protection, medical imaging, and digital forensics. As technology advances, RDH techniques become essential, but the trade-off between embedding capacity and visual quality must be heeded. In this paper, the relative correlation between the pixel's local complexity and its directional prediction error is employed to enhance an efficient RDH without using a location map. An embedding process based on multiple cumulative peak region localization (MCPRL) is proposed to hide information in the 3D-directional prediction error histogram with a lower local complexity value and avoid the underflow/overflow problems. The carrier image is divided into three color channels, and then each channel is split into two non-overlapping sets: blank and shadow. Two half-directional prediction errors (the blank set and the shadow set) are constructed to generate a full-directional prediction error for each color channel belonging to the host image. The local complexity value and directional prediction error are critical metrics in the proposed embedding process to improve security and robustness. By utilizing these metrics to construct a 3D stego-Blank Set, the 3D stego-shadow Set will be subsequently constructed using the 3D blank set. The proposed technique outperforms other state-of-the-art techniques in terms of embedding capacity, image quality, and robustness against attacks without an extra location map. The experimental results illustrate the effectiveness of the proposed method for various 3D RDH techniques.

Adaptive 3D Reversible Data Hiding Technique Based on the Cumulative Peak Bins in the Histogram of Directional Prediction Error

Reversible data hiding (RDH) is crucial in modern data security, ensuring confidentiality and tamper-proofness in various industries like copyright protection, medical imaging, and digital forensics. As technology advances, RDH techniques become essential, but the trade-off between embedding capacity and visual quality must be heeded. In this paper, the relative correlation between the pixel’s local complexity and its directional prediction error is employed to enhance an efficient RDH without using a location map. An embedding process based on multiple cumulative peak region localization (MCPRL) is proposed to hide information in the 3D-directional prediction error histogram with a lower local complexity value and avoid the underflow/overflow problems. The carrier image is divided into three color channels, and then each channel is split into two non-overlapping sets: blank and shadow. Two half-directional prediction errors (the blank set and the shadow set) are constructed to generate a full-directional prediction error for each color channel belonging to the host image. The local complexity value and directional prediction error are critical metrics in the proposed embedding process to improve security and robustness. By utilizing these metrics to construct a 3D stego-Blank Set, the 3D stego-shadow Set will be subsequently constructed using the 3D blank set. The proposed technique outperforms other state-of-the-art techniques in terms of embedding capacity, image quality, and robustness against attacks without an extra location map. The experimental results illustrate the effectiveness of the proposed method for various 3D RDH techniques.

Mechanical behavior and reloading reinforcement characteristics of fractured coal under low confining pressure

To study the basic mechanical behavior and the reloading reinforcement characteristics of fractured coal, conventional triaxial loading tests with different fissure angle were first carried out. On this basis, conventional triaxial loading and unloading tests were conducted to investigate the reloading reinforcement characteristics of fractured coal. The results reveal that when the fissure angle was small, the stress–strain curve exhibited the multi-peak phenomena. As the fissure angle increased, the stress drop phenomenon in the peak region was weakened. With the increase of the fissure angle, the peak stress of the specimens increased and then decreased, while the elastic modulus showed an overall increasing trend, demonstrating the controlling effect of the crack angle. Meanwhile, the cyclic loading exhibited a certain enhancement effect on the strength of the fractured coals when the specimens was unloaded near the crack closure stress. The findings can provide a better understanding of the failure mechanism and reloading reinforcement characteristics of fractured coal.

Annealing parameters effect on microstructure evolution, tensile properties and deformation behaviors of direct-cold-rolled UNS S32101 duplex stainless steel with heterogeneous layered structure

