Search

Previous diffusion tensor imaging (DTI) studies have mainly focused on dose-dependent white matter (WM) alterations 1 month to 1 year after radiation therapy (RT) with a tract-average method. However, WM alterations immediately after RT are subtle, resulting in early WM alterations that cannot be detected by tract-average methods. Therefore, we performed a study with an along-tract method in patients with brain metastases to explore the early dose-response pattern of WM alterations after RT.Sixteen patients with brain metastases underwent DTI before and 1-3 days after brain RT. DTI metrics, such as fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD), were calculated. Along-tract statistics were then used to resample WM fibre streamlines and generate a WM skeleton fibre tract. DTI metric alterations (post_RT-pre_RT DTI metrics) and the planned doses (max or mean doses) were mapped to 18 WM tracts. A linear fixed model was performed to analyse the main effect of dose on DTI metric alterations.AD alterations in the left hemispheric uncinated fasciculus (UNC_L) were associated with max doses, in which decreased AD alterations were associated with higher doses.Our findings may provide pathological insight into early dose-dependent WM alterations and may contribute to the development of max dose-constrained RT techniques to protect brain microstructure in the UNC_L.

To develop and validate a pretreatment magnetic resonance imaging (MRI)-based radiomic-clinical model to assess the treatment response of whole-brain radiotherapy (WBRT) by using SHapley Additive exPlanations (SHAP), which is derived from game theory, and can explain the output of different machine learning models.We retrospectively enrolled 228 patients with brain metastases from two medical centers (184 in the training cohort and 44 in the validation cohort). Treatment responses of patients were categorized as a non-responding group vs. a responding group according to the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. For each tumor, 960 features were extracted from the MRI sequence. The least absolute shrinkage and selection operator (LASSO) was used for feature selection. A support vector machine (SVM) model incorporating clinical factors and radiomic features wase used to construct the radiomic-clinical model. SHAP method explained the SVM model by prioritizing the importance of features, in terms of assessment contribution.Three radiomic features and three clinical factors were identified to build the model. Radiomic-clinical model yielded AUCs of 0.928 (95%CI 0.901-0.949) and 0.851 (95%CI 0.816-0.886) for assessing the treatment response in the training cohort and validation cohort, respectively. SHAP summary plot illustrated the feature's value affected the feature's impact attributed to model, and SHAP force plot showed the integration of features' impact attributed to individual response.The radiomic-clinical model with the SHAP method can be useful for assessing the treatment response of WBRT and may assist clinicians in directing personalized WBRT strategies in an understandable manner.• Radiomic-clinical model can be useful for assessing the treatment response of WBRT. • SHAP could explain and visualize radiomic-clinical machine learning model in a clinician-friendly way.

Inkjet printing technology is expected to enhance printed display mass production technology in the future. Nozzle-array printheads form the basis for printed display mass production applications. However, jet instability caused by air bubble entrapment and nozzle wettability changes during the printing process is a major challenge in the application of this technology. To adapt to possible nozzle abnormalities, a high-adaptability nozzle-array printing system based on a set covering printing planning (SCPP) model for printed display manufacturing is designed in this study. The study consists of two parts. First, a printing system based on multistep visual inspection and closed-loop feedback is proposed to accurately detect and screen abnormal nozzle positions. Notably, the inkjet printing system can identify nozzles with abnormal ejection characteristics and ensure that the remaining nozzles work accurately and stably. Then, an SCPP model is established for display pixel printing planning by using the remaining normal nozzles on the nozzle-array printhead. This model can output the most efficient printing path and nozzle printing action and can adapt to any pixel pattern, nozzle type, and abnormal nozzle distribution. The system and technology are highly adaptable and scalable for fabricating large-area printed display devices.

