Signature Patterns Research Articles

Outcomes and Immunogenicity of pancreatic cancer stratified by the HRDetect score.

4630 Background: The HRDetect score uses whole genome sequencing (WGS) to incorporate patterns of substitution base signatures and structural variation to identify tumours deficient in homologous recombination repair (HRD). HRD-tumours, with a higher mutational burden, may be more immunogenic. Methods: We applied HRDetect to 182 resected pancreatic cancers (PDA) and 233 advanced PDA enrolled on the COMPASS trial; both cohorts underwent WGS after tumour enrichment. Patients were classified as high(hi) or low(lo) according to the published score threshold of 0.7; clinical characteristics and survival outcomes were determined. Immunogenicity of the cohorts was explored by analyzing cytolytic activity (CYT) as measured by RNA expression of perforin and granzyme A. Results: 14% of resected (25/182) and 14% of advanced cases (32/233) were considered HRDetecthi . The median age at PDA diagnosis was younger in HRDetecthi vs HRDetectlo (61 vs 66 years, p = 0.005), with no difference in sex between groups. Of the 57 cases identified, 37 (65%) were considered true HRD-PDA with inactivation of BRCA1, BRCA2, PALB2, RAD51C and XRCC2. The remaining 20 cases, were considered false positives for HRD; of these 7 had evidence of a tandem duplicator phenotype with duplications ranging from 10Kbp to 1Mbp in size and 13 had no defining genomic characteristics of the HRD-subtype. In resected PDA, the HRDetect score after adjusting for stage, was not prognostic. In contrast in a multivariable analysis of advanced cases, both HRDetect (HR 0.51, 95% CI 0.30-0.87, p = 0.01) and the Moffitt RNA classifier were highly prognostic (HR 1.99, 95% CI 1.32-3.00, p = 0.0001) with improved survival in HRDetecthi and classical PDA. Of patients receiving platinum in advanced disease (n = 128) HRDetecthi PDA had longer survival compared to the HRDetectlo (15.6 vs. 9.9 months, p = 0.02) although the interaction term between chemotherapy regimen (gemcitabine vs. platinum) and HRDetect score was not significant in this cohort. HRDetecthi tumours had increased cytolytic activity than HRDetectlo PDA; furthermore, within the cohort of HRDetecthi PDA, higher CYT scores were evident in primary lesions compared to metastatic sites sequenced. Conclusions: A high HRDetect score is prognostic in advanced PDA where patients treated with platinum have longest survival. HRDetecthi tumours have increased cytolytic activity with differences observed between primary and metastatic lesions.

Whole genome sequencing of colorectal neuroendocrine tumors and in-depth mutational analyses.

Colorectal neuroendocrine tumors (NETs) are rare neoplasms and studies on colorectal NETs are relatively few compared to other tumors. To better understand the pathogenesis of this tumor, we performed whole-genome sequencing and follow-up verification using Sanger sequencing of the colorectal NETs and paired para-tumor tissue. We analyzed the features of the gene mutation spectrum and mutation signature patterns, and analyzed the four pathways that were altered by gene mutation in pancreatic neuroendocrine tumors, including DNA damage and repair, chromatin remodeling, telomere maintenance and mTOR signaling activation. We found that PARP4 which is related to the DNA damage and repair pathway; TSC2, which is related to the mTOR signaling activation pathway; and SLX1A, which is related to telomere maintenance, were mutated in colorectal NETs. Our data analyzed characteristics of gene mutation in colorectal NETs at the whole-genome level, and may help to better understand the pathogenesis of colorectal NETs and may be helpful for potential tumor therapy in the future.

Quantitative alterations in bovine milk proteome from healthy, subclinical and clinical mastitis during S. aureus infection