Microstructure evolution, strain-induced martensite transformation (SIMT) kinetics, tensile properties, deformation behaviors of UNS S32101 duplex stainless steel (DSS) with heterogeneous layered structure (HLS) were investigated. HLS composed of multiscale grains (spanning coarse, fine, and ultrafine grains) was prepared by direct cold rolling in combination with short-time annealing, being dominated by coarse-grained ferrite (CGed α) and fine-grained austenite (FGed γ). A quantitative SIMT kinetics model was established to predict the α′-martensite fraction at various strain/annealing parameters, indicating that increased average grain size (AGS) for γ not only contributed to the SIM formation but also promoted the monotonic increase of SIMT rate until annealing for 10 min. Relatively high stacking fault energy (SFE, 35.89∼39.34 mJ/m2) favored mechanical twinning as the dominant deformation mode of γ accompanied by SIMT and dislocation glide. And α deformation was mainly coordinated by wavy slip. Both SFE and Olson-Cohen parameters were strongly correlated with the γ AGS, which could reasonably interpret the dependence of SIMT on the AGS. The A and B values increased progressively with grain coarsening along with the rapid decline in SFE, facilitating the martensite formation. Further increasing the AGS beyond the peak region severely suppressed SIMT probably due to the low probability of martensite embryo generation at deformation twins (DTs) intersections, coinciding with the sharp decrease A value.

Modeling ultra-high dose rate electron and proton FLASH effect with the physicochemical approach

Objective. A physicochemical model built on the radiochemical kinetic theory was recently proposed in (Labarbe et al ) to explain the FLASH effect. We performed extensive simulations to scrutinize its applicability for oxygen depletion studies and FLASH-related experiments involving both proton and electron beams. Approach. Using the dose and beam delivery parameters for each FLASH experiment, we numerically solved the radiochemical rate equations comprised of a set of coupled nonlinear ordinary differential equations to obtain the area under the curve (AUC) of radical concentrations. Main results. The modeled differences in AUC induced by ultra-high dose rates appeared to correlate well with the FLASH effect. (i) For the whole brain irradiation of mice performed in (Montay-Gruel et al ), the threshold dose rate values for memory preservation coincided with those at which AUC started to decrease much less rapidly. (ii) For the proton pencil beam scanning FLASH of (Cunningham et al ), we found linear correlations between radicals’ AUC and the biological endpoints: TGF-β1, leg contracture and plasma level of cytokine IL-6. (iii) Compatible with the findings of the proton FLASH experiment in (Kim et al ), we found that radicals’ AUC at the entrance and mid-Spread-Out Bragg peak regions were highly similar. In addition, our model also predicted ratios of oxygen depletion G-values between normal and UHDR irradiation similar to those observed in (Cao et al ) and (El Khatib et al ). Significance. Collectively, our results suggest that the normal tissue sparing conferred by UHDR irradiation may be due to the lower degree of exposure to peroxyl and superoxide radicals. We also found that the differential effect of dose rate on the radicals’ AUC was less pronounced at lower initial oxygen levels, a trait that appears to align with the FLASH differential effect on normal versus tumor tissues.

Banana Current in the Inner Magnetosphere Observed by Van Allen Probes

AbstractBy using the magnetic field data from Van Allen Probes, we analyzed the distribution characteristics of the electromagnetic environment in the inner magnetosphere on different Dst* index and magnetic local time. Our results show that for the response of different current systems, the dawn‐dusk and noon‐midnight asymmetry distribution of the residual magnetic field δB increases with Dst* index. When Dst* < −60 nT, a “banana”‐shaped geomagnetic field negative disturbance peak region appears in the sector from midnight to dusk. Then, we obtained the azimuthal current density and found the asymmetric internal eastward and external westward ring current. Through the vector analysis of three‐dimensional current density, the current density vector distribution in the magnetic equatorial plane is completely displayed for the first time, which directly proves the existence of banana current near r = 3.0–4.0 RE during strong geomagnetic storms.

Statistical Study of EMIC Waves and Related Proton Distributions Observed by the Arase Satellite

AbstractWe performed a statistical study of electromagnetic ion cyclotron (EMIC) wave distributions and their coupling with energetic protons in the inner magnetosphere using the Arase satellite data from May 2017 to December 2020. We investigated the energetic proton pitch‐angle distributions and partial thermal pressures associated with EMIC waves using inter‐calibrated proton data in the energy range of 30 eV/q–187 keV/q. With a cold plasma approximation, we computed the proton minimum resonance energies using the observed EMIC wave frequency and plasma density values. We found that the EMIC waves had left‐handed polarization near the magnetic equator close to the threshold of proton cyclotron instability, and propagated to higher latitudes along the field line with polarization reversal. H‐EMIC waves showed two peak occurrence regions in the morning and noon sectors at L = 7.5–9 outside the plasmasphere. The flux enhancements associated with morning side H‐EMIC waves appeared at E < 1 keV/q among all pitch angles, while H‐EMIC waves in the noon sector exhibited flux enhancement in field‐aligned directions at E = 1–100 keV/q. He‐EMIC waves showed a broad occurrence region from 12 to 20 magnetic local time at L = 5.5–8.5 inside the plasmasphere with strong flux enhancements at all pitch‐angle ranges at E = 1–100 keV/q. The proton minimum resonance energy using the obtained central frequency was consistent with the observed flux enhancements at different peak occurrence regions. We conclude that the free energy sources of EMIC waves in different geomagnetic environments drive various types of EMIC waves, and they interact with energetic protons at different energy ranges.