Pore-forming Gasdermin protein-induced pyroptosis in tumor cells promotes anti-tumor immune response through the release of pro-inflammatory cytokines and immunogenic substances after cell rupture. However, endosomal sorting complexes required for transport (ESCRT) III-mediated cell membrane repair significantly diminishes the tumor cell pyroptosis by repairing and subsequently removing gasdermin pores. Here, we show that blocking calcium influx-triggered ESCRT III-dependent membrane repair through a biodegradable nanoparticle-mediated sustained release of calcium chelator (EI-NP) strongly enhances the intracellularly delivered GSDMD-induced tumor pyroptosis via a bacteria-based delivery system (VNP-GD). An injectable hydrogel and a lyophilized hydrogel-based cell patch are developed for peritumoral administration for treating primary and metastatic tumors, and implantation for treating inoperable tumors respectively. The hydrogels, functioning as the local therapeutic reservoirs, can sustainedly release VNP-GD to effectively trigger tumor pyroptosis and EI-NP to prevent the ESCRT III-induced plasma membrane repair to boost the pyroptosis effects, working synergistically to augment the anti-tumor immune response.

Immunosuppressive cells residing in the tumor microenvironment, especially tumor associated macrophages (TAMs), hinder the infiltration and activation of T cells, limiting the anti-cancer outcomes of immune checkpoint blockade. Here, we report a biocompatible alginate-based hydrogel loaded with Pexidartinib (PLX)-encapsulated nanoparticles that gradually release PLX at the tumor site to block colony-stimulating factor 1 receptors (CSF1R) for depleting TAMs. The controlled TAM depletion creates a favorable milieu for facilitating local and systemic delivery of anti-programmed cell death protein 1 (aPD-1) antibody-conjugated platelets to inhibit post-surgery tumor recurrence. The tumor immunosuppressive microenvironment is also reprogrammed by TAM elimination, further promoting the infiltration of T cells into tumor tissues. Moreover, the inflammatory environment after surgery could trigger the activation of platelets to facilitate the release of aPD-1 accompanied with platelet-derived microparticles binding to PD-1 receptors for re-activating T cells. All these results collectively indicate that the immunotherapeutic efficacy against tumor recurrence of both local and systemic administration of aPD-1 antibody-conjugated platelets could be strengthened by local depletion of TAMs through the hydrogel reservoir.

In population-based health research, the so-called population attributable fraction is an important quantity that calculates the percentage of excess risk of morbidity and mortality associated with modifiable risk factors for a given population. While the concept of “risk” is usually measured by event probabilities, in practice it may be of a more direct interest to know the excess life expectancy associated with the modifiable risk factors instead, particularly when mortality is of the ultimate concern. In this paper, we thus propose to study a novel quantity, termed “attributable life expectancy,” to measure the population attributable fraction of life expectancy. We further develop a model-based approach for the attributable life expectancy under the Oakes–Dasu proportional mean residual life model, and establish its asymptotic properties for inferences. Numerical studies that include Monte-Carlo simulations and an actual analysis of the mortality associated with smoking cessation in an Asia Cohort Consortium are conducted to evaluate the performance of our proposed method.

In this paper, a magnetic core–shell composite with MgNi2FeO4.5 nanotubes as core and carbon nanotubes (CNTs) as shell was synthesized by in situ growth of CNTs on the surface of MgNi2FeO4.5 nanotubes via a catalytic chemical vapor deposition method. The MgNi2FeO4.5 nanotubes were prepared using a mixed aqueous solution of Mg(NO3)2, Ni(NO3)2 and Fe(NO3)3 (molar ratio of 1:2:1) and anodic aluminum oxide as template. Both the growth temperature and time of CNTs brought about effect on the structure and magnetic property of the composite were investigated. X-ray diffraction, transmission electron microscope, field emission scanning electron microscope, Raman spectroscopy and vibrating sample magnetometer were used to characterize the as-prepared samples. The MgNi2FeO4.5 nanotubes are parallel arranged, and the exterior surface of which is wrapped by CNTs when the growth temperature exceeding 480 °C. Magnetic measurement demonstrates the composite with higher growth temperature and shorter growth time possesses more excellent magnetic property.

