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A high efficiency simulation method for propagation-based phase-contrast imaging, called directional macro-wavefront (DMWF), is developed with the aim of simulating high-energy phase-contrast imaging. This method takes both Monte Carlo and wave optical propagation into consideration. Traditional wave-optics-based simulation methods for phase-contrast imaging encounter unacceptable computational complexity when high-energy radiation is used. In contrast, this method effectively addresses this issue by using macro-wavefront integration. Several simulation examples using typical parameters of inverse Compton scattering sources are presented to illustrate the excellent energy adaptability and efficiency of the DMWF method. This method provides a more efficient approach for phase-contrast imaging simulations, which will drive the advancement of high-energy phase-contrast imaging., (© 2024. The Author(s).)

Background: The low absorption of x-rays in lung tissue and the poor resolution of conventional computed tomography (CT) limits its use to detect lung disease. However, x-ray dark-field imaging can sense the scattered x-rays deflected by the structures being imaged. This technique can facilitate the detection of small alveolar lesions that would be difficult to detect with conventional CT. Therefore, it may provide an alternative imaging modality to diagnose lung disease at an early stage., Methods: Eight mice were inoculated with lung cancers simultaneously. Each time two mice were scanned using a grating-based dark-field CT on days 4, 8, 12, and 16 after the introduction of the cancer cells. The detectability index was calculated between nodules and healthy parenchyma for both attenuation and dark-field modalities. High-resolution micro-CT and pathological examinations were used to crosscheck and validate our results. Paired t-test was used for comparing the ability of dark-field and attenuation modalities in pulmonary nodule detection., Results: The nodules were shown as a signal decrease in the dark-field modality and a signal increase in the attenuation modality. The number of nodules increased from day 8 to day 16, indicating disease progression. The detectability indices of dark-field modality were higher than those of attenuation modality (p = 0.025)., Conclusions: Compared with the standard attenuation CT, the dark-field CT improved the detection of lung nodules., Relevance Statement: Dark-field CT has a higher detectability index than conventional attenuation CT in lung nodule detection. This technique could improve the early diagnosis of lung cancer., Key Points: • Lung cancer progression was observed using x-ray dark-field CT. • Dark-field modality complements with attenuation modality in lung nodule detection. • Dark-field modality showed a detectability index higher than that attenuation in nodule detection., (© 2024. The Author(s).)

MLL/KMT2A amplifications and translocations are prevalent in infant, adult, and therapy-induced leukemia. However, the molecular contributor(s) to these alterations are unclear. Here, we demonstrate that histone H3 lysine 9 mono- and di-methylation (H3K9me1/2) balance at the MLL/KMT2A locus regulates these amplifications and rearrangements. This balance is controlled by the crosstalk between lysine demethylase KDM3B and methyltransferase G9a/EHMT2. KDM3B depletion increases H3K9me1/2 levels and reduces CTCF occupancy at the MLL/KMT2A locus, in turn promoting amplification and rearrangements. Depleting CTCF is also sufficient to generate these focal alterations. Furthermore, the chemotherapy doxorubicin (Dox), which associates with therapy-induced leukemia and promotes MLL/KMT2A amplifications and rearrangements, suppresses KDM3B and CTCF protein levels. KDM3B and CTCF overexpression rescues Dox-induced MLL/KMT2A alterations. G9a inhibition in human cells or mice also suppresses MLL/KMT2A events accompanying Dox treatment. Therefore, MLL/KMT2A amplifications and rearrangements are controlled by epigenetic regulators that are tractable drug targets, which has clinical implications., Competing Interests: Declaration of interests J.R.W. has served or is serving as a consultant or advisor for Qsonica, Salarius Pharmaceuticals, Daiichi Sankyo, Inc., Vyne Therapeutics, and Lily Asia Ventures. J.R.W. also receives funding for research from Salarius Pharmaceuticals and Oryzon Genomics. O.G. is a scientific cofounder and shareholder of EpiCypher, Inc., K36 Therapeutics, Inc., and Alternative Bio, Inc. J.J. received research funds from Celgene Corporation, Levo Therapeutics, Inc., Cullgen, Inc., and Cullinan Oncology, Inc. J.J. is a cofounder and equity shareholder in Cullgen, Inc., a scientific cofounder and scientific advisory board member of Onsero Therapeutics, Inc., and a consultant for Cullgen, Inc., EpiCypher, Inc., and Accent Therapeutics, Inc. C.D. receives research funds from Janssen outside the submitted work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The conserved WD40-repeat protein WDR5 interacts with multiple proteins both inside and outside the nucleus. However, it is currently unclear whether and how the distribution of WDR5 between complexes is regulated. Here, we show that an unannotated microprotein EMBOW (endogenous microprotein binder of WDR5) dually encoded in the human SCRIB gene interacts with WDR5 and regulates its binding to multiple interaction partners, including KMT2A and KIF2A. EMBOW is cell cycle regulated, with two expression maxima at late G1 phase and G2/M phase. Loss of EMBOW decreases WDR5 interaction with KIF2A, aberrantly shortens mitotic spindle length, prolongs G2/M phase, and delays cell proliferation. In contrast, loss of EMBOW increases WDR5 interaction with KMT2A, leading to WDR5 binding to off-target genes, erroneously increasing H3K4me3 levels, and activating transcription of these genes. Together, these results implicate EMBOW as a regulator of WDR5 that regulates its interactions and prevents its off-target binding in multiple contexts., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Abnormal activation of Wnt/β-catenin-mediated transcription is closely associated with the malignancy of pancreatic cancer. Family with sequence similarity 83 member A (FAM83A) was shown recently to have oncogenic effects in a variety of cancer types, but the biological roles and molecular mechanisms of FAM83A in pancreatic cancer need further investigation. Here, we newly discovered that FAM83A binds directly to β-catenin and inhibits the assembly of the cytoplasmic destruction complex thus inhibiting the subsequent phosphorylation and degradation. FAM83A is mainly phosphorylated by the SRC non-receptor kinase family member BLK (B-lymphoid tyrosine kinase) at tyrosine 138 residue within the DUF1669 domain that mediates the FAM83A-β-catenin interaction. Moreover, FAM83A tyrosine 138 phosphorylation enhances oncogenic Wnt/β-catenin-mediated transcription through promoting β-catenin-TCF4 interaction and showed an elevated nucleus translocation, which inhibits the recruitment of histone deacetylases by TCF4. We also showed that FAM83A is a direct downstream target of Wnt/β-catenin signaling and correlates with the levels of Wnt target genes in human clinical pancreatic cancer tissues. Notably, the inhibitory peptides that target the FAM83A-β-catenin interaction significantly suppressed pancreatic cancer growth and metastasis in vitro and in vivo. Our results revealed that blocking the FAM83A cascade signaling defines a therapeutic target in human pancreatic cancer., (© 2022. The Author(s).)

