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Effect of mutating individual cysteine residues of DPP3 on its interaction with KEAP1.

mRNA levels of DPP3, NRF2, NQO1, GCLM, KEAP1 and p62 in MCF7 cell lines stably overexpressing wt and mutant DPP3 species.

Effect of mutating individual cysteine residues of KEAP1 on DPP3 binding.

NRF2 is a transcription factor serving as a master regulator of the expression of many genes involved in cellular responses to oxidative and other stresses. In the absence of stress, NRF2 is constantly synthesized but maintained at low levels as it is targeted by KEAP1 for ubiquitination and proteasome-mediated degradation. NRF2 binds KEAP1 mainly through a conserved “ETGE” motif that has also been found in several other proteins, such as DPP3, which has been shown to bind KEAP1 and enhance NRF2 function upon overexpression. Here we demonstrate the interaction between endogenous DPP3 and endogenous KEAP1. We further show that the DPP3–KEAP1 interaction is strongly induced by hydrogen peroxide and that DPP3 is required for timely NRF2 induction and nuclear accumulation in the estrogen receptor (ER)-positive MCF7 breast cancer cells. Moreover, we present evidence that the binding of DPP3 to KEAP1 stabilizes the latter. Finally, we show that DPP3 is overexpressed in breast cancer and that elevated levels of DPP3 mRNA correlate with increased NRF2 downstream gene expression and poor prognosis, particularly for ER-positive breast cancer. Our studies reveal novel insights into the regulation of NRF2 and identify DPP3 and an NRF2 transcriptional signature as potential biomarkers for breast cancer prognosis and treatment. Cancer Res; 77(11); 2881–92. ©2017 AACR.

Effect of N-acetylcystein (NAC) on the DPP3-KEAP1 interaction.

High DPP3 mRNA expression correlates with poor relapse-free survival (RFS) of breast cancer patients in the Kaplan-Meier Plotter database.

Quantification of mRNA amount, qRT-PCR primer sequences, and transfection and immunoprecipitation methods.

BACKGROUND The immunologic effects of maintenance therapy in patients (pts) with AML in remission are not well-characterized but of high clinical interest, as rapid recovery of bone marrow (BM) after intensive chemotherapy (IC) may help delay relapse. Post IC, immunological interactions in the BM microenvironment present several immunosuppressive mechanisms. PD-L1 is commonly overexpressed on AML blasts, which is associated with worse prognosis. Oral azacitidine (Oral-AZA [CC-486]) is a hypomethylating agent recently approved in the US for pts with AML in complete remission (CR) or CR with incomplete hematologic recovery (CRi). To better understand the effects of Oral-AZA on immune cells, checkpoint expression of PD-L1/2 on AML blasts and normal myeloid progenitors (MPs), and the kinetics of T cell recovery and activation/exhaustion (eg, PD1, TIM3) were assessed. METHODS Biomarker-evaluable pts aged ≥ 55 years with AML were randomized 1:1 to Oral-AZA 300 mg (n=56) or placebo (PBO, n=52) post IC within 4 months of achieving CR. Flow cytometry evaluations of BM aspirates were performed at screening (ie, baseline [BL]), every 3 cycles until cycle 24 and every 6 cycles thereafter to cycle 36, or as clinically indicated. Correlative analyses of baseline immune parameters with median (med) relapse-free survival (RFS) were computed using Kaplan-Meier methods. RESULTS In the biomarker-evaluable pts, PD-L1 and PD-L2 expression at BL were higher on AML blasts (med intensity 7.1 and 2.9) than normal MPs (0.7 and 1.6). Most AML blasts were PD-L2+ (79%), whereas only 1.9% were PD-L1+. When stratified by the med, higher BL CD3 T cell numbers (as a % of total BM ) were associated with favorable RFS in both Tx arms (Oral-AZA: ≥ med, 562 days[d] and < med, 235d [P = .0308]; PBO: ≥ med, 325d and < med, 155d [P = .0391]). At cycle 3, pts in the Oral-AZA arm had a 1.7-fold increase in CD3 T cells from BL (PBO, 1.1; P = .0450), suggesting Oral-AZA can promote immunologic recovery during early Tx cycles. There was an inverse correlation between T cell exhaustion marker phenotypes (PD1/TIM3+) with CD4 (r = -.5967; P < .0001) and CD8 (r = -.2484; P = .0095) T cell numbers. An increase in RFS was seen in the PBO arm with lower PD1/TIM3+ CD4 numbers (< med, 429d; ≥ med, 155d; P = .0037), with a nominal increase observed in the Oral-AZA arm (< med, 428d; ≥ med, 303d; P = .6764). In a subset of pts, Oral-AZA appeared to suppress CD4 T cell exhaustion (PD1/TIM3+) compared with PBO. CONCLUSIONS Pts in CR/CRi post-IC have a unique immune profile defined by high expression of PD-L1 on a subset of blasts and a high % of PD-L2+ blasts. A higher BL CD3 T cell count after IC in BM was prognostic. Additionally, Oral-AZA appears to contribute to an increase in T cells while also suppressing exhaustion, potentially promoting T cell signaling that could activate functional immune-mediated responses against residual leukemic cells. Citation Format: Daniel L. Menezes, Wendy L. See, Alberto Risueno, Jianglin Ma, Ignazia La Torre, Barry Skikne, CL Beach, Keshava Kumar, Anjan Thakurta. Oral azacitidine modulates the immune microenvironment in acute myeloid leukemia (AML) patients in remission: A subanalysis from the QUAZAR AML-001 Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 505.