We report the development of a small interfering RNA (siRNA) delivery vector based on cationic perfluorocarbon nanoemulsions. We have prepared perfluorodecalin (PFD) emulsions with a positive surface charge provided by a fluorinated poly(ethylenimine) (F-PEI). The fluorinated emulsion (F-PEI@PFD) reduced cytotoxicity of F-PEI and demonstrated effective binding with siRNAs to form nanosized emulsion polyplexes. The prepared emulsion polyplexes enhanced cellular uptake and improved endosomal escape of the siRNA. In addition to increased reporter gene silencing in multiple cancer cell lines, when compared with control F-PEI and PEI polyplexes, the siRNA emulsion polyplexes showed an excellent resistance to serum deactivation and maintained high activity, even in high-serum conditions. The F-PEI@PFD emulsion polyplexes carrying an siRNA to silence the expression of Bcl2 gene induced apoptosis and inhibited tumor growth in a melanoma mouse model in vivo and showed potential for in vivo ultrasound imaging. This study demonstrates the potential of F-PEI@PFD emulsions as a multifunctional theranostic nanoplatform for safe siRNA delivery, with integrated ultrasound imaging functionality.

In our previous study, six subgroup J strains of avian leukosis virus (ALV-J)-associated acutely transforming viruses carrying different lengths of the v-fps oncogene, designated as Fu-J and Fu-J1-5, were isolated and characterized from fibrosarcomas in ALV-J-infected chickens. In the present study, the oncogenic potential of Fu-J and Fu-J1-5 was investigated using a reverse genetics technique. Six replication-defective viruses, named rFu-J and rFu-J1-5, were rescued with the replication-competent rescued ALV-J strain rSDAU1005 as a helper virus by co-transfection of chicken embryo fibroblast monolayers with infectious clone plasmids. Experimental bird studies were performed, demonstrating that only the rescued rFu-J virus carrying the complete v-fps oncogene with rSDAU1005 as the helper virus could induce acute fibrosarcoma after inoculation in specific-pathogen-free (SPF) chickens. These results provide direct evidence that the replication-defective acutely transforming Fu-J virus, with the complete v-fps oncogene, was associated with acute fibrosarcoma in chickens infected with ALV-J in the field, as reported previously.

Background Recurrent pregnancy loss (RPL) refers to two or more spontaneous abortions that occur consecutively with the same spouse. RPL severely affects human reproduction health, and causes extreme physical and mental suffering to patients and their families. Methods We used isobaric tags for relative and absolute quantitation (iTRAQ), which was coupled with liquid chromatography mass spectrometry (LC-MS) proteomic analysis, in order to identify differentially expressed proteins. Moreover, we used western blot to analyze differentially expressed proteins. Results Of the 2350 non-redundant proteins identified, 38 proteins were significantly altered and were identified as potential biomarkers for RPL. The protein-protein interaction network constructed using GeneMANIA revealed that 35.55% displayed similar co-expression, 30.87% were predicted, and 20.95% had physical interaction characteristics. Based on Gene ontology classification and KEGG pathway enrichment analyses, the majority of these differentially expressed proteins were found to be related to biological regulation, metabolic and cellular processes, protein binding and different enzymes activities, as well as disorder of fat and glucose metabolic pathways. It is noteworthy that three metabolism related biomarkers (HK1, ACLY, and FASN) were further confirmed through western blot analysis. Conclusions These results suggest that these differentially expressed proteins may be used as biomarkers for RPL, and related signaling pathways may play crucial roles in male induced RPL. Electronic supplementary material The online version of this article (10.1186/s12958-019-0496-5) contains supplementary material, which is available to authorized users.

Let L=−Δ+μ $\mathcal{L}=-\Delta +\mu $ be a generalized Schrödinger operator, where the measure μ is a nonnegative Radon measure. In this paper, we establish the molecular characterization of the Hardy type space HL1(Rn) $H^{1}_{\mathcal{L}}(\mathbb{R}^{n})$ associated with L $\mathcal{L}$. As applications, we obtain the HL1 $H^{1}_{\mathcal{L}}$-boundedness of Riesz transforms and the imaginary power related to L $\mathcal{L}$.