Respiratory diseases are one of the most common causes of death, and their early detection is crucial for prompt treatment. X-ray dark-field radiography (XDFR) is a promising tool to image objects with unresolved micro-structures such as lungs. Using Talbot-Lau XDFR, we imaged inflated porcine lungs together with Polymethylmethacrylat (PMMA) microspheres (in air) of diameter sizes between 20 and 500 [Formula: see text] over an autocorrelation range of 0.8-5.2 [Formula: see text]. The results indicate that the dark-field extinction coefficient of porcine lungs is similar to that of densely-packed PMMA spheres with diameter of [Formula: see text], which is approximately the mean alveolar structure size. We evaluated that, in our case, the autocorrelation length would have to be limited to [Formula: see text] in order to image [Formula: see text]-thick lung tissue without critical visibility reduction (signal saturation). We identify the autocorrelation length to be the critical parameter of an interferometer that allows to avoid signal saturation in clinical lung dark-field imaging., (© 2023. The Author(s).)

Breast cancer remains the most prevalent malignancy in women in many countries around the world, thus calling for better imaging technologies to improve screening and diagnosis. Grating interferometry (GI)-based phase contrast X-ray CT is a promising technique which could make the transition to clinical practice and improve breast cancer diagnosis by combining the high three-dimensional resolution of conventional CT with higher soft-tissue contrast. Unfortunately though, obtaining high-quality images is challenging. Grating fabrication defects and photon starvation lead to high noise amplitudes in the measured data. Moreover, the highly ill-conditioned differential nature of the GI-CT forward operator renders the inversion from corrupted data even more cumbersome. In this paper, we propose a novel regularized iterative reconstruction algorithm with an improved tomographic operator and a powerful data-driven regularizer to tackle this challenging inverse problem. Our algorithm combines the L-BFGS optimization scheme with a data-driven prior parameterized by a deep neural network. Importantly, we propose a novel regularization strategy to ensure that the trained network is non-expansive, which is critical for the convergence and stability analysis we provide. We empirically show that the proposed method achieves high quality images, both on simulated data as well as on real measurements., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Breast cancer is the most common malignancy in women. Unfortunately, current breast imaging techniques all suffer from certain limitations: they are either not fully three dimensional, have an insufficient resolution or low soft-tissue contrast. Grating interferometry breast computed tomography (GI-BCT) is a promising X-ray phase contrast modality that could overcome these limitations by offering high soft-tissue contrast and excellent three-dimensional resolution. To enable the transition of this technology to clinical practice, dedicated data-processing algorithms must be developed in order to effectively retrieve the signals of interest from the measured raw data., Methods: This article proposes a novel denoising algorithm that can cope with the high-noise amplitudes and heteroscedasticity which arise in GI-BCT when operated in a low-dose regime to effectively regularize the ill-conditioned GI-BCT inverse problem. We present a data-driven algorithm called INSIDEnet, which combines different ideas such as multiscale image processing, transform-domain filtering, transform learning, and explicit orthogonality to build an Interpretable NonexpanSIve Data-Efficient network (INSIDEnet)., Results: We apply the method to simulated breast phantom datasets and to real data acquired on a GI-BCT prototype and show that the proposed algorithm outperforms traditional state-of-the-art filters and is competitive with deep neural networks. The strong inductive bias given by the proposed model's architecture allows to reliably train the algorithm with very limited data while providing high model interpretability, thus offering a great advantage over classical convolutional neural networks (CNNs)., Conclusions: The proposed INSIDEnet is highly data-efficient, interpretable, and outperforms state-of-the-art CNNs when trained on very limited training data. We expect the proposed method to become an important tool as part of a dedicated plug-and-play GI-BCT reconstruction framework, needed to translate this promising technology to the clinics., (© 2022 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Grating interferometry breast computed tomography (GI-BCT) has the potential to provide enhanced soft tissue contrast and to improve visualization of cancerous lesions for breast imaging. However, with a conventional scanning protocol, a GI-BCT scan requires longer scanning time and higher operation complexity compared to conventional attenuation-based CT. This is mainly due to multiple grating movements at every projection angle, so-called phase stepping, which is used to retrieve attenuation, phase, and scattering (dark-field) signals. To reduce the measurement time and complexity and extend the field of view, we have adopted a helical GI-CT setup and present here the corresponding tomographic reconstruction algorithm. This method allows simultaneous reconstruction of attenuation, phase contrast, and scattering images while avoiding grating movements. Experiments on simulated phantom and real initial intensity, visibility and phase maps are provided to validate our method.

Background: X-ray grating interferometry normally requires multiple steps and exposures, causing a prolonged imaging time. There is motivation to use fewer steps to reduce scanning time and complexity, while keeping fidelity of the retrieved signals., Objective: We propose an iterative signal retrieval method, extracting attenuation, dark field contrast (DFC), and differential phase contrast (DPC) signals from two X-ray exposures., Methods: Two shots were captured at G2 grating positions with difference of 1/4 grating period. The algorithm consists of two stages. At the first stage, amplitude of sample phase stepping curve retrieved by virtual phase stepping (VPS) method, visibility and local phase of background phase stepping curve are used to limit the results to the proximity of the ground truth. After the second stage, three high-quality parameters, amplitude, visibility, and local phase, are retrieved through finetuning, and three signals are calculated. Simulated and real-sample experiments were conducted to validate this method., Results: We used standard phase stepping result as benchmark and calculated structural similarity (SSIM) and peak signal-to-noise ratio (PSNR) between benchmark and parameters retrieved by our dual-shot method and virtual phase stepping (VPS) method. For both simulated and real-sample experiments, the SSIM and PSNR value of dual-shot method are higher than those of VPS method. For real-sample method, we also conducted a three-step PS, and the SSIM and PSNR value of dual-shot method are slightly lower than those of three-step PS., Conclusion: Using our dual-shot method demonstrates higher performance than other single-shot method in retrieving high-quality signals, and it also reduces radiation dose and time.