INFLUENCE OF CeO2 ON THE FORMATION OF PLASMONIC Au NANOPARTICLES IN GLASSES OF THE ZnO–MgO–Al2O3–SiO2 SYSTEM

Using absorption spectroscopy, differential scanning calorimetry, and X-ray powder diffraction, we studied the effect of a small addition of CeO2 on the process of thermally stimulated formation of plasmonic Au nanoparticles in the glass of the ZnO–MgO–Al2O3–SiO2 system containing TiO2 and ZrO2 as nucleating agents. It is shown that when the glass is heated from temperatures slightly above Tg to temperatures in the region of the exothermic peak, the plasmon resonance band of Au nanoparticles undergoes a nonlinear shift; however, the addition of CeO2 significantly expands the the shift to the long wavelength region of the spectrum. We performed the computer simulation of the experimental optical absorption spectra, estimated the sizes of the formed nanoparticles and proposed the mechanism of the effect of the CeO2 addition on the formation of plasmonic Au nanoparticles.

Hydrogen-free Wolf-Rayet stars: Helium stars with envelope-inflation structure and rotation

Context. Observations have shown that the effective temperature of hydrogen-free Wolf-Rayet (WR) stars is considerably lower than that of the standard model, which means that the radius of the observed H-free WR stars is several times larger than that estimated by the standard model. The envelope inflation structure (EIS) caused by the radiation luminosity being close to the Eddington luminosity in the iron opacity peak region of H-free WR stars may be the key to resolving the radius problem of H-free WR stars. Aims. We study the structure and evolution of helium (He) stars with the EIS and discuss the influence of rotation on these He stars. We aim to explain the radius problem of H-free WR stars observed in the Milky Way (MW) and the Large Magellanic Cloud (LMC) through the He stars. Methods. Using the Modules for Experiments in Stellar Astrophysics code, we compute the evolution of He stars with and without MLT++ prescriptions, and discuss their effects on the EIS. We calculated the evolution of He stars using a new mass-loss rate formula and three different relative rotational velocities and compared our results with observations on Hertzsprung–Russell diagrams. Results. The EIS has different effects on the structure and evolution of He stars with different masses. Due to the luminosity well below the Eddington limit, low-mass He stars with an initial mass of less than 12 M⊙ do not produce EIS with or without the MLT++ prescription. High-mass He stars with an initial mass exceeding 12 M⊙ and without the MLT++ prescription produce the EIS. Since the EIS is Eddington factor Γ-dependent, its radius increases with the increase in metallicity and decreases with rotational velocity increase. For rotating low-mass He stars, since the rotational mixing timescale is smaller than the evolutionary timescale, rotational mixing can increase the lifetime and allow He stars to evolve into WC stars during the helium giant phase. For rotating high-mass He stars, since rotation increases the mass-loss rate, the radius of the EIS decreases as rotational velocity increases. The rotation-decay timescale of rapidly rotating He stars is very short, and the rapidly rotating He stars only appear within the first one-tenth of their lifetime, which is consistent with the observations of WR stars. Conclusions. The low-luminosity (log(L/L⊙)≤5.2) H-free WR stars in the MW and the LMC can be explained by the helium giant phase in low-mass He stars, the high XC and XO in WC stars can only evolve through low-mass He stars with a rapid rotation. High-mass He stars with the EIS can explain H-free WR stars with a luminosity exceeding 105.7 L⊙ and an effective temperature above 104.7 K in the MW. They can also explain H-free WR stars on the right-hand side of the He zero-age main sequence in the LMC. High-mass stars with the EIS evolve into WO stars at the final evolution stage, and the shorter lifetime fraction is consistent with the small number of observed WO stars.