Introduction Spebrutinib (CC-292) is an orally administered, covalent, small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), part of the B-cell and Fc receptor signaling pathways. This study evaluated spebrutinib pharmacology and mechanism of action over a 4-week treatment period in patients with active rheumatoid arthritis (RA). Methods Primary human B cells, T cells, natural killer cells, macrophages, dendritic cells, basophils, and osteoclasts were treated with spebrutinib in vitro. Clinical pharmacodynamics were studied in 47 patients with active RA on background methotrexate therapy randomized to oral spebrutinib 375 mg/day or placebo. Results In vitro, spebrutinib inhibited B-cell proliferation more potently than T-cell proliferation and reduced both lymphoid and myeloid cytokine production and degranulation, as well as osteoclastogenesis. Clinical efficacy trended higher in spebrutinib-treated RA patients, with 41.7% (10/24) achieving ≥ 20% improvement in ACR response criteria (ACR20) versus 21.7% (5/23) of placebo patients at week 4 (P = 0.25). Treatment-emergent adverse events were comparable between treatment groups. In spebrutinib-treated patients, median BTK occupancy in peripheral blood was 83%, and significant increases in total CD19+ and mature-naive CD27−CD38−IgD+ B cells and decreases in transitional CD27−CD38+ B cells were observed. Spebrutinib significantly reduced serum chemokines chemokine ligand 13 (CXCL13), macrophage inflammatory protein-1β (MIP-1β), and the bone resorption biomarker carboxy-terminal collagen cross-linking telopeptide (CTX-I) (P

When an optical remote sensing satellite is imaging the Earth in-orbit, the propagation direction of the Line of Sight (LOS) will be changed because of atmospheric refraction. This will result in a geolocation deviation on the collinear rigorous geometric model for direct georeferencing, pushbroom images. To estimate and correct the atmospheric refraction geolocation error, the LOS vector tracking algorithm is introduced and a weighted mean algorithm is used to simplify the ISO standard atmospheric model into a troposphere and stratosphere, i.e., two layers spherical atmosphere. The simulation result shows the atmospheric refraction will introduce about 2 m and 7.5 m geometric displacement when the spacecraft is off-pointed view at 30 and 45 degree angle, respectively. For a state-of-the-art high resolution satellite, the atmospheric refraction displacement shall be corrected. The method has been practiced in the DMC3/TripleSat Constellation to remove the atmospheric refraction geolocation error without ground control points.