The well-established functions of UHRF1 converge to DNA biological processes, as exemplified by DNA methylation maintenance and DNA damage repair during cell cycles. However, the potential effect of UHRF1 on RNA metabolism is largely unexplored. Here, we revealed that UHRF1 serves as a novel alternative RNA splicing regulator. The protein interactome of UHRF1 identified various splicing factors. Among them, SF3B3 could interact with UHRF1 directly and participate in UHRF1-regulated alternative splicing events. Furthermore, we interrogated the RNA interactome of UHRF1, and surprisingly, we identified U snRNAs, the canonical spliceosome components, in the purified UHRF1 complex. Unexpectedly, we found H3R2 methylation status determines the binding preference of U snRNAs, especially U2 snRNAs. The involvement of U snRNAs in UHRF1-containing complex and their binding preference to specific chromatin configuration imply a finely orchestrated mechanism at play. Our results provided the resources and pinpointed the molecular basis of UHRF1-mediated alternative RNA splicing, which will help us better our understanding of the physiological and pathological roles of UHRF1 in disease development., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

We present a method to produce small pitch gratings for X-ray interferometric imaging applications, allowing the phase sensitivity to be increased and/or the length of the laboratory setup to be minimized. The method is based on fabrication of high aspect ratio silicon microstructures using deep reactive ion etching (Bosch technique) of dense grating arrays and followed by conformal electroplating of Au. We demonstrated that low resistivity Si substrates (<0.01 Ohm·cm) enable the metal seeding layer deposition step to be avoided, which is normally required to initiate the electroplating process. Etching conditions were optimized to realize Si recess structures with a slight bottom tapering, which ensured the void-free Au filling of the trenches. Vapor HF was used to remove the native oxide layer from the Si grating surface prior to electroplating in the cyanide-based Au electrolyte. Fabrication of Au gratings with pitch in the range 1.2-3.0 µm was successfully realized. A substantial improved aspect ratio of 45:1 for a pitch size of 1.2 µm was achieved with respect to the prior art on 4-inch wafer-based technology. The fabricated Au gratings were tested with X-ray interferometers in Talbot-Laue configuration with measured visibility of 13% at an X-ray design energy of 26 keV.

X-ray phase contrast imaging is a powerful analysis technique for materials science and biomedicine. Here, we report on laboratory grating-based X-ray interferometry employing a microfocus X-ray source and a high Talbot order (35th) asymmetric geometry to achieve high angular sensitivity and high spatial resolution X-ray phase contrast imaging in a compact system (total length <1 m). The detection of very small refractive angles (∼50 nrad) at an interferometer design energy of 19 keV was enabled by combining small period X-ray gratings (1.0, 1.5 and 3.0 µm) and a single-photon counting X-ray detector (75 µm pixel size). The performance of the X-ray interferometer was fully characterized in terms of angular sensitivity and spatial resolution. Finally, the potential of laboratory X-ray phase contrast for biomedical imaging is demonstrated by obtaining high resolution X-ray phase tomographies of a mouse embryo embedded in solid paraffin and a formalin-fixed full-thickness sample of human left ventricle in water with a spatial resolution of 21.5 µm.

Introduction: Occurrence of urinary calculi is a common medical condition. Since treatment and prevention measures depend on the type of stone found, reliable diagnostic tools are required. Dual energy computed tomography (CT) allows for rough classification of the stones found. After extraction, stone composition can be confirmed by laboratory analysis.We investigated to which degree gratings-based X-ray interferometry, which can measure attenuation, refraction and scattering (dark-field) properties of samples, allows for the discrimination of urinary stone type by calculating the ratio (R) of attenuation and scattering signals., Material and Methods: In an experimental setup we investigated 322 renal stone fragments from 96 patients which were extracted during routine clinical practice. Laboratory analysis showed the chemical composition of the urinary stones.These were correlated with dark field analysis of the stone samples. Measurements were performed on a X-rays gratings interferometer prototype. The attenuation, refraction and scattering signals were measured and the R-value calculated., Results: The spread of R-values of a given type of calculi is large, reducing the specificity of the method. Only uric acid stones can reliably be distinguished (sensitivity of 0.86 at a specificity of 0.9) from the other stones., Conclusions: Gratings-based dark-field imaging is a non-destructive and potentially non-invasive technique that allows to discriminate between uric acid and non-uric acid stones, which from a clinical point of view represents by far the most important question for stone treatment., Competing Interests: The authors declare no conflicts of interest., (Copyright by Polish Urological Association.)

Purpose: In addition to absorption imaging, grating interferometry-based mammography (GIM) is capable of detecting differential-phase and scattering signals. In particular, the scattering signal can enable a quantifiable characterization of breast lesions. The purpose of this study was to determine if suspicious microcalcifications associated with benign or malignant lesions can be discriminated based on their absorption and scattering properties., Materials and Methods: In this prospective, ethically approved study, 62 patients (mean age 60 y, range 39-89) with suspicious microcalcifications, who underwent stereotactic biopsies, were included. Biopsies were measured with an experimental GIM device and the ratios of the scattering and absorption signal (R-value) for microcalcifications were calculated. The mean R-values for benign and malignant lesions associated with microcalcifications were compared with the final histopathological diagnosis using a t-test., Results: Twenty of the 62 participants had microcalcifications associated with malignancy. Comparing the two largest histopathological sub-groups of fibrosis (n = 23) vs. ductal carcinoma in situ (n = 15) resulted in an average R-value of 4.08 for benign and 2.80 for malignant lesions; p = 0.07. All microcalcifications associated with malignancy had an R-value below 4.71. Excluding microcalcifications with an R-value above this threshold would result in an 11 % reduction of false positives., Conclusion: The novel GIM modality has the potential to non-invasively characterize microcalcifications and might aid in the discrimination of benign from malignant lesions in fresh biopsy samples., Competing Interests: Declaration of Competing Interest All authors have approved the manuscript and agree with submission to European Journal of Radiology. The authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

X-ray grating interferometry (XGI) can provide access to unresolved sub-pixel information by utilizing the so-called dark-field or visibility reduction contrast. A recently developed variant of conventional XGI named dual-phase grating interferometer, based only on phase-shifting structures, has allowed for straightforward micro-structural investigations over multiple length scales with conventional X-ray sources. Nonetheless, the theoretical framework of the image formation for the dark-field signal has not been fully developed yet, thus hindering the quantification of unresolved micro-structures. In this work, we expand the current theoretical formulation of dual-phase grating interferometers taking into account polychromatic sources and beam hardening effects. We propose a model that considers the contribution of beam hardening to the visibility reduction and accounts for it. Finally, the method is applied to previously acquired and new experimental data showing that discrimination between actual micro-structures and beam hardening effects can be achieved.