Two-loop bottom mass effects on the Higgs transverse momentum spectrum in top-induced gluon fusion

We compute bottom mass (mb) corrections to the transverse momentum (qT) spectrum of Higgs bosons produced by gluon fusion in the regime qT ∼ mb ≪ mH at leading power in mb/mH and qT/mH, where the gluons couple to the Higgs via a top loop. To this end we calculate the quark mass dependence of the transverse momentum dependent gluon beam functions (aka gluon TMDPDFs) at two loops in the framework of SCET. These functions represent the collinear matrix elements in the factorized gluon-fusion cross section for small qT. We discuss in detail technical subtleties regarding rapidity regulators and zero-bin subtractions in the calculation of the virtual corrections present for massive quarks. Combined with the known soft function for mb ≠ 0 our results allow to determine the resummed Higgs qT distribution in the top-induced gluon fusion channel at NNLL′ (and eventually N3LL) with full dependence on mb/qT. We perform a first phenomenological analysis at fixed order, where the new corrections to the massless approximation lead to percent-level effects in the peak region of the Higgs qT spectrum. Upon resummation they may thus be relevant for state-of-the-art precision predictions for the LHC.

Combined Use of Frameless Neuronavigation and In Situ Optical Guidance in Brain Tumor Needle Biopsies.

Brain tumor needle biopsies are performed to retrieve tissue samples for neuropathological analysis. Although preoperative images guide the procedure, there are risks of hemorrhage and sampling of non-tumor tissue. This study aimed to develop and evaluate a method for frameless one-insertion needle biopsies with in situ optical guidance and present a processing pipeline for combined postoperative analysis of optical, MRI, and neuropathological data. An optical system for quantified feedback on tissue microcirculation, gray-whiteness, and the presence of a tumor (protoporphyrin IX (PpIX) accumulation) with a one-insertion optical probe was integrated into a needle biopsy kit that was used for frameless neuronavigation. In Python, a pipeline for signal processing, image registration, and coordinate transformation was set up. The Euclidian distances between the pre- and postoperative coordinates were calculated. The proposed workflow was evaluated on static references, a phantom, and three patients with suspected high-grade gliomas. In total, six biopsy samples that overlapped with the region of the highest PpIX peak without increased microcirculation were taken. The samples were confirmed as being tumorous and postoperative imaging was used to define the biopsy locations. A 2.5 ± 1.2 mm difference between the pre- and postoperative coordinates was found. Optical guidance in frameless brain tumor biopsies could offer benefits such as quantified in situ indication of high-grade tumor tissue and indications of increased blood flow along the needle trajectory before the tissue is removed. Additionally, postoperative visualization enables the combined analysis of MRI, optical, and neuropathological data.

Delineation Evaluation and Variation of Debris-Covered Glaciers Based on the Multi-Source Remote Sensing Images, Take Glaciers in the Eastern Tomur Peak Region for Example

As a particular type of alpine glacier, debris-covered glaciers are essential for local water resources and glacial disaster warnings. The Eastern Tomur Peak Region (EPTR) is the most concentrated glacier in Tien Shan Mountain, China, where the glaciers have not been studied in detail. This paper evaluates the delineation accuracy of Landsat8 OLI, Sentinel-1A, and GF images for debris-covered glaciers in the EPTR. Each image uses the most advanced delineation method for itself to minimize the error of inherent resolutions. The results show that the accuracy of these images for delineating debris-covered glaciers is very high, and the F1 scores are expressed as 96.73%, 93.55%, and 95.81%, respectively. Therefore, Landsat images were selected to analyze the area change of EPTR from 2000 to 2022 over a 5-year time scale. The results indicate that glaciers of the EPTR decreased by 19.05 km2 from 2000 to 2020, accounting for 1.9% (0.08% a−1), and debris increased by 10.8%, which validates the opinion that the presence of debris inhibits glacier melting. The most varied time was 2010–2022, but it was much less than other Tien Shan regions. The lower glacier ablation rate in this area results from the combined effect of decreased bare ice and increased debris. The main reason for the change in debris-covered glaciers is the increase in temperature.