Background: Luspatercept is a first-in-class erythroid maturation agent that binds TGF-β superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis. The phase 3 MEDALIST trial evaluated luspatercept in pts with RBC transfusion-dependent, IPSS-R-defined very low-, low-, and intermediate-risk MDS with ring sideroblasts (RS+) who were refractory, intolerant, or ineligible to receive erythropoiesis-stimulating agents. This study explored associations of gene mutations, as analyzed by next-generation sequencing (NGS), with response to luspatercept, as well as dynamics of gene mutations on therapy in MEDALIST pts. Methods: DNA was isolated from bone marrow (BM) mononuclear cells from 222 of 229 pts enrolled in the study (148 luspatercept, 74 placebo) at screening and, when available, following treatment. NGS of 23 MDS-relevant genes was performed at screening and every 24 weeks; mean coverage was 1,000-fold and the variant allele frequency (VAF) cutoff was ≥ 1%. BM cell populations were analyzed by cytomorphology. Response criterion of RBC transfusion independence (RBC-TI) of ≥ 8 weeks within the first 24 weeks of treatment was used for correlative analyses. Results: Mutations in SF3B1 were found in 91.0% of pts analyzed at screening (median VAF 42%, range 6-71%), consistent with the study population being RS+. Overall, a median of 2 (range 0-5) of the 23 MDS-relevant genes analyzed were mutated per pt. In addition to SF3B1, the most frequently mutated genes were TET2 (41.9%), DNMT3A (18.9%), ASXL1 (13.1%), and SRSF2 (8.1%). Mutation profiles were similar to those found in previous studies of refractory anemia with RS (RARS; Malcovati L, et al. Blood. 2015;126:233-41) and balanced between luspatercept and placebo arms. Numbers of mutated genes at baseline were distributed similarly in luspatercept responders (R) and non-responders (NR) (Figure A), and comparable response rates were achieved irrespective of number of mutations, with response rates of 36.4%, 34.9%, 42.4%, and 33.3% for pts with 1 mutation, 2 mutations, 3 mutations, and 4 or 5 mutations in the 23 MDS-relevant genes analyzed, respectively. Response to luspatercept was independent of the presence of mutations in any of the genes analyzed individually (Figure B) or when grouped by functional categories (e.g. spliceosome, epigenetic regulation, transcription factor, etc.) (Figure C). Circos plots of co-occurring mutations showed similar mutation profiles in R and NR (Figure D). Response rates were also similar regardless of baseline SF3B1 allelic burden (R: 43%, NR: 42%; P = 0.11). At baseline, BM erythroid precursors were higher in R (R: 32.8%, NR: 26%; P = 0.008; while R and NR had similar levels of RS+ cells [R: 80%, NR: 84%; P = 0.25], Figure E), consistent with the postulated activity of luspatercept on the erythroid lineage. When comparing the frequency of mutation changes in luspatercept- vs placebo-treated pts at week 24 of the study, no statistically significant differences were observed in the frequency of newly acquired mutations (13/126 [10.3%] pts in luspatercept vs 8/64 [12.5%] pts in placebo, P = 0.63) or mutation losses (4/126 [3.2%] in luspatercept vs 5/64 [7.8%] in placebo, P = 0.17). Evaluation of changes in allele burden (median VAF at week 24 vs baseline) for mutations in genes associated with adverse prognosis (ASXL1, SRSF2, U2AF1, NRAS, IDH2, GATA2, TP53, RUNX1, and EZH2; Bejar R. Curr Opin Hematol. 2017;24:73-8) showed no change between luspatercept- or placebo-treated pts (1.01-fold, n = 58 and 0.95-fold, n = 19, respectively, P = 0.69). Conclusions: Pts enrolled in the MEDALIST study had mutations consistent with RS+, lower-risk MDS with a preponderance of SF3B1 mutations; genes associated with poor prognosis (and other genes) were balanced between study arms. RBC-TI responses with luspatercept were achieved regardless of SF3B1 allelic burden, number of baseline mutations, and presence of individual mutations, including adverse mutations, or co-mutations. Disclosures Platzbecker: Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Dunshee:Celgene Corporation: Employment, Equity Ownership. Komrokji:DSI: Consultancy; pfizer: Consultancy; Agios: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy; celgene: Consultancy; JAZZ: Speakers Bureau. Mufti:Cellectis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Garcia-Manero:Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding. Buckstein:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding. Santini:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Díez-Campelo:Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. See:Celgene Corporation: Other: Contractor. Tsai:Celgene Corporation: Employment. Risueño:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties: Named in Celgene patent filings related to predictive patient response biomarkers in hematological malignancies. Ma:Celgene Corporation: Employment, Equity Ownership. Schwickart:Celgene Corporation: Employment, Equity Ownership. Rampersad:Celgene Corp: Employment, Equity Ownership. Zhang:Celgene Corporation: Employment, Equity Ownership. Laadem:Celgene Corporation: Employment, Equity Ownership. Menezes:Celgene Corporation: Employment, Equity Ownership. MacBeth:Celgene Corporation: Employment, Equity Ownership. Linde:Acceleron Pharma: Employment, Equity Ownership; Abbott Laboratories, Inc.: Equity Ownership; Fibrogen, Inc.: Equity Ownership. Reynolds:Acceleron Pharma: Employment, Equity Ownership. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux:Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Aprea: Research Funding. OffLabel Disclosure: Luspatercept is an investigational therapy that is not approved for any use in any country. Luspatercept is currently being evaluated for potential use in patients with anemia due to myelodysplastic syndromes, beta-thalassemia, or myelofibrosis.