Molecular mechanisms underlying adaptive targeted therapy resistance in pancreatic ductal adenocarcinoma (PDAC) are poorly understood. Here, we identify SETD5 as a major driver of PDAC resistance to MEK1/2 inhibition (MEKi). SETD5 is induced by MEKi resistance and its deletion restores refractory PDAC vulnerability to MEKi therapy in mouse models and patient-derived xenografts. SETD5 lacks histone methyltransferase activity but scaffolds a co-repressor complex, including HDAC3 and G9a. Gene silencing by the SETD5 complex regulates known drug resistance pathways to reprogram cellular responses to MEKi. Pharmacological co-targeting of MEK1/2, HDAC3, and G9a sustains PDAC tumor growth inhibition in vivo. Our work uncovers SETD5 as a key mediator of acquired MEKi therapy resistance in PDAC and suggests a context for advancing MEKi use in the clinic., Competing Interests: Declarations of Interests O.G. is a co-founder of EpiCyphe and Athelas Therapeutics. M.C.K., M.J.M., M.A.C., and S.A.H. are employees and shareholders of EpiCypher., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Grating-interferometry-based mammography (GIM) might facilitate breast cancer detection, as several research works have demonstrated in a pre-clinical setting, since it is able to provide attenuation, differential phase contrast, and scattering images simultaneously. In order to translate this technique to the clinics, it has to be adapted to cover a large field-of-view within a clinically acceptable exposure time and radiation dose., Methods: We set up a grating interferometer that fits into a standard mammography system and fulfilled the aforementioned conditions. Here, we present the first mastectomy images acquired with this experimental device., Results and Conclusion: Our system performs at a mean glandular dose of 1.6 mGy for a 5-cm-thick, 18%-dense breast, and a field-of-view of 26 × 21 cm2. It seems to be well-suited as basis for a clinical-environment device. Further, dark-field signals seem to support an improved lesion visualization. Evidently, the effective impact of such indications must be evaluated and quantified within the context of a proper reader study., Key Points: • Grating-interferometry-based mammography (GIM) might facilitate breast cancer detection, since it is sensitive to refraction and scattering and thus provides additional tissue information. • The most straightforward way to do grating-interferometry in the clinics is to modify a standard mammography device. • In a first approximation, the doses given with this technique seem to be similar to those of conventional mammography.

Purpose: Grating-based x-ray phase-contrast imaging (GPCI) is a promising technique for clinical applications as it can provide two newly emerging imaging modalities (differential phase-contrast and dark-field contrast) in addition to the conventional absorption contrast. As far, phase-stepping strategy is the most commonly used approach in GPCI to indirectly acquire differential phase-contrast and dark-field contrast. It is known that the obtained phase-stepping curves (PSCs) have the cosine property and the convolution property, leading to two types of information retrieval approaches in literature: the Fourier component analysis and the multi-order moment analysis. The purpose of this paper is to derive a new property of PSCs and apply the property to noise optimization for information retrieval., Methods: Based on the cosine expression of the flat PSC without the sample and the well-established convolution relationship between the flat PSC and the sample PSC, we reveal an important integral property of PSCs: the inner product of PSCs and an arbitrary function contains only zero-order and first-order components in the Fourier series. Furthermore, we apply the property to the direct multi-order moment analysis and propose a set of generalized forms including an optimal one in the presence of noise., Results: To validate the effectiveness of our analysis, we compared the simulated and real experiment results retrieved by the original direct multi-order moment analysis with the ones retrieved by our proposed noise-optimal form. A significant improvement of noise performance by our method is observed and the improvement ratio in differential phase-contrast is consistent with our theoretical calculation (39.2%)., Conclusions: In this paper, we reveal a new integral property of the acquired PSCs with and without samples in GPCI, which can be applied to information retrieval approaches like the direct multi-order moment analysis. Then we optimize these approaches to improve the noise performance, offering great potentials of dose reduction in practical applications., (© 2019 American Association of Physicists in Medicine.)

Insights into the micro- and nano-architecture of materials is crucial for understanding and predicting their macroscopic behaviour. In particular, for emerging applications such as meta-materials, the micrometer scale becomes highly relevant. The micro-architecture of such materials can be tailored to exhibit specific mechanical, optical or electromagnetic behaviours. Consequently, quality control at micrometer scale must be guaranteed over extended areas. Mesoscale investigations over millimetre sized areas can be performed by scanning small angle X-ray scattering methods (SAXS). However, due to their long measurement times, real time or operando investigations are hindered. Here we present a method based on X-ray diffractive optics that enables the acquisition of SAXS signals in a single shot (few milliseconds) over extended areas. This method is applicable to a wide range of X-ray sources with varying levels of spatial coherence and monochromaticity, as demonstrated from the experimental results. This enables a scalable solution of spatially resolved SAXS.

Grating interferometry mammography (GIM) is an experimental breast imaging method at the edge of being clinically implemented. Besides attenuation, GIM can measure the refraction and scattering of x-rays resulting in differential phase contrast (DPC) and dark-field (DF) images. In this exploratory study, we assessed the feasibility of using microbubbles as a contrast agent in GIM. Two millilitres of microbubbles and iodine were respectively injected into ex vivo breast phantoms, consisting of fresh chicken breasts. Native and postcontrast images were acquired with a clinically compatible GIM setup, operated at 38 kVp, 14-s acquisition time, and with a dose of 1.3 mGy. The visibility of the contrast agents was analysed in a side-by-side comparison by three radiologists. The contrast-to-noise-ratio (CNR) was calculated for each contrast agent. We found that both contrast agents were judged to be visible by the readers. The mean CNR was 3.1 ± 1.9 for microbubbles in DF and 24.2 ± 6.5 for iodine in attenuation. In conclusion, this is a first proof-of-mechanism study that microbubbles could be used as a contrast agent in clinically compatible GIM, due to their scattering properties, which implies the potential use of a contrast agent with a high safety profile in x-ray-based breast imaging.