Characterization of a Gd-based color CMOS detector for proton dosimetry

A color scintillation detector for relative dose distribution measurement was developed at PSI. The system consists of a gadolinium-based scintillating screen mounted perpendicularly to the beam axis and coupled with a color CMOS camera in a light-tight box. The camera is equipped with an iris (aperture) controller to remotely adjust the number of photons reaching the image sensor. To improve the measurement accuracy and decrease the image artifacts, we investigated different methods for spatial calibration and optimized the internal light reflection by adjusting the detector structure. The response dependence on camera working distance, iris setting, and color channels was assessed. The depth-dose curves of the gadolinium-based scintillator in three RGB channels were compared with reference curves measured by an Advanced Markus plane-parallel ion chamber. The quenching effect of the ▪ screen measured with this system amounts to about 10% in the Bragg peak region of a 150 MeV proton beams. The shape of the emission spectrum was observed to be independent of the ionization density. Preliminary investigations showed that it is possible to correlate the ratio of the detector response in different color channels with the proton ionization density.

Experimental and numerical study of TGO-induced stresses of plasma-sprayed thermal barrier coating

Experimental and numerical studies were conducted in order to investigate the stress changes of ZrO2-8 wt% Y2O3 (YSZ) thermal barrier coatings (TBC) under isothermal loading. After conducting the isothermal oxidation test at a temperature of 1070 °C, the Thermally Grown Oxide (TGO) growth process and the life of samples were evaluated using scanning electron microscopy (SEM). The X-ray diffraction (XRD) approach was selected for the measurement of surface residual stress and its change in terms of TGO growth. Furthermore, a finite element model based on a real TGO profile, extracted by SEM, was executed, where TGO-induced stress was measured at the TGO/Top Coat (TC) interface direction. Employing the finite element model, following the selection of the appropriate creep strength based on experimental results, the stress evolution and distribution were assessed during time exposure at maximum temperature. It was shown that the lifetime of samples was about 240 h under isothermal loading of 1070℃. By increasing the time exposure, stresses increased and resulted in the formation of a delamination line above peak regions.

The effects of atmospheric dust and solar radiation on the dayside ionosphere of Mars derived from 17 years of Mars Express radio science observations

This work combines 17 years of Mars Express radio science (MaRS) observations with proxies for insolation and local/global atmospheric dust to investigate the combined and individual effects on the dayside ionosphere of Mars from the top down to the ionospheric base.The increase in insolation from orbital apocenter to pericenter in combination with Mars‘ dust cycle causes an average rise of the whole photochemically dominated region of the dayside ionosphere, ranging from 13 km at the ionospheric base up to 22 km above the main peak during conditions without a global dust storm. The declining phase of the 2018 global dust storm was observed by MaRS on the southern hemisphere and close to pericenter. The observed lifting effect on the whole photochemically dominated region of the ionosphere from the increased insolation and the high local and global atmospheric dust levels exceeds that seen by MaRS from similar seasons during years without a global dust storm.The average ionospheric peak altitude at the subsolar point rises for increasing levels of local atmospheric dust until a maximum elevation is reached. This maximum depends on the available insolation at the top of the planetary atmosphere. Further increases of the local atmospheric dust levels do not lead to a further rise of the average ionospheric peak altitude in the investigated data set. This indicates a limit for the warming/expansion of the lower neutral atmosphere and the consecutive lifting of the ionosphere based on the available insolation and explains why regional dust storms can cause a similar lifting of the ionospheric main peak region as global dust storms.

Neural tube defects: Prevalence, mortality, and maternal characteristics in two departmental hospitals in the northwestern region of Nicaragua, 2006-2018.