This paper proposes a hybrid fusion method that can combine the advantages of two popular image fusion schemes: fusion in the spatial domain and fusion in the transform domain. The Extend IHS (EIHS) fusion method is chosen within the spatial domain fusion scheme because this method can well maintain the spatial details of the panchromatic image while reducing the spectral distortion of the multispectral images by taking into account the spectral response of each spectral band. However, using EIHS may lead to severe spectral distortion in some cases as we will discover in this paper, hence Nonsubsampled Contourlet Transform (NSCT) is introduced as it can preserve the spectrum discontinuity of multispectral images. By doing so, both spatial details in the panchromatic image and spectral information in the multispectral image are kept in the fused image. Experiments with QuickBird and IKONOS satellite images show that the proposed method can obtain better visual fusion results than traditional image fusion methods, which is also supported by the image fusion numerical criteria.

NRF2 is a transcription factor serving as a master regulator of the expression of many genes involved in cellular responses to oxidative and other stresses. In the absence of stress, NRF2 is constantly synthesized but maintained at low levels as it is targeted by KEAP1 for ubiquitination and proteasome-mediated degradation. NRF2 binds KEAP1 mainly through a conserved “ETGE” motif that has also been found in several other proteins, such as DPP3, which has been shown to bind KEAP1 and enhance NRF2 function upon overexpression. Here we demonstrate the interaction between endogenous DPP3 and endogenous KEAP1. We further show that the DPP3–KEAP1 interaction is strongly induced by hydrogen peroxide and that DPP3 is required for timely NRF2 induction and nuclear accumulation in the estrogen receptor (ER)-positive MCF7 breast cancer cells. Moreover, we present evidence that the binding of DPP3 to KEAP1 stabilizes the latter. Finally, we show that DPP3 is overexpressed in breast cancer and that elevated levels of DPP3 mRNA correlate with increased NRF2 downstream gene expression and poor prognosis, particularly for ER-positive breast cancer. Our studies reveal novel insights into the regulation of NRF2 and identify DPP3 and an NRF2 transcriptional signature as potential biomarkers for breast cancer prognosis and treatment. Cancer Res; 77(11); 2881–92. ©2017 AACR.

This paper proposes a novel method of segment-tree filtering to improve the classification accuracy of hyperspectral image (HSI). Segment-tree filtering is a versatile method that incorporates spatial information and has been widely applied in image preprocessing. However, to use this powerful framework in hyperspectral image classification, we must reduce the original feature dimensionality to avoid the Hughes problem; otherwise, the computational costs are high and the classification accuracy by original bands in the HSI is unsatisfactory. Therefore, feature extraction is adopted to produce new salient features. In this paper, the Semi-supervised Local Fisher (SELF) method of discriminant analysis is used to reduce HSI dimensionality. Then, a tree-structure filter that adaptively incorporates contextual information is constructed. Additionally, an initial classification map is generated using multi-class support vector machines (SVMs), and segment-tree filtering is conducted using this map. Finally, a simple Winner-Take-All (WTA) rule is applied to determine the class of each pixel in an HSI based on the maximum probability. The experimental results demonstrate that the proposed method can improve HSI classification accuracy significantly. Furthermore, a comparison between the proposed method and the current state-of-the-art methods, such as Extended Morphological Profiles (EMPs), Guided Filtering (GF), and Markov Random Fields (MRFs), suggests that our method is both competitive and robust.

This paper presents a robust locally weighted least-squares kernel regression method for superresolution (SR) enhancement of multi-angle remote sensing imagery. The method is based on the concept of kernel-based regression, where the local image patch is approximated by an \mbiN-term Taylor series. To reduce the impact of high frequency noise on SR performance, a robust fitting procedure is adopted. The approach proposed is tested with simulated multi-angle data derived from panchromatic WorldView-2 imagery and with real multi-angle WorldView-2 remote sensing images.