Background Metabolic disorders such as insulin resistance, obesity, and hyperglycemia are prominent risk factors for the development of non-alcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH). Dietary rodent models employ high fat, high cholesterol, high fructose, methionine/choline deficient diets or combinations of these to induce NAFLD/NASH. The FATZO mice spontaneously develop the above metabolic disorders and type 2 diabetes (T2D) when fed with a normal chow diet. The aim of the present study was to determine if FATZO mice fed a high fat and fructose diet would exacerbate the progression of NAFLD/NASH. Methods Male FATZO mice at the age of 8 weeks were fed with high fat Western diet (D12079B) supplemented with 5% fructose in the drinking water (WDF) for the duration of 20 weeks. The body weight, whole body fat content, serum lipid profiles and liver function markers were examined monthly along with the assessment of liver histology for the development of NASH. In addition, the effects of obeticholic acid (OCA, 30 mg/kg, QD) on improvement of NASH progression in the model were evaluated. Results Compared to normal control diet (CD), FATZO mice fed with WDF were heavier with higher body fat measured by qNMR, hypercholesterolemia and had progressive elevations in AST (~ 6 fold), ALT (~ 6 fold), liver over body weight (~ 2 fold) and liver triglyceride (TG) content (1.4–2.9 fold). Histological examination displayed evidence of NAFLD/NASH, including hepatic steatosis, lobular inflammation, ballooning and fibrosis in FATZO mice fed WDF. Treatment with OCA for 15 weeks in FATZO mice on WDF significantly alleviated hypercholesterolemia and elevation of AST/ALT, reduced liver weight and liver TG contents, attenuated hepatic ballooning, but did not affect body weight and blood TG levels. Conclusion WDF fed FATZO mice represent a new model for the study of progressive NAFLD/NASH with concurrent metabolic dysregulation.

Many lakes exist in southeastern Badain Jaran Desert and its hinterland, including 110 perennial lakes and some seasonal or extinct lakes. Geomorphological, sedimentological, and bioglyph evidence obtained from field investigations on Badain Jaran Desert lake group, alongside measurements and dating performed on lake relic, prove that these lakes expanded while the climate was relatively wet during early and middle Holocene. The dating results suggest that the pan-lake period of the Badain Jaran Desert began at 10 cal kyr BP, before which the limnic peat period occurred (11–10 cal kyr BP). Many lakes reached their maximal water-level during 8.6–6.3 cal kyr BP and retreated or dried up in the late Holocene (about 3.5–0 cal kyr BP). During that period, the precipitation at Badain Jaran Desert may have reached 200 mm yr?1 for 7.7–5.3 cal kyr BP, inferred from both the age and precipitation rate of calcareous root tubes. The water balance calculation shows that wetter and warmer climate and the increase of underground water recharge were key factors in maintaining and developing the lake group at both centennial and millennial time scales. Furthermore, lake surface expansion and the increasing fresh water availability set the background for the prosperous prehistoric culture.

Transduction of oncogenes by ALVs and generation of acute transforming viruses is common in natural viral infections. In order to understand the molecular basis for the rapid oncogenicity of Fu-J, an acutely transforming avian leukosis virus isolated from fibrosarcomas in crossbreed broilers infected with subgroup J avian leukosis virus (ALV-J) in China, complete genomic structure of Fu-J virus was determined by PCR amplification and compared with those of Fu-J1, Fu-J2, Fu-J3, Fu-J4, and Fu-J5 reported previously. The results showed that the genome of Fu-J was defective, with parts of gag gene replaced by the complete v-fps oncogene and encoded a 137 kDa Gag-fps fusion protein. Sequence analysis revealed that Fu-J and Fu-J1 to Fu-J5 were related quasi-species variants carrying different lengths of v-fps oncogenes generated from recombination between helper virus and c-fps gene. Comparison of virus carrying v-fps oncogene also gave us a glimpse of the molecular characterization and evolution process of the acutely transforming ALV.