Bovine mastitis, caused by Staphylococcus aureus, is a major impediment to milk production and lacks markers to indicate disease progression in cows and buffaloes. Thus, the focus of this study was to identify proteins marking the transition from subclinical to clinical mastitis. Whey proteins were isolated from 6 group's i.e. healthy, subclinical and clinical mastitis of Holstein Friesian cow and Murrah buffalo. Mass spectrometry and statistical analysis (ANOVA and t-tests) were performed on 12 biological samples each from cow and buffalo (4 per healthy, subclinical and clinical mastitis) resulting in a total of 24 proteome datasets. Collectively, 1479 proteins were identified of which significant proteins were shortlisted by a combination of fold change (≤ 0.5 or ≥ 2) and q < 0.05. Of these proteins, 128 and 163 indicated disease progression in cow and buffalo, respectively. Change in expression of haptoglobin and fibronectin from Holstein Friesian while spermadhesin and osteopontin from Murrah correlated with disease progression. Similarly, angiogenin and cofilin-1 were upregulated while ubiquitin family members were downregulated during disease transition. Subsequently, selected proteins (e.g. osteopontin and fibrinogen-α) were validated by Western blots. The results of this study provide deeper insights into whey proteome dynamics and signature patterns indicative of disease progression. Biological significanceBovine mastitis is the most lethal infectious disease causing a huge economic loss in the dairy industry. In an attempt, to understand the dynamics of whey proteome in response to S. aureus infection, whey protein collected from healthy, subclinical and clinical mastitic HF and Mu were investigated. A total of 1479 proteins were identified, of which 128 and 163 had signature pattern in each stage indicative of the progression of the disease. The results of the present study provide a foundation to better understand the complexity of mastitis that will ultimately help facilitate early therapeutic and husbandry-based intervention to improve animal health and milk quality.

RNA-seq and network analysis reveal unique glial gene expression signatures during prion infection

BackgroundPrion diseases and prion-like disorders, including Alzheimer’s disease and Parkinson’s disease, are characterized by gliosis and accumulation of misfolded aggregated host proteins. Ablating microglia in prion-infected brain by treatment with the colony-stimulating factor-1 receptor (CSF-1R) inhibitor, PLX5622, increased accumulation of misfolded prion protein and decreased survival time.MethodsTo better understand the role of glia during neurodegeneration, we used RNA-seq technology, network analysis, and hierarchical cluster analysis to compare gene expression in brains of prion-infected versus mock-inoculated mice. Comparisons were also made between PLX5622-treated prion-infected mice and untreated prion-infected mice to assess mechanisms involved in disease acceleration in the absence of microglia.ResultsRNA-seq and network analysis suggested that microglia responded to prion infection through activation of integrin CD11c/18 and did not adopt the expression signature associated with other neurodegenerative disease models. Instead, microglia acquired an alternative molecular signature late in the disease process. Furthermore, astrocytes expressed a signature pattern of genes which appeared to be specific for prion diseases. Comparisons were also made with prion-infected mice treated with PLX5622 to assess the impact of microglia ablation on astrocyte gene expression during prion infection. In the presence of microglia, a unique mix of transcripts associated with A1- and A2-reactive astrocytes was increased in brains of prion-infected mice. After ablation of microglia, this reactive astrocyte expression pattern was enhanced. Thus, after prion infection, microglia appeared to decrease the overall A1/A2-astrocyte responses which might contribute to increased survival after infection.ConclusionsRNA-seq analysis indicated dysregulation of over 300 biological processes within the CNS during prion disease. Distinctive microglia- and astrocyte-associated expression signatures were identified during prion infection. Furthermore, astrogliosis and the unique astrocyte-associated expression signature were independent of microglial influences. Astrogliosis and the unique astrocyte-associated gene expression pattern were increased when microglia were ablated. Our findings emphasize the potential existence of alternative pathways for activating the A1/A2 paradigm in astrocytes during neurodegenerative disease.

Implementasi Jaringan Syaraf Tiruan (JST) untuk Mengenali Pola Tanda Tangan dengan Metode Backpropagation

Artificial Neural Networks (ANN) is a computer technology in the field of artificial intelligence that is able to understand complex data patterns. One of ANN's technological capabilities is being able to predict solutions based on training patterns provided during the system learning process. This study aims to apply the signature pattern by applying ANN using the Backpropagation method. Backpropagation method is one of the learning algorithms related to the preparation of weights based on the value of errors in learning. The image will be processed using the Backpropagation method which will be obtained by the introduction. The results introduce 50 signature data samples and 50 signature sample data. The test is carried out using 50 samples, where each sample will be requested once. From the results of the research that has been done it can be concluded that the results obtained from the parameters with a learning rate of 0.5, epoch 100, objectives 1e-5 and momentum 0.9 with the results of 68% system testing.