This cross-sectional study compared 120 children having severe acute malnutrition with 120 healthy children for exposure to 40 behaviors, by measuring psychosocial care based on Home Observation for Measurement of the Environment (HOME) inventory. The mean (SD) psychosocial care score of cases and controls significantly differed [18.2 (2.2) vs 23.5 (2.1); P

We studied the level of high mobility group box 1(HMGB1) in preterm infants with intraventricular hemorrhage (IVH). Using enzyme-linked immunosorbent assay (ELISA), the concentration of HMGB1 in cord blood obtained from 41 infants with IVH and 67 infants without IVH were measured. The cord blood concentration of HMGB1 in infants with IVH were significantly higher than those without IVH (P=0.041). Increased levels of HMGB1 might be associated with IVH in preterm infants.

PALB2/FANCN is mutated in breast and pancreatic cancers and Fanconi anemia (FA). It controls the intranuclear localization, stability, and DNA repair function of BRCA2 and links BRCA1 and BRCA2 in DNA homologous recombination repair and breast cancer suppression. Here, we show that PALB2 directly interacts with KEAP1, an oxidative stress sensor that binds and represses the master antioxidant transcription factor NRF2. PALB2 shares with NRF2 a highly conserved ETGE-type KEAP1 binding motif and can effectively compete with NRF2 for KEAP1 binding. PALB2 promotes NRF2 accumulation and function in the nucleus and lowers the cellular reactive oxygen species (ROS) level. In addition, PALB2 also regulates the rate of NRF2 export from the nucleus following induction. Our findings identify PALB2 as a regulator of cellular redox homeostasis and provide a new link between oxidative stress and the development of cancer and FA.

Superresolution (SR) image reconstruction is a technique to obtain a high-resolution (HR) image from a set of low-resolution images. Compact High Resolution Imaging Spectrometer (CHRIS)/Project for On-Board Autonomy (Proba) is a transitional hyperspectral-oriented satellite which acquires multiple angular images of the same scene. The angular images acquired within a very short period of time are ideal for SR operation. Recent developments point to the possibility of a SR-enhanced CHRIS data set at higher resolution. Apparently, the additional details are valuable information for many applications. This letter presents the preliminary evaluation of the SR CHRIS images for ecotope mapping and subpixel classification of sealed surface using two different scenes in Belgium. Accuracy obtained from SR CHRIS images is comparable to that of the original CHRIS, but with significantly more detail in the final classification map. In view of the demands for HR hyperspectral data sets, SR operation can be an interesting option to mitigate the lower spatial resolution of the current and future spaceborne hyperspectral images. Properties such as quick revisiting time and angular acquisition of a hyperspectral satellite are important for the success of SR operations.

Subpixel image registration is the key to successful image fusion and superresolution enhancement of multiangle satellite data. Multiangle image registration poses two main challenges: 1) Images captured at large view angles are susceptible to resolution change and blurring, and 2) local geometric distortion caused by topographic effects and/or platform instability may be important. In this paper, we propose a two-step nonrigid automatic registration scheme for multiangle satellite images. In the first step, control points (CPs) are selected in a preregistration process based on the scale-invariant feature transform (SIFT). However, the number of CPs obtained in this first step may be too few and/or CPs may be unevenly distributed. To remediate these problems, in a second step, the preliminary registered image is subdivided into chips of 64 x 64 pixels, and each chip is matched with a corresponding chip in the reference image using normalized cross correlation (NCC). By doing so, more CPs with better spatial distribution are obtained. Two criteria are applied during the generation of CPs to identify outliers. Selected SIFT and NCC CPs are used for defining a nonrigid thin-plate-spline model. The proposed registration scheme has been tested using data from the Compact High Resolution Imaging Spectrometer (CHRIS) onboard the Project for On-Board Autonomy (Proba) satellite. Experimental results demonstrate that the proposed method works well in areas with little variation in topography. Application in areas with more pronounced relief would require the use of orthorectified image data in order to achieve subpixel registration accuracy.