The censored linear regression model, also referred to as the accelerated failure time model, is a useful alternative to the popular Cox model in the analysis of censored survival data. In this paper, we combine the quantile information with censored least-squares normal equations to get estimators with smaller estimated standard error for regression parameters. An inverse probability-weighted method is proposed to construct unbiased estimating equations with censored data and the lack of smoothness of the objective equations is overcome by replacing them with smooth approximations. The proposed estimators are established based on the empirical likelihood method and generalized method of moments, respectively, and their asymptotic properties are studied under some regular conditions. We also conduct some simulation experiments to investigate the finite-sample properties of the proposed estimators. The Stanford Heart Transplant data are used to illustrate the proposed estimating method.

The power conversion efficiency of organometallic perovskite-based solar cells has skyrocketed in recent years. Intensive efforts have been made to prepare high-quality perovskite films tailored to various device configurations. Planar heterojunction devices have achieved record efficiencies; however, the preparation of perovskite films for planar junction devices requires the use of expensive vacuum facilities and/or the fine control of experimental conditions. Here, we demonstrate a facile preparation of perovskite films using solid-state chemistry. Solid-state precursor thin films of CH3NH3I and PbI2 are brought into contact with each other and allowed to react via thermally accelerated diffusion. The resulting perovskite film displays good optical absorption and a smooth morphology. Solar cells based on these films show an average efficiency of 8.7% and a maximum efficiency of 10%. The solid-state synthesis of organometallic perovskite can also be carried out on flexible plastic substrates. Using this method on a PET/ITO substrate produces devices with an efficiency of 3.2%. Unlike existing synthetic methods for organometallic perovskite films, the solid-state reaction method does not require the use of orthogonal solvents or careful adjustment of reaction conditions, and thus shows good potential for mass production in the future.

This article proposes a simple nonparametric estimator of quantile residual lifetime function under left-truncated and right-censored data. The asymptotic consistency and normality of this estimator are proved and the variance expression is calculated. Two bootstrap procedures are employed in the simulation study, where the latter bootstrap from Zeng and Lin (2008) is 4000 times faster than the former naive one, and the numerical results in both methods show that our estimating approach works well. A real data example is used to illustrate its application.

One of the hallmarks of human solid tumors is chromosomal instability (CIN). We studied global patterns as well as individual levels of CIN and determined the prognostic relevance among breast cancer subtypes. For this, we used single nucleotide polymorphism copy number data of 313 primary lymph-node negative breast cancers. The level of CIN for individual samples was determined by counting the total number of chromosomal segments showing a gain or loss per specimen. Hierarchical clustering resulted in four groups showing distinct patterns of abnormalities, predominantly characterized by 1q gain, 8q gain, 1q&8q gain, or no gain of these loci. Estrogen receptor (ER)-positive and ER-negative samples showed an uneven distribution (statistically significant) across the cluster-groups, as did the molecular subtypes and triple-negative tumors (negative for estrogen-, progesterone-, and her2/neu-receptor). The CIN-score was significantly higher in ER-negative and triple-negative samples. Among luminal cancers, luminal B had a higher CIN-score than luminal A. The CIN-score was significantly associated with prognosis, measured by the time to distant metastasis, in ER-positive, luminal B, and her2/neu subtypes, but not in ER-negative patients. Our study points to a multifaceted role for CIN in breast cancer. Within ER-negative samples, CIN is likely related to the onset but other factors govern the progression of the disease. In contrast, CIN is clearly associated with progression in ER-positive, luminal B, and her2/neu subtypes; thus, assessing CIN in these subtypes may contribute to personalized patient management.