Lysine methylation is a prevalent post-translational modification (PTM) used by the cell to reversibly regulate protein function. Although it has been extensively studied in the context of histones and the associated chromatin, the remaining methyllysine proteome remains largely unexplored. This SnapShot provides an overview of the current state of lysine methylation research and its emergence as a dynamic PTM occurring on histone and non-histone proteins., (Copyright © 2017. Published by Elsevier Inc.)

An X-ray grating interferometer (GI) suitable for clinical mammography must comply with quite strict dose, scanning time and geometry limitations, while being able to detect tumors, microcalcifications and other abnormalities. Such a design task is not straightforward, since obtaining optimal phase-contrast and dark-field signals with clinically compatible doses and geometrical constraints is remarkably challenging. In this work, we present a wave propagation based optimization that uses the phase and dark-field sensitivities as figures of merit. This method was used to calculate the optimal interferometer designs for a commercial mammography setup. Its accuracy was validated by measuring the visibility of polycarbonate samples of different thicknesses on a Talbot-Lau interferometer installed on this device and considering some of the most common grating imperfections to be able to reproduce the experimental values. The optimization method outcomes indicate that small grating pitches are required to boost sensitivity in such a constrained setup and that there is a different optimal scenario for each signal type.

MÖNCH is a 25 µm-pitch charge-integrating detector aimed at exploring the limits of current hybrid silicon detector technology. The small pixel size makes it ideal for high-resolution imaging. With an electronic noise of about 110 eV r.m.s., it opens new perspectives for many synchrotron applications where currently the detector is the limiting factor, e.g. inelastic X-ray scattering, Laue diffraction and soft X-ray or high-resolution color imaging. Due to the small pixel pitch, the charge cloud generated by absorbed X-rays is shared between neighboring pixels for most of the photons. Therefore, at low photon fluxes, interpolation algorithms can be applied to determine the absorption position of each photon with a resolution of the order of 1 µm. In this work, the characterization results of one of the MÖNCH prototypes are presented under low-flux conditions. A custom interpolation algorithm is described and applied to the data to obtain high-resolution images. Images obtained in grating interferometry experiments without the use of the absorption grating G 2 are shown and discussed. Perspectives for the future developments of the MÖNCH detector are also presented.

Nono is a component of the para-speckle, which stores and processes RNA. Mouse embryonic stem cells (mESCs) lack para-speckles, leaving the function of Nono in mESCs unclear. Here, we find that Nono functions as a chromatin regulator cooperating with Erk to regulate mESC pluripotency. We report that Nono loss results in robust self-renewing mESCs with epigenomic and transcriptomic features resembling the 2i (GSK and Erk inhibitors)-induced "ground state." Erk interacts with and is required for Nono localization to a subset of bivalent genes that have high levels of poised RNA polymerase. Nono loss compromises Erk activation and RNA polymerase poising at its target bivalent genes in undifferentiated mESCs, thus disrupting target gene activation and differentiation. These findings argue that Nono collaborates with Erk signaling to regulate the integrity of bivalent domains and mESC pluripotency., Competing Interests: Statement F.L. is a shareholder of Constellation Pharmaceuticals. Y.S. is a co-founder of Constellation Pharmaceuticals, Inc., as well as a member of its scientific advisory board. F.L. and Y.S. are also consultants for Active Motif, Inc., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

In X-ray grating interferometry, dark-field contrast arises due to partial extinction of the detected interference fringes. This is also called visibility reduction and is attributed to small-angle scattering from unresolved structures in the imaged object. In recent years, analytical quantitative frameworks of dark-field contrast have been developed for highly diluted monodisperse microsphere suspensions with maximum 6% volume fraction. These frameworks assume that scattering particles are separated by large enough distances, which make any interparticle scattering interference negligible. In this paper, we start from the small-angle scattering intensity equation and, by linking Fourier and real-space, we introduce the structure factor and thus extend the analytical and experimental quantitative interpretation of dark-field contrast, for a range of suspensions with volume fractions reaching 40%. The structure factor accounts for interparticle scattering interference. Without introducing any additional fitting parameters, we successfully predict the experimental values measured at the TOMCAT beamline, Swiss Light Source. Finally, we apply this theoretical framework to an experiment probing a range of system correlation lengths by acquiring dark-field images at different energies. This proposed method has the potential to be applied in single-shot-mode using a polychromatic X-ray tube setup and a single-photon-counting energy-resolving detector.

Regulation of enhancer activity is important for controlling gene expression programs. Here, we report that a biochemical complex containing a potential chromatin reader, RACK7, and the histone lysine 4 tri-methyl (H3K4me3)-specific demethylase KDM5C occupies many active enhancers, including almost all super-enhancers. Loss of RACK7 or KDM5C results in overactivation of enhancers, characterized by the deposition of H3K4me3 and H3K27Ac, together with increased transcription of eRNAs and nearby genes. Furthermore, loss of RACK7 or KDM5C leads to de-repression of S100A oncogenes and various cancer-related phenotypes. Our findings reveal a RACK7/KDM5C-regulated, dynamic interchange between histone H3K4me1 and H3K4me3 at active enhancers, representing an additional layer of regulation of enhancer activity. We propose that RACK7/KDM5C functions as an enhancer "brake" to ensure appropriate enhancer activity, which, when compromised, could contribute to tumorigenesis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Given the raw absorption and differential phase-contrast images obtained from a grating-based x-ray radiography, we formulate the joint denoising of the absorption image and retrieval of the non-differential phase image as a regularized inverse problem. The choice of the regularizer is driven by the existing correlation between absorption and differential phase; it leads to the linear combination of a total-variation norm with a total-variation nuclear norm. We then develop the corresponding algorithm to efficiently solve this inverse problem. We evaluate our method using different experiments, including mammography data. We conclude that our method provides useful information in the context of mammography screening and diagnosis.

X-ray scattering imaging can provide complementary information to conventional absorption based radiographic imaging about the unresolved microstructures of a sample. The scattering signal can be accessed with various methods based on coherent illumination, which span from self-imaging to speckle scanning. The directional sensitivity of the existing real space imaging methods is limited to a few directions on the imaging plane and requires scanning of the optical components, or the rotation of either the sample or the imaging setup, in order to cover the full range of possible scattering directions. In this Letter the authors propose a new method that allows the simultaneous acquisition of scattering images in all possible directions in a single shot. This is achieved by a specialized phase grating and a detector with sufficient spatial resolution to record the generated interference fringe. The structural length scale sensitivity of the system can be tuned by varying its geometry for a fixed grating design. Taking into account ongoing developments in the field of compact x-ray sources that allow high brightness and sufficient spatial coherence, the applicability of omnidirectional scattering imaging in industrial and medical settings is boosted significantly.