Congenital anomalies are the fifth most common cause of neonatal mortality in Nicaragua, and neural tube defects (NTDs) are the most common of all cases of lethality associated with a birth defect. Prevalence and mortality estimates are needed to propose effective intervention strategies that prevent NTDs over time. A cross-sectional study was carried out in northwestern Nicaragua from January 2006 to December 2018. All cases of NTDs (anencephaly, spina bifida, and encephalocele) were registered in hospital surveillance systems, and the medical histories of the mothers and newborns were reviewed. Prevalence was calculated by considering the number of live births and stillbirths older than 20 weeks of gestation with NTDs, divided by the total number of live births and stillbirths in each study year. Neonatal mortality rate (NMR) for NTD, and case fatality for spina bifida was calculated. Two hundred fifty cases of NTDs were identified from 178,498 deliveries (177,316 live births and 1,182 stillbirths). The prevalence of NTDs during this time period was 14.01 (95% CI: 12.27-15.74) per 10,000 births. The prevalence of spina bifida (n = 140), anencephaly (n = 97), and encephalocele (n = 13) was 7.84, (95% CI: 6.54-9.14), 5.43 (95% CI: 4.30-6.45), and 0.73 (95% CI: 0.33-1.12) per 10,000 births, respectively. Mothers with fetus or newborns affected with NTDs did not use folic acid prior to conception, and 11% experienced periods of hyperthermia during the first trimester of pregnancy. NMR for NTDs was 0.55 per 1.000 livebirths. Case fatality for all NTDs and for spina bifida were 55% and 18%, respectively. The prevalence and mortality of NTDs in the northwestern region of Nicaragua present peaks and troughs during the study period. Spina bifida was the most frequent type of NTD. We believe that these findings could be of use by health policy makers to strengthen the primary prevention of NTDs in the region through the monitoring of the food fortification policy and folic acid supplementation to women of childbearing age. Additional etiologic studies of NTDs should be considered to identify additional prevention measures.

Abstract 1462: Oncogenic Foxl2 is a chromatin-remodeling pioneer transcription factor in adult-type ovarian granulosa cell tumors

Abstract Background: A missense mutation in the Forkhead domain-containing FOXL2 (Foxl2 p.C134W) transcription factor is found in nearly all adult-type granulosa cell tumors, but the oncogenic mechanism of this mutation is not known. Other Forkhead family transcription factors have well-described “pioneer” activity, binding to compacted, nucleosome-bound DNA and increasing accessibility for other regulatory proteins. Objectives: To develop novel cell culture model systems and determine whether oncogenic Foxl2-C134W has pioneering activity. Methods: CRISPR/Cas9 editing was used to generate isogenic granulosa cell tumor cells lacking either the FOXL2 wild-type allele (single knock-out; SKO) or both the mutant and wild-type FOXL2 alleles (double knock-out; DKO). ATAC-Seq and endogenous Foxl2 ChIP-Seq were performed on these isogenic lines to determine the differential chromatin accessibility at Foxl2-bound regulatory regions across genotypes. ENCODE pipelines and data standards were used for analysis, and the irreproducible discovery rate was used to identify high-reliability ATAC-seq and ChIP-seq peaks. De novo motifs were identified with STREME. Promoter capture HiC was performed using a bespoke genome-wide hybrid capture probe set, and CHiCAGO was used to identify significant HiC interactions. Results: Endogenous ChIP-seq of Foxl2-C134W from the SKO cell line identified 1147 high-confidence peaks. De novo motif discovery identified the canonical Foxl2 binding motif (TGTTTACATT, P = 1.4 x 10-7) in 44.9% of peaks, as well as a novel variant motif (TGTTTTGTCT, P = 6.7 x 10-15) in 68.5% of peaks. Median chromatin accessibility at Foxl2-C134W peak regions, as measured by ATAC-seq, was significantly decreased in the DKO cells compared to either SKO or parental cell lines (P < 2 x 10-16 for both comparisons). No difference was observed between SKO and parental cell lines (P = 0.19). Decreased chromatin accessibility at Foxl2-C134W ChIP-seq peaks in the DKO cells was driven by peaks containing the novel variant Foxl2 binding motif. Promoter capture HiC identified promoter-enhancer interactions lost in the DKO cell line involving several genes, including HUNK, NOVA1, andSFRP2 (adjusted P < 0.05). Conclusion: Foxl2-C134W exhibits “pioneering” activity, increasing chromatin accessibility at key gene regulatory elements with associated re-programming of promoter-enhancer interactions. The oncogenic mechanism of Foxl2-C134W in granulosa cell tumors may involve changes in DNA binding specificity, re-directing this pioneering function to sites containing a novel variant Foxl2 binding motif. Citation Format: Veena Vuttaradhi, Eleonora Khlebus, Thomas Welte, Namrata Khurana, Barrett Lawson, Robert Tyler Hillman. Oncogenic Foxl2 is a chromatin-remodeling pioneer transcription factor in adult-type ovarian granulosa cell tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1462.