With the increase of size and number of shared risk link groups (SRLGs) in WDM networks, path protection tends to have longer working paths and backup paths due to SRLG-disjoint constraints, which makes physical impairment a major concern in working path and backup path provisioning, particularly in large-sized all optical networks. As a simple and efficient algorithm, the working path first algorithm is often used for path protection against SRLG failures, where the working path is calculated first by using the shortest-path algorithm on the graph, followed by using the SRLG-disjoint shortest path as backup path. Compared with the working path, the backup path calculated after the working path in the working path first algorithm is more vulnerable to physical impairment, since it may be much longer than the working path. As a result, if we reject those connections that cannot meet the physical impairment requirement, with SRLGs the blocking probability of path protection will be much higher. We argue that impairment must be taken into account together with capacity efficiency in a comprehensive way during SRLG-disjoint working path and backup path selection. To solve this problem, we motivate the needs to study physical impairment-aware shared-path protection by considering two policies. Policy I uses two SRLG-disjoint least impairment paths as working path and backup path, respectively, and Policy II tries to benefit from both the shortest path and the least impairment path by choosing them intelligently. Analytical and simulation results show: (1) compared with impairment-unawareness, impairment-aware SRLG failure protection performs much better in terms of blocking probability especially with strong physical impairment constraints; (2) impairment-aware SRLG failure protection can significantly reduce physical-layer blocking probability; and (3) the algorithm based on Policy II achieves a good balance between capacity efficiency and physical impairment requirement.

A total of 45 moderately halophilic bacteria was isolated from sediment and saline water collected from the Weihai Solar Saltern (China). The phylogenetic position of all the isolated strains was determined by 16S rRNA sequencing. The halophilic strains were tested for their antimicrobial activity. Cytotoxicity assay was performed to determine which of the halophilic strains could inhibit proliferation of human hepatocellular carcinoma Bel 7402 cells. Our results showed that all of the isolated 45 strains displayed moderately halophilic characteristics. Phylogenetic analysis indicated that 17 of the isolated strains were related to the phylum Firmicutes and belonged to four genera, Bacillus, Halobacillus, Planococcus and Salinicoccus. The other strains identified as genus of Halomonas belonged to phylum gamma-Proteobacteria. Most of the halophilic bacterial strains showed potent activities against Gram-positive bacteria, human pathogenic fungi and plant pathogenic fungi. In addition, the crude extracts from 14 halophilic bacterial strains showed cytotoxic activity against tumor cells Bel 7402, and five of them showed remarkable activities with IC(50) less than 40 mu g ml(-1). Our results suggest that the moderately halophilic bacteria may be developed as promising sources for the discovery of novel bioactive substances.

For 100% shared risk link group (SRLG) failure protection, conventional full path protection has to satisfy SRLG-disjoint constraints, i.e., its working path and backup path cannot go though the same SRLG. With the increase of size and number of SRLGs, capacity efficiency of conventional shared full path protection becomes poorer due to SRLG-disjoint constraints and the blocking probability becomes much higher due to severe traps. To solve these problems, we present a partial path protection scheme where SRLG-disjoint backup paths may only cover part of the working path. Full path protection becomes a special case of partial path protection, in which the backup path covers the full working path. By choosing the most survivable partial backup path as backup path, we can make the impact of SRLG failures as low as possible and accept as many as possible connection requests. Assuming every SRLG has the same probability to fail, we present a heuristic algorithm to find the most survivable partial backup path by choosing full path protection first, iteratively computing partial backup paths and choosing the most survivable one. The benefit of this heuristic algorithm is that it can find the optimal results within less iteration. Analytical and simulation results show that, compared to conventional full path protection, our proposed scheme can significantly reduce blocking probability with little sacrifice on survivability. The proposed scheme is very useful particularly when the network contains a lot of SRLGs and the blocking probability of conventional full path protection becomes too high.