Optimizing spatial distribution to minimize the inline directivity for a marine air-gun source

The spatial distribution of an air-gun array and the ghost reflection from the air-water interface cause a directional pattern of the source signature and introduce notches at certain frequencies. This significantly limits the bandwidth of the seismic data and the ability to obtain high-resolution subsurface imaging. With mathematical derivation and numerical simulation, we have determined that the inline directivity relies on the number of air guns and their spacing. Furthermore, the effective width of the take-off angles for an air-gun array is highly correlated with the reciprocal of the distance variance along the inline direction, which is subsequently used for optimizing the source design. For a normal horizontal source, one could adjust the distance between two consecutive air guns to improve the source signature. We optimize the spatial distribution for air guns along the inline and depth directions, that is, by using the synchronized multidepth stimulation mode, to minimize the inline directivity. Simulated results show that a six-gun composed multidepth source could be designed to achieve nearly identical energy distribution with up to ±30° take-off angle for the high-frequency end up to 250 Hz. This represents a significant improvement compared to a normal horizontal source and is more suitable for high-resolution seismic acquisition.

Distinct Patterns of Somatic Genomic Alterations and Mutational Signatures in Central and Peripheral-Type Small-Cell Lung Cancer

Background: Only a few studies have mentioned the differences in survival between patients with central and peripheral-type small-cell lung cancer (SCLC). Genomic landscape and genetic heterogeneity between central and peripheral-type SCLC is scarce. Methods: A total of 41 tumor/control pairs were to move forward for whole-exome sequencing. Distinct patterns of somatic genomic alterations and mutational signatures in central and peripheral-type SCLCs were analyzed. Findings: Tumor mutation burden (TMB) of peripheral-type SCLCs were higher than central-type. And smoking patients had significantly higher weighted genome instability index (wGII) and copy number alteration (CNA) burden than the non-smokers in SCLCs, these alterations were more obviosly in central-types. Furthermore, the driver recurrent somatic CNA (SCNA) regions of central and peripheral-type SCLCs were different. Central and peripheral-type SCLCs had no common recurrent amplification cytobands or genes, but had common recurrent deletion inculding 4 cytobands and 5 genes. Interestingly, the recurrent amplification 12q24.31 was negative correlation with overall survival (OS) in central but not peripheral-type. Moreover, a de novo signature A was found significantly higher in peripheral than central-type SCLCs. In parallel, signature D was predictive of poor outcome, which was mainly in peripheral SCLC patients. COSMIC signatures analysis revealed that the association with signature D and OS was similar to the positive relationship between signature 13 and outcome. Interpretation: Although central and peripheral-type SCLCs had similar significantly mutated genes (SMGs), immunotherapy response, genome instability, the driver SCNAs and mutational signatures may be largely distinct. These mutations leaded to different prognosis between central and peripheral-type SCLCs. Funding Statement: None Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: Experimental plans and protocols for this study (NO K18-203Y) were approved by the ethics/licensing committee of the Shanghai Pulmonary Hospital for review and confirmation. Written informed consent was obtained from all patients participating in the study.

Abstract B80: High dimensional DNA damage and repair (DDR) cytometric profiling of human T cell subsets revealed distinct DDR signatures