Given the hyperspectral-oriented waveband configuration of multiangular CHRIS/Proba imagery, the scope of its application could widen if the present 18-m resolution would be improved. The multiangular images of CHRIS could be used as input for superresolution (SR) image reconstruction. A critical procedure in SR is an accurate registration of the low-resolution images. Conventional methods based on affine transformation may not be effective given the local geometric distortion in high off-nadir angular images. This paper examines the use of a nonrigid transform to improve the result of a nonuniform interpolation and deconvolution SR method. A scale-invariant feature transform is used to collect control points (CPs). To ensure the quality of CPs, a rigorous screening procedure is designed: 1) an ambiguity test; 2) the m-estimator sample consensus method; and 3) an iterative method using statistical characteristics of the distribution of random errors. A thin-plate spline (TPS) nonrigid transform is then used for the registration. The proposed registration method is examined with a Delaunay triangulation-based nonuniform interpolation and reconstruction SR method. Our results show that the TPS nonrigid transform allows accurate registration of angular images. SR results obtained from simulated LR images are evaluated using three quantitative measures, namely, relative mean-square error, structural similarity, and edge stability. Compared to the SR methods that use an affine transform, our proposed method performs better with all three evaluation measures. With a higher level of spatial detail, SR-enhanced CHRIS images might be more effective than the original data in various applications.

SummaryBRCA1 and BRCA2 are often mutated in familial breast and ovarian cancer. Both tumor suppressors play key roles in the DNA-damage response [1, 2]. However, it remains unclear whether these two tumor suppressor function together in the same DNA-damage response pathway. Here, we show that BRCA1 associates with BRCA2 through PALB2/FANCN, a major binding partner of BRCA2 [3]. The interaction between BRCA1 and BRCA2 is abrogated in PALB2-deficient Fanconi anemia cells and in the cells depleted of PALB2 by small interfering RNA. Moreover, we show that BRCA1 promotes the concentration of PALB2 and BRCA2 at DNA-damage sites and the interaction between BRCA1 and PALB2 is important for the homologous recombination repair. Taken together, our results indicate that BRCA1 is an upstream regulator of BRCA2 in the DNA-damage response, and PALB2 is the linker between BRCA1 and BRCA2.

A regulated shift from the production of membrane to secretory forms of Immunoglobulin M (IgM) mRNA occurs during B cell differentiation due to the activation of an upstream secretory poly(A) site. U1A plays a key role in inhibiting the expression of the secretory poly(A) site by inhibiting both cleavage at the poly(A) site and subsequent poly(A) tail addition. However, how the inhibitory effect of U1A is alleviated in differentiated cells, which express the secretory poly(A) site, is not known. Using B cell lines representing different stages of B cell differentiation, we show that the amount of U1A available to inhibit the secretory poly(A) site is reduced in differentiated cells. Undifferentiated B cells have more total U1A than differentiated cells and a greater proportion of this is not associated with the U1snRNP. We show that this is available to inhibit poly(A) addition at the secretory poly(A) site using cold competitor RNA oligos to de-repress poly(A) addition in nuclear extracts from the respective cell lines. In addition, endogenous non-snRNP associated U1A—immunopurified from the different cell lines—inhibits poly(A) polymerase activity proportional to U1A recovered, suggesting that available U1A level alone is responsible for changes in its inhibitory effect at the secretory IgM poly (A) site.

NRF2 is a transcription factor serving as a master regulator of the expression of many genes involved in cellular responses to oxidative and other stresses. In the absence of stress, NRF2 is constantly synthesized but maintained at low levels as it is targeted by KEAP1 for ubiquitination and proteasome-mediated degradation. NRF2 binds KEAP1 mainly through a conserved “ETGE” motif that has also been found in several other proteins, such as DPP3, which has been shown to bind KEAP1 and enhance NRF2 function upon overexpression. Here we demonstrate the interaction between endogenous DPP3 and endogenous KEAP1. We further show that the DPP3-KEAP1 interaction is strongly induced by hydrogen peroxide and that DPP3 is required for hydrogen peroxide-induced NRF2 nuclear accumulation in the estrogen receptor (ER)-positive MCF7 breast cancer cells. Finally, we present evidence that DPP3 is overexpressed in breast cancer and that elevated levels of DPP3 mRNA correlate with increased NRF2 downstream gene expression and poor prognosis, particularly for ER-positive breast cancer. Our studies reveal novel insights into the regulation of NRF2 and identify DPP3 and an NRF2 transcriptional signature as potential biomarkers for breast cancer prognosis and treatment.