Phase contrast mammography using a grating interferometer is an emerging technology for breast imaging. It provides complementary information to the conventional absorption-based methods. Additional diagnostic values could be further obtained by retrieving quantitative information from the three physical signals (absorption, differential phase and small-angle scattering) yielded simultaneously. We report a non-parametric quantitative volumetric breast density estimation method by exploiting the ratio (dubbed the R value) of the absorption signal to the small-angle scattering signal. The R value is used to determine breast composition and the volumetric breast density (VBD) of the whole breast is obtained analytically by deducing the relationship between the R value and the pixel-wise breast density. The proposed method is tested by a phantom study and a group of 27 mastectomy samples. In the clinical evaluation, the estimated VBD values from both cranio-caudal (CC) and anterior-posterior (AP) views are compared with the ACR scores given by radiologists to the pre-surgical mammograms. The results show that the estimated VBD results using the proposed method are consistent with the pre-surgical ACR scores, indicating the effectiveness of this method in breast density estimation. A positive correlation is found between the estimated VBD and the diagnostic ACR score for both the CC view (p = 0.033) and AP view (p = 0.001). A linear regression between the results of the CC view and AP view showed a correlation coefficient γ = 0.77, which indicates the robustness of the proposed method and the quantitative character of the additional information obtained with our approach.

Differential phase contrast imaging using grating interferometer is a promising alternative to conventional X-ray radiographic methods. It provides the absorption, differential phase and scattering information of the underlying sample simultaneously. Phase retrieval from the differential phase signal is an essential problem for quantitative analysis in medical imaging. In this paper, we formalize the phase retrieval as a regularized inverse problem, and propose a novel discretization scheme for the derivative operator based on B-spline calculus. The inverse problem is then solved by a constrained regularized weighted-norm algorithm (CRWN) which adopts the properties of B-spline and ensures a fast implementation. The method is evaluated with a tomographic dataset and differential phase contrast mammography data. We demonstrate that the proposed method is able to produce phase image with enhanced and higher soft tissue contrast compared to conventional absorption-based approach, which can potentially provide useful information to mammographic investigations.

Our previous study identified five new heat shock factor 4 (HSF4) mutations in 150 age-related cataract (ARC) patients which indicated that HSF4 mutations may be associated with this disease. Hypoxia-inducible factor (Hif1α) is an important downstream target of HSF4b. It has been found that Hif1α play also important roles in cataract development. To identify if HSF4b play it role in cataract development through HIF1α, we transfected SRA01/04 lens epithelial cells with small hairpin RNA of HSF4b and measured expressions Hif1α after transfection. Then, we perform chromatin immunoprecipitation quantitative PCR to see the relationship between HSF4b and HIF1α. We found that HSF4 downregulation led to decrease of HIF1α mRNA expression. Furthermore, we demonstrated by ChIP followed by quantitative PCR (ChIP-qPCR) that these HIF-1α is bound by HSF4b near promoters, not gene bodies., (Copyright © 2014. Published by Elsevier Inc.)

BS69 (also called ZMYND11) contains tandemly arranged PHD, BROMO, and PWWP domains, which are chromatin recognition modalities. Here, we show that BS69 selectively recognizes histone variant H3.3 lysine 36 trimethylation (H3.3K36me3) via its chromatin-binding domains. We further identify BS69 association with RNA splicing regulators, including the U5 snRNP components of the spliceosome, such as EFTUD2. Remarkably, RNA sequencing shows that BS69 mainly regulates intron retention (IR), which is the least understood RNA alternative splicing event in mammalian cells. Biochemical and genetic experiments demonstrate that BS69 promotes IR by antagonizing EFTUD2 through physical interactions. We further show that regulation of IR by BS69 also depends on its binding to H3K36me3-decorated chromatin. Taken together, our study identifies an H3.3K36me3-specific reader and a regulator of IR and reveals that BS69 connects histone H3.3K36me3 to regulated RNA splicing, providing significant, important insights into chromatin regulation of pre-mRNA processing.

Among the existent X-ray phase-contrast modalities, grating interferometry appears as a very promising technique for commercial applications, since it is compatible with conventional X-ray tubes and is robust from a mechanical point of view. However, since applications such as medical imaging and homeland security demand covering a considerable field of view, the fabrication of large-area gratings, which is known to be challenging and expensive, would be needed. A scanning setup is a good solution for this issue, because it uses cheaper line instead of large-area 2D detectors and, therefore, would require smaller gratings. In such a setup, the phase-retrieval using the conventional phase-stepping approach would be very slow, so having a faster method to record the signals becomes fundamental. To tackle this problem, we present a scanning-mode grating interferometer design, in which a grating is tilted to form Moiré fringes perpendicular to the grating lines. The sample is then translated along the fringes, so each line detector records a different phase step for each slice of the sample. This new approach was tested both in a simulated scenario and in an experimental setting, and its performance was quantitatively satisfactory compared to the traditional phase-stepping method and another existing scanning-mode technique.

Microcalcifications can be indicative in the diagnosis of early breast cancer. Here we report a non-invasive diagnostic method that may potentially distinguish between different types of microcalcifications using X-ray phase-contrast imaging. Our approach exploits the complementary nature of the absorption and small-angle scattering signals of microcalcifications, obtained simultaneously with an X-ray grating interferometer on a conventional X-ray tube. We demonstrate that the new approach has 100% sensitivity and specificity when applied to phantom data, and we provide evidence of the solidity of the technique by showing its discrimination power when applied to fixed biopsies, to non-fixed tissue specimens and to fresh, whole-breast samples. The proposed method might be further developed to improve early breast cancer diagnosis and has the potential to increase the diagnostic accuracy and reduce the number of uncomfortable breast biopsies, or, in case of widespread microcalcifications, to select the biopsy site before intervention.