Abstract DNA damage and repair (DDR) has been extensively studied in the context of inducing cell death of tumor cells. Tumor cells are often highly-proliferating and vulnerable to DNA damage, a foundation for many chemotherapy and radiotherapy approaches. Accumulating evidence indicates the improved clinical prognosis when immune checkpoint blockade (ICB) are combined with chemotherapy or radiotherapy. However, the paradox of the combinational benefit of these proliferation-targeting cytotoxic therapies and proliferation-inducing immunotherapies remains poorly understood. Here, we aimed to interrogate the impact of DNA damage on T cell differentiation and function to better understand the mechanism of the paradox, and to better interrogate how T cell-intrinsic DDR can impact clinical responses to ICBs. We hypothesized that T cell subsets have different DDR responses that contribute to distinct biological outcomes upon exposure to DNA damaging agents and/or proliferative stress induced by ICBs. To test this hypothesis, we developed a novel high dimensional cytometry platform that enables simultaneous analysis of T cell differentiation state and interrogation of multiple DDR pathways at single cell resolution. After introduction of DNA damage by γ-irradiation (IR), UV irradiation (UV) or proliferative stress (i.e. aCD3/28 stimulation) DNA damage accumulation and response varied depending on the state of T cell differentiation. For example, terminally differentiated effector cells (TEMRA) had significantly higher DNA damage accumulation and cell death. In contrast, stem cell memory (TSCM) and regulatory T cells (Treg) displayed high DDR with less cell death, suggesting perhaps better cell-intrinsic DDR against genotoxic stress. Overall, this platform revealed consistent, T cell subset specific patterns of DDR as well as specific DDR pathways induced by different types of DNA damage. DDR-Immune profiling of PBMC from uterine cancer patients treated with the combination of chemotherapy and ICB indicated the correlation between distinct patterns of DDR-Immune signatures and therapeutic response. Notably, in clinical responders, Ki67+ CD8 T cells responding to PD-1 blockade had increased pATM, perhaps in response to proliferative stress induced by PD-1 blockade. This increase in pATM was not observed in clinical non-responders. In addition, Treg from clinical non-responders had elevated DDR responses compared to responders, suggesting the possibility of greater resistance to genotoxic/proliferative stress. Collectively, our new platform shed lights on previously unrecognized roles of T cell-intrinsic DDR as a novel determinant of T cell differentiation and immune responsiveness. These findings may have relevance to apply to understanding the paradox of synergy of chemotherapy and radiotherapy with ICBs. Citation Format: Yuki Muroyama, Alexander C. Huang, Sasikanth Manne, Ramin S. Herati, Lakshmi Chilukuri, Caiyue Xu, Claire F. Friedman, Dmitriy Zamarin, E. John Wherry. High dimensional DNA damage and repair (DDR) cytometric profiling of human T cell subsets revealed distinct DDR signatures [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B80.

Optimal PZT transducer location for effective damage identification in thin fixed plate

ABSTRACT In the recent advance, the employment of piezoelectric ceramic lead zirconate titanate (PZT) transducers has been widely increased because of its noticeable role in the domain of structural health monitoring (SHM) particularly in non-destructive evaluation. PZT-based electro-mechanical impedance (EMI) technique has been successfully applied to evaluate the inhomogeneities in the structure due to local damages and flaws. A numerical simulation based on EMI technique has been done using the coupled field finite element analysis on a homogenous fixed metallic plate bonded with PZT patches at different locations, to investigate the effect of damage at the fixed end and the centre of the span, induced by local reduction of stiffness, on the admittance signature pattern in ANSYSTM. The observations are discussed using RMSD as damage index computed between the states of pristine and damaged. The parametric study of PZT location and structure stiffness gives better insight into the analysis of admittance signatures, which is vital in SHM applications.

Signature patterns in region V4 of small ruminant lentivirus surface protein in sheep and goats

The env gene in Small Ruminant Lentiviruses (SRLV) encodes the surface glycoprotein (SU) that divides into conserved (C1-C4) and variable regions (V1-V5). SRLV region V4 has been found to be homologous to the V3 region of human lentivirus (HIV). HIV V3 is responsible for tropism and the development of nervous clinical patterns when there is a tendency to conserve amino acids in specific “signature pattern” positions. The goal of this study was to identify signature patterns in the V4 region of the SU, which is encoded by the SRLV env gene. Secondarily, to understand how these signature patterns are associated with different clinical status in naturally infected sheep and goats.Starting with 244 samples from seropositive animals from nine Mexican states, we amplified the V4 region using nested PCR and obtained 49 SRLV sequences from peripheral blood leukocytes. Based on phylogenetic analysis results, we identified three groups: asymptomatic genotypes A (Ssx GA) and B (Ssx GB), as well as animals with arthritic presentation, genotype B (A GB). Similarity levels between group sequences ranged from 67.9%–86.7%, with a genetic diversity ranging from 12.7%–29.5% and a dN / dS ratio that indicated negative selection.Analyses using Vespa and Entropy programs identified four residues at positions 54, 78, 79 and 82 in SU region V4 as possible signature patterns, although with variable statistical significance. However, position 54 residues “N” (p = 0.017), "T" (p = 0.001) and "G" (p = 0.024) in groups A GB, Ssx GA and Ssx GB respectively, best characterized the signature patterns. The results obtained identified a signature pattern related to different genotypes and clinical status by SRLV in sheep and goats.