Background Patient prognosis and response to endocrine therapy in breast cancer correlate with protein expression of both estrogen receptor (ER) and progesterone receptor (PR), with poorer outcome in patients with ER+/PR− compared to ER+/PR+ tumors. Methods To better understand the underlying biology of ER+/PR− tumors, we examined RNA expression (n > 1000 tumors) and DNA copy number profiles from five previously published studies of human breast cancers with clinically assigned hormone receptor status (ER+/PR+, ER+/PR−, and ER−/PR−). Results We identified an expression “signature” of genes with either elevated or diminished RNA levels specifically in ER+/PR+ compared to ER−/PR− and ER+/PR− tumors. We similarly identified a gene signature specific to ER−/PR− tumors. ER+/PR− tumors, on the other hand, were a mixture of three different subtypes: tumors manifesting the ER+/PR+ signature, tumors manifesting the ER−/PR− signature, and tumors not associating with ER+/PR+ or ER−/PR− tumors (which we considered “true” ER+/PR−). In analyses of both tamoxifen-treated and untreated patients, ER+/PR− breast cancers defined by RNA profiling were associated with poor patient outcome, worse than those with pure ER+/PR+ patterns; these differences were not observed when using clinical assays to assign ER and PR status. ER+/PR− tumors also showed twice as many DNA copy number gains or losses compared to ER+/PR+ and ER−PR− tumors. Targets of transcriptional up-regulation by specific oncogenic pathways, including PI3 K/Akt/mTOR, were enriched in both ER+/PR− and ER−/PR− compared to ER+/PR+ tumors. Conclusion ER+/PR− tumors as defined by RNA profiling represent a distinct subset of breast cancer with aggressive features and poor outcome, despite being clinically ER+. Multigene assays derived from our gene signatures could conceivably provide an improved clinical assay for inferring PR status for prognostic and therapeutic purposes.

Mucosa-associated lymphoma antigen 1 (MALT1) is a lymphoma oncogene that regulates signal transduction as a paracaspase and an adaptor protein. Yet, the role of MALT1 in other solid cancers such as melanoma is not well-understood. Here, we demonstrate that MALT1 is overexpressed in malignant melanoma cells, and predicts a poor disease-free survival. MALT1 inhibition via shRNA-mediated gene silencing or pharmacologically with MI-2 compound markedly reduced cell growth and migration of A2058 and A375 melanoma cell lines in vitro. Subcutaneous tumor growth analysis revealed that MALT1 gene silencing significantly reduced tumor growth and metastasis to the lung. Consistently, the subcutaneous tumors with MALT1 loss had increased cell apoptosis and decreased proliferation. In addition, these tumors showed signs of mesenchymal–epithelial transition as indicated by the upregulation of E-cadherin and downregulation of N-cadherin and β1-intergrin. Further molecular analysis revealed that MALT1 is required for c-Jun and nuclear factor-κB (NF-κB) activation by tumor necrosis factor-α. Forced expression of the c-Jun upstream activator MKK7 reversed the cell growth and migration defects caused by MALT1 loss. In contrast, NF-κB activation via expression of p65ER, a fusion protein containing NF-κB p65 and the tamoxifen-responsive mutant estrogen receptor, induced minimal effects on cell proliferation, but diminished cell death induced by MALT1 loss and TRAIL treatment. Together, these findings demonstrate that MALT1 promotes melanoma cell proliferation and motility through JNK/c-Jun, and enhances melanoma cell survival through NF-κB, underscoring MALT1 as a potential therapeutic target and biomarker for malignant melanoma.

In an attempt to understand the signaling pathway mediating redox-induced apoptosis, we cloned SAG, an evolutionarily conserved zinc RING finger gene that, when overexpressed, protects cells from apoptosis induced by redox agents. Here we report functional characterization of SAG by the use of yeast genetics approach. Targeted disruption of ySAG, yeast homolog of human SAG, and subsequent tetrad analysis revealed that ySAG is required for yeast viability. Complementation experiment showed that the lethal phenotype induced by the ySAG deletion is fully rescued by wildtype SAG, but not by several hSAG mutants. Complementation experiment has also confirmed that ySAG is essential for normal vegetative growth, rather than being required for sporulation. Furthermore, cell death induced by SAG deletion was accompanied by cell enlargement and abnormal cell cycle profiling with an increased DNA content. Importantly, SAG was found to be the second family member of Rbx (RING box protein) or ROC (Regulator of cullins) or Hrt that is a component of SCF E3 ubiquitin ligase. Indeed, like ROC1/Rbx1/Hrt1, SAG binds to Cul1 and SAG-Cul1 complex has ubiquitin ligase activity to promote poly-ubiquitination of E2/Cdc34. This ligase activity is required for complementation of death phenotype induced by ySAG disruption. Finally, chip profiling of the entire yeast genome revealed induction of several G1/S as well as G2/M checkpoint control genes upon SAG withdrawal. Thus, SAG appears to control cell cycle progression in yeast by promoting ubiquitination and degradation of cell cycle regulatory proteins. Oncogene (2000) 19, 2855 - 2866