In this paper, the potential of superresolution (SR) image reconstruction methods for sub-pixel land-cover mapping in dense urban areas is studied. A multiple endmember approach (MESMA) is used for unmixing both original hyperspectral CHRIS/Proba and SR enhanced CHRIS/Proba data. Validation based on high resolution orthophotos (25 cm) shows that land-cover fraction maps generated from SR-enhanced CHRIS/Proba data (9 m) have a lower overall fractional error compared to the land-cover fractions produced from the original CHRIS data (18 m), when validating both results at the 18 m resolution. Validation of SR results at the 9 m resolution produces an overall mean absolute error (OMAE) of 16.7% compared to an OMAE of 14.3% at the 18 m resolution, with the original data, yet the impervious surface map produced at 9 m has a much higher level of detail than the original map, better representing the built-up pattern of the urban environment. Detailed analysis of impervious surface mapping results for different reference proportion intervals points at smaller average fractional errors for impervious surface fractions produced from SR-enhanced data when validation is done at the original 18 m resolution, over the entire range of proportions. Only for pixels not containing any impervious surface cover the fractional error is marginally higher than with the original data. These results demonstrate the potential of SR-enhanced data for more accurate impervious surface mapping in dense and heterogeneous urban areas.

BackgroundHeterogeneous nuclear ribonucleoprotein C1/C2 (hnRNP C) is a core component of 40S ribonucleoprotein particles that bind pre-mRNAs and influence their processing, stability and export. Breast cancer tumor suppressors BRCA1, BRCA2 and PALB2 form a complex and play key roles in homologous recombination (HR), DNA double strand break (DSB) repair and cell cycle regulation following DNA damage.MethodsPALB2 nucleoprotein complexes were isolated using tandem affinity purification from nuclease-solubilized nuclear fraction. Immunofluorescence was used for localization studies of proteins. siRNA-mediated gene silencing and flow cytometry were used for studying DNA repair efficiency and cell cycle distribution/checkpoints. The effect of hnRNP C on mRNA abundance was assayed using quantitative reverse transcriptase PCR.Results and significanceWe identified hnRNP C as a component of a nucleoprotein complex containing breast cancer suppressor proteins PALB2, BRCA2 and BRCA1. Notably, other components of the 40S ribonucleoprotein particle were not present in the complex. hnRNP C was found to undergo significant changes of sub-nuclear localization after ionizing radiation (IR) and to partially localize to DNA damage sites. Depletion of hnRNP C substantially altered the normal balance of repair mechanisms following DSB induction, reducing HR usage in particular, and impaired S phase progression after IR. Moreover, loss of hnRNP C strongly reduced the abundance of key HR proteins BRCA1, BRCA2, RAD51 and BRIP1, which can be attributed, at least in part, to the downregulation of their mRNAs due to aberrant splicing. Our results establish hnRNP C as a key regulator of BRCA gene expression and HR-based DNA repair. They also suggest the existence of an RNA regulatory program at sites of DNA damage, which involves a unique function of hnRNP C that is independent of the 40S ribonucleoprotein particles and most other hnRNP proteins.

In this paper we propose an operational superresolution (SR) approach for multi-temporal and multi-angle remote sensing imagery. The method consists of two stages: registration and reconstruction. In the registration stage a hybrid patch-based registration scheme that can account for local geometric distortion and photometric disparity is proposed. Obstacles like clouds or cloud shadows are detected as part of the registration process. For the reconstruction stage a SR reconstruction model composed of the L1 norm data fidelity and total variation (TV) regularization is defined, with its reconstruction object function being efficiently solved by the steepest descent method. Other SR methods can be easily incorporated in the proposed framework as well. The proposed algorithms are tested with multi-temporal and multi-angle WorldView-2 imagery. Experimental results demonstrate the effectiveness of the proposed approach.