Objectives: Differential phase contrast and scattering-based x-ray mammography has the potential to provide additional and complementary clinically relevant information compared with absorption-based mammography. The purpose of our study was to provide a first statistical evaluation of the imaging capabilities of the new technique compared with digital absorption mammography., Materials and Methods: We investigated non-fixed mastectomy samples of 33 patients with invasive breast cancer, using grating-based differential phase contrast mammography (mammoDPC) with a conventional, low-brilliance x-ray tube. We simultaneously recorded absorption, differential phase contrast, and small-angle scattering signals that were combined into novel high-frequency-enhanced images with a dedicated image fusion algorithm. Six international, expert breast radiologists evaluated clinical digital and experimental mammograms in a 2-part blinded, prospective independent reader study. The results were statistically analyzed in terms of image quality and clinical relevance., Results: The results of the comparison of mammoDPC with clinical digital mammography revealed the general quality of the images to be significantly superior (P < 0.001); sharpness, lesion delineation, as well as the general visibility of calcifications to be significantly more assessable (P < 0.001); and delineation of anatomic components of the specimens (surface structures) to be significantly sharper (P < 0.001). Spiculations were significantly better identified, and the overall clinically relevant information provided by mammoDPC was judged to be superior (P < 0.001)., Conclusions: Our results demonstrate that complementary information provided by phase and scattering enhanced mammograms obtained with the mammoDPC approach deliver images of generally superior quality. This technique has the potential to improve radiological breast diagnostics.

X-ray grating interferometry is a promising tool for medical imaging because of its capability of providing additional and complementary information to conventional absorption-based methods. This technology can simultaneously measure absorption, differential phase and small-angle scattering signals from the sample, significantly improving the diagnostic content. In this work, we present a method which uses the image (dubbed the R image) obtained by taking the ratio of the absorption and small-angle scattering signals to gain quantitative insight from a radiographic x-ray projection. We demonstrate that with the help of the R image we can successfully distinguish among different (light-Z) plastic materials, which are usually used to mimic soft tissues. Two potential applications in medical imaging, such as quantitative x-ray radiography and volumetric breast density estimation, are demonstrated.

Traditional mammography can be positively complemented by phase contrast and scattering x-ray imaging, because they can detect subtle differences in the electron density of a material and measure the local small-angle scattering power generated by the microscopic density fluctuations in the specimen, respectively. The grating-based x-ray interferometry technique can produce absorption, differential phase contrast (DPC) and scattering signals of the sample, in parallel, and works well with conventional X-ray sources; thus, it constitutes a promising method for more reliable breast cancer screening and diagnosis. Recently, our team proved that this novel technology can provide images superior to conventional mammography. This new technology was used to image whole native breast samples directly after mastectomy. The images acquired show high potential, but the noise level associated to the DPC and scattering signals is significant, so it is necessary to remove it in order to improve image quality and visualization. The noise models of the three signals have been investigated and the noise variance can be computed. In this work, a wavelet-based denoising algorithm using these noise models is proposed. It was evaluated with both simulated and experimental mammography data. The outcomes demonstrated that our method offers a good denoising quality, while simultaneously preserving the edges and important structural features. Therefore, it can help improve diagnosis and implement further post-processing techniques such as fusion of the three signals acquired.

UHRF1 (Ubiquitin-like, with PHD and RING finger domains 1) plays an important role in DNA CpG methylation, heterochromatin function and gene expression. Overexpression of UHRF1 has been suggested to contribute to tumorigenesis. However, regulation of UHRF1 is largely unknown. Here we show that the deubiquitylase USP7 interacts with UHRF1. Using interaction-defective and catalytic mutants of USP7 for complementation experiments, we demonstrate that both physical interaction and catalytic activity of USP7 are necessary for UHRF1 ubiquitylation and stability regulation. Mass spectrometry analysis identified phosphorylation of serine (S) 652 within the USP7-interacting domain of UHRF1, which was further confirmed by a UHRF1 S652 phosphor (S652ph)-specific antibody. Importantly, the S652ph antibody identifies phosphorylated UHRF1 in mitotic cells and consistently S652 can be phosphorylated by the M phase-specific kinase CDK1-cyclin B in vitro. UHRF1 S652 phosphorylation significantly reduces UHRF1 interaction with USP7 in vitro and in vivo, which is correlated with a decreased UHRF1 stability in the M phase of the cell cycle. In contrast, UHRF1 carrying the S652A mutation, which renders UHRF1 resistant to phosphorylation at S652, is more stable. Importantly, cells carrying the S652A mutant grow more slowly suggesting that maintaining an appropriate level of UHRF1 is important for cell proliferation regulation. Taken together, our findings uncovered a cell cycle-specific signaling event that relieves UHRF1 from its interaction with USP7, thus exposing UHRF1 to proteasome-mediated degradation. These findings identify a molecular mechanism by which cellular UHRF1 level is regulated, which may impact cell proliferation.

Phase retrieval from unidirectional radiographic differential phase contrast images requires integration of noisy data. A method is presented, which aims to suppress stripe artifacts arising from direct image integration. It is purely algorithmic and therefore, compared to alternative approaches, neither additional alignment nor an increased scan time is required. We report on the theory of this method and present results using numerical as well as experimental data. The method shows significant improvements on the phase retrieval accuracy and enhances contrast in the phase image. Due to its general applicability, the proposed method provides a valuable tool for various 2D imaging applications using differential data.

Objectives: Phase-contrast and scattering-based x-ray imaging are known to provide additional and complementary information to conventional, absorption-based methods, and therefore have the potential to play a crucial role in medical diagnostics. We report on the first mammographic investigation of 5 native, that is, freshly dissected, breasts carried out with a grating interferometer and a conventional x-ray tube source. Four patients in this study had histopathologically proven invasive breast cancer. One male patient, without the presence of any malignant formations within the resected breast, was included as a control specimen., Materials and Methods: We used a Talbot-Lau grating setup installed on a conventional, low-brilliance x-ray source; the interferometer operated at the fifth Talbot distance, at a tube voltage of 40 kVp with mean energy of 28 keV, and at a current of 25 mA. The device simultaneously recorded absorption, differential phase and small-angle scattering signals from the native breast tissue. These quantities were then combined into novel color- and high-frequency-enhanced radiographic images. Presurgical images (conventional mammography, ultrasonography, and magnetic resonance imaging) supported the findings and clinical relevance was verified., Results: Our approach yields complementary and otherwise inaccessible information on the electron density distribution and the small-angle scattering power of the sample at the microscopic scale. This information can be used to potentially answer clinically relevant, yet unresolved questions such as unequivocally discerning between malignant and premalignant changes and postoperative scars and distinguishing cancer-invaded regions within healthy tissue., Conclusions: We present the first ex vivo images of fresh, native breast tissue obtained from mastectomy specimens using grating interferometry. This technique yields improved diagnostic capabilities when compared with conventional mammography, especially when discerning the type of malignant conversions and their breadth within normal breast tissue. These promising results advance us toward the ultimate goal, using grating interferometry in vivo on humans in a clinical setting.