We have isolated and characterized from rice three repetitive DNA sequences, Os48, Osc-567, and OsG3-430. Our results indicate that these repetitive sequences are highly transcribed, and transcripts complementary to both strands of the Os48 family of sequences account for up to 3% of the total cellular RNA. Pulsed-field gel electrophoresis, restriction mapping, and DNA sequence analyses have revealed a complex pattern of structural organization of the three families of repetitive sequences. Os48 and Osc-567 are organized in long tandem arrays, whereas copies of the OsG3-340 sequence are interspersed with other sequences including arrays of the Os48 and Osc-567 families. Interestingly, the three families of repetitive sequences are closely linked not only to each other, but also to telomeric sequences of rice, suggesting that transcription of these repetitive sequences may occur in regions very close to telomeres in rice.

Background Published prognostic gene signatures in breast cancer have few genes in common. Here we provide a rationale for this observation by studying the prognostic power and the underlying biological pathways of different gene signatures. Methods Gene signatures to predict the development of metastases in estrogen receptor-positive and estrogen receptor-negative tumors were identified using 500 re-sampled training sets and mapping to Gene Ontology Biological Process to identify over-represented pathways. The Global Test program confirmed that gene expression profilings in the common pathways were associated with the metastasis of the patients. Results The apoptotic pathway and cell division, or cell growth regulation and G-protein coupled receptor signal transduction, were most significantly associated with the metastatic capability of estrogen receptor-positive or estrogen-negative tumors, respectively. A gene signature derived of the common pathways predicted metastasis in an independent cohort. Mapping of the pathways represented by different published prognostic signatures showed that they share 53% of the identified pathways. Conclusion We show that divergent gene sets classifying patients for the same clinical endpoint represent similar biological processes and that pathway-derived signatures can be used to predict prognosis. Furthermore, our study reveals that the underlying biology related to aggressiveness of estrogen receptor subgroups of breast cancer is quite different.

Background Farnesyl protein transferase inhibitors (FTIs) were originally developed to inhibit oncogenic ras, however it is now clear that there are several other potential targets for this drug class. The FTI tipifarnib (ZARNESTRA™, R115777) has recently demonstrated clinical responses in adults with refractory and relapsed acute leukemias. This study was conducted to identify genetic markers and pathways that are regulated by tipifarnib in acute myeloid leukemia (AML). Methods Tipifarnib-mediated gene expression changes in 3 AML cell lines and bone marrow samples from two patients with AML were analyzed on a cDNA microarray containing approximately 7000 human genes. Pathways associated with these expression changes were identified using the Ingenuity Pathway Analysis tool. Results The expression analysis identified a common set of genes that were regulated by tipifarnib in three leukemic cell lines and in leukemic blast cells isolated from two patients who had been treated with tipifarnib. Association of modulated genes with biological functional groups identified several pathways affected by tipifarnib including cell signaling, cytoskeletal organization, immunity, and apoptosis. Gene expression changes were verified in a subset of genes using real time RT-PCR. Additionally, regulation of apoptotic genes was found to correlate with increased Annexin V staining in the THP-1 cell line but not in the HL-60 cell line. Conclusions The genetic networks derived from these studies illuminate some of the biological pathways affected by FTI treatment while providing a proof of principle for identifying candidate genes that might be used as surrogate biomarkers of drug activity.