It is important to measure the spatial performance of an in-flight satellite sensor to determine if any spatial resolution degradations occur over time; then some compensation methods can be adopted to improve the image quality. In satellite on-orbit measurements of spatial resolution, the performance of the sensors can be objectively evaluated through the point spread function (PSF) or modulation transfer function (MTF). The well-known image-based PSF derivation method of sampling along a slanted linear step structure from the degraded image is widely used in the satellite image restoration area. Due to the non-uniformity of the linear ground objects, generally, the operators have to pick out good profiles from all the profiles along the edge in order to increase the estimation accuracy. However, only some qualitative criteria have been proposed in the literature to instruct researchers how to pick out good profiles. In this article, we propose a method to quantitatively measure the homogeneity and contrast of the candidate linear structures in order to extract the optimal profiles. This method first automatically detects and locates the slanted linear step edge object in the image. Then it measures the homogeneity and the contrast at each location along the edge by using two adjacent square regions on both sides of the linear step structure. The locations that have high measurement values are regarded as the optimal locations. Finally, the optimal profiles can be extracted at these edge locations to derive an accurate PSF estimation by differentiation. This method makes an automatic optimal step edge detection method for PSF derivation to be practical. Experiment results on simulated and real images are provided. This article shows that using only the 'optimal' profiles can play a real and important role and can achieve a good PSF estimation result.

Floor Area Ratio (FAR) is an important indicator in urban planning and other urban applications, therefore, it is of great significance to acquire FAR of the functional areas in the city. Traditional method to acquire FAR is slow and of low efficiency. FAR calculation by remote sensing methods can overcome these shortcomings above, so many scholars in recent year's concerns about it. But methods through aerial photography or satellite optical images are of low accuracy and much manual intervention is needed. Airborne Laser Scanning remote sensing is a new three-dimensional information acquisition means in the urban areas. This paper presents a new method to calculate FAR using Airborne Laser Scanning Data. Experiment shows that this method can get a high rate of accuracy without a lot of human intervention.

A classifier-based method to select and fuse grey level co-occurrence matrix (GLCM), Gaussian Markov random field (GMRF) and discrete wavelet transform (DWT) features to improve texture discrimination is presented. Feature selection via wrapper approaches is applied to find the optimal combination of texture features. The fused features have obtained higher discrimination accuracy compared with individual features. The curse of dimensionality is shown to affect discrimination accuracy, and feature selection and reduction helps obtain higher accuracy. Overall our proposed classifier-based method obtains the highest discrimination accuracy compared to other feature reduction methods such as principal component analysis (PCA) and linear discriminant analysis (LDA). Meanwhile GLCM features are found to produce higher discrimination accuracy than GMRF and DWT, and LDA is demonstrated to obtain higher discrimination accuracy than PCA.

CHRIS/Proba represents a new generation of hyperspectral-oriented data that provides different viewing angles of the same scene. This multi-angle acquisition, with 18 bands between 0.4-1 micrometer at five different angles, can substantially improve characterization of various land-cover types. However, with around 18m pixel size, the spatial resolution is still too coarse for many applications. To improve the resolution of CHRIS data, we propose the use of a superresolution (SR) image reconstruction method utilizing the information present in the multi-angle imagery. CHRIS images were first pre-processed and atmospherically corrected. Then a selected superresolution method was applied to upscale the spatial resolution to around 10m. The SR enhanced images show significant improvements in terms of contrasts and detail. The added value of SR imagery for land-cover classification and spectral unmixing was evaluated. In terms of classification accuracy, the use of SR CHRIS images leads to marginal increase in classification accuracies. The large amount of additional classification detail requires extended ground truth for validation. Spectral unmixing applied on SR CHRIS shows that fraction images have more detail and are more accurate than the fraction images derived from the original CHRIS images.

Subpixel image registration is the key to successful multi-angle remote sensing image applications such as image fusion,superresolution and classification. However, multi-angle remote sensing images pose some difficulties for automatic image registration, namely, 1) precisely locating control points (CPs) is difficult as large view angle images are susceptible to resolution change and blurring; and 2) local geometric distortion caused by variations in platform stability makes rigid transform models such as the projective model unreliable. In this paper we propose a two-stage automatic registration scheme for multi-angle remote sensing imagery. In the first step, CPs are gathered via the scale invariant feature transform (SIFT). However, CPs collected by SIFT may be too few or unevenly distributed. Therefore, another CPs collecting procedure based on normalized cross-correlation follows. In order to eliminate outliers in the CPs a geometric constraint is utilized; after outlier elimination in order to get CPs of high accuracy for the estimation of the thin plate spline model, which is used to solve the local geometric distortion problem, a pre-fitting procedure is adopted. The methodology developed in this paper is applied to three Compact High Resolution Imaging Spectrometer onboard the Project for On-board Autonomy (CHRIS/Proba) images. Experimental results demonstrate the efficiency and accuracy of the proposed method.