Histone methylation occurs on both lysine and arginine residues, and its dynamic regulation plays a critical role in chromatin biology. Here we identify the UHRF1 PHD finger (PHD(UHRF1)), an important regulator of DNA CpG methylation, as a histone H3 unmodified arginine 2 (H3R2) recognition modality. This conclusion is based on binding studies and cocrystal structures of PHD(UHRF1) bound to histone H3 peptides, where the guanidinium group of unmodified R2 forms an extensive intermolecular hydrogen bond network, with methylation of H3R2, but not H3K4 or H3K9, disrupting complex formation. We have identified direct target genes of UHRF1 from microarray and ChIP studies. Importantly, we show that UHRF1's ability to repress its direct target gene expression is dependent on PHD(UHRF1) binding to unmodified H3R2, thereby demonstrating the functional importance of this recognition event and supporting the potential for crosstalk between histone arginine methylation and UHRF1 function., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Differential phase contrast imaging computed tomography (DPCI-CT) is a novel x-ray inspection method to reconstruct the distribution of refraction index rather than the attenuation coefficient in weakly absorbing samples. In this paper, we propose an iterative reconstruction algorithm for DPCI-CT which benefits from the new compressed sensing theory. We first realize a differential algebraic reconstruction technique (DART) by discretizing the projection process of the differential phase contrast imaging into a linear partial derivative matrix. In this way the compressed sensing reconstruction problem of DPCI reconstruction can be transformed to a resolved problem in the transmission imaging CT. Our algorithm has the potential to reconstruct the refraction index distribution of the sample from highly undersampled projection data. Thus it can significantly reduce the dose and inspection time. The proposed algorithm has been validated by numerical simulations and actual experiments.

High-resolution hard X-ray grating-based imaging method with conventional X-ray sources provides attenuation, refraction and scattering information synchronously, and it is regarded as the next-generation X-ray imaging technology for medical and industrial applications. In this letter, a large phase-stepping approach with at least one order of magnitude lower resolution of the movement is presented to equivalently substitute the current high-positioning-resolution phase-stepping approach. Both the theoretical deduction and actual experiment prove that the new approach is available to relax the requirement of high positioning resolution and strict circumstances so as to benefit the future commercial applications of the grating-based multiple-information imaging technology., ((c) 2010 Optical Society of America.)

A case-control study was conducted to examine the association between two single nucleotide polymorphisms (SNPs) in exon 2 of the bone morphogenetic protein-2 gene (BMP-2) and ossification of the posterior longitudinal ligament (OPLL), and to investigate whether SNPs of the Ser37Ala (T/G) and the Ser87Ser (A/G) in the BMP-2 gene are associated with genetic susceptibility to OPLL and its severity in Chinese subjects. The Ser87Ser (A/G) SNP has been implicated in bone mineral density (BMD) and increases the risk of OA in women. The Ser37Ala (T/G) SNP is associated with BMD and the rate of bone loss in osteoporosis and osteoporosis fractures. A total of 57 OPLL patients and 135 non-OPLL controls were studied. Radiographs of the cervical spine were analyzed to determine the presence and the severity of OPLL. The association of two SNPs with the occurrence and the extent of OPLL were statistically evaluated. There was a significant association between the Ser37Ala (T/G) polymorphism and the occurrence of OPLL in the cervical spine. However, no significant association was found between the Ser37Ala (T/G) polymorphism and the more number of ossified cervical vertebrae in OPLL patients. There was a significant association between the Ser87Ser (A/G) polymorphism and the more number of ossified cervical vertebrae in OPLL patients. However, there was no statistical difference between the Ser87Ser (A/G) SNP and the occurrence of OPLL in the cervical spine. In addition, the Ser87Ser (A/G) polymorphism in male patients and in female patients showed no statistical difference between cases and controls. The present results demonstrate that BMP-2 Gene is not only a factor associated with the occurrence of OPLL, but also a factor related to more extensive OPLL. The "G" allele in the Ser37Ala (T/G) polymorphism is associated with the occurrence of OPLL, but not more extensive OPLL in the cervical spine. The "G" allele in the Ser87Ser (A/G) polymorphism promotes the extent of OPLL, whereas the "A" allele in the Ser87Ser (A/G) polymorphism restricts ectopic ossification in the cervical spine at least in Chinese subjects.

The X-ray repair cross-complementing group 3 (XRCC3) is a highly suspected candidate gene for cancer susceptibility. However, association studies on the XRCC3 polymorphisms (4541A>G, Thr(241)Met, 17893A>G) in cancer have shown conflicting results. Therefore, we performed a meta-analysis to better assess the purported associations. Forty eight eligible case-control studies including 24,975 cancer patients and 34, 209 controls were selected for our meta-analysis. Overall, individuals carrying the XRCC3 Met/Met genotype showed a small cancer risk under a recessive genetic model. The subgroup and meta-regression analysis demonstrated different scenarios concerning the XRCC3 Met/Met genotype's role in cancer susceptibility for different subgroups. Specially, there was a significantly increased risk of breast cancer (OR, 1.14; P=0.0004; 95% CI, 1.06-1.23; P=0.37 for heterogeneity), elevated but not significant risk of cancer for head and neck, bladder, surprisingly, a significantly decreased risk of non-melanoma skin cancer (OR, 0.76; P=0.007; 95% CI, 0.62-0.93; P=0.61 for heterogeneity). A significantly elevated risk of cancer was observed in population-based case-control studies but not in nested or hospital based studies. Similarly, we found a significantly increased risk of cancer for A4541G and a decreased risk for A17893G under dominant genetic models. Our meta-analysis results support that the XRCC3 might represent a low-penetrance susceptible gene especially for cancer of breast, bladder, head and neck, and non-melanoma skin cancer. A single larger study should be required to further evaluate gene-gene and gene-environment interactions on XRCC3 polymorphisms and tissue-specific cancer risk in an ethnicity specific population.