Abstract P6-10-04: Landscape of immune-cell signatures in early high-risk breast cancer (BC) reveals clinically-relevant enrichment of immune subpopulations

Abstract Background: Immunosurveillance suppression, evasion, or avoidance, has emerged as a key targetable hallmark of cancer, driven by e.g. checkpoint expression, T-cell exhaustion, and immunosuppressive tumor microenvironment (TME). Many of these processes generate defined combinations of immune-cell infiltrates at the tumor site, which can be detected by immunohistochemistry (IHC), CyTOF, or more recently can be inferred from gene-expression deconvolution. While significant work has been done to study gene signatures in the TME, the clinical relevance of such immune-cell gene signature on therapy has not been studied to a great extent. We investigate the hypothesis that the individual patterns of immune-cell signatures determine the clinical behavior of breast cancer (BC), in particular response to neoadjuvant chemotherapy. Methods: We performed a retrospective-prospective analysis of a subset of the GeparSepto study (NCT01583426) in which women with primary invasive BC were randomized to either nab-paclitaxel or solvent-based paclitaxel followed by EC. This study was limited to 279 HER2- patients with sufficient quality sample remaining to perform whole-transcriptome RNAseq (~200 × 106 reads per tumor). Immune activity in the TME was inferred by comparing expression of 23 immune-cell-specific gene signatures derived by Bindea et al. (Immunity, 2013) to those from a background population of 1467 similarly-profiled unselected tumor samples from the NantOmics database. Results: Within this cohort the most predominant high immune-cell signatures were for natural killer (NK) cells (71%), and regulatory T-cells (70%). Stimulatory T-cell signatures were high in approximately half of the population including Th2 (53%), effector-memory (53%), follicular helper (51%), Th1 (41%), and Gamma-delta T-cells (39%). While cytotoxic CD8+ T-cell signature was high in only 19.0% of patients, the signature for the CD56dim cytolytic subset of NK cells was high in 48.0% of patients. The most infrequently detected gene signatures were for innate response cell-types: Mast cells (7.5%), Macrophages (10.8%), immature dendritic cells (11.5%) and neutrophils (11.8%). Of the 23 immune signatures, 17 were significantly differentially activated in TNBC compared to hormone-receptor positive (HR+) patients (p&amp;lt;0.05 respectively): 8/10 signatures more active in TNBC are associated with adaptive immune response (e.g. T-cell and B-cell signatures), whereas 5/7 signatures associated with HR+ are related to innate immune response (e.g. eosinophils and dendritic cells). Select adaptive immune signatures were associated with aggressive tumors: Elevated NK CD56dim, Th1, and activated dendritic cell (aDC), signatures were associated with grade 3 tumors as well as with elevated levels of Ki67 (p&amp;lt;0.0001 respectively). The most predictive TME signature for paclitaxel-based therapy was T follicular helper cells (TFH) with DFS and OS hazard ratio of 0.62 (95% CI: 0.47-0.81; p=0.0004) and 0.55 (95% CI: 0.39-0.77; p=0.0005) respectively, as well as a 1.63 (95% CI: 1.12-2.36; p=0.0107) odds-ratio for achieving pCR. Conclusion: Whole-transcriptome sequencing in breast cancer FFPE core biopsies from clinical cohorts can be used to identify immune-cell signatures. Specifically, adaptive immunity through NK rather than T-cell response appears prevalent in high-risk TNBC. The patterns of these immune signatures, in particular the presence of T follicular helper cells, reflect the clinical behavior of breast cancer and might be used to identify tumors with an increased response rate to neoadjuvant chemotherapy. Citation Format: Christopher Szeto, Carsten Denkert, Peter A Fasching, Stephen Benz, Karsten E Weber, Jan Budczies, Andreas Schneeweiss, Elmar Stickeler, Sabine Schmatloch, Christian Jackisch, Thomas Karn, Hans P Sinn, Mathias Warm, Marion van Mackelenbergh, Shahrooz Rabizadeh, Christian Schem, Ernst Heinmöller, Volkmar Müller, Frederik Marmé, Patrick Soon-Shiong, Valentina Nekljudova, Sibylle Loibl, Michael Untch. Landscape of immune-cell signatures in early high-risk breast cancer (BC) reveals clinically-relevant enrichment of immune subpopulations [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-04.

Epigenetic loss of heterozygosity of Apc and an inflammation-associated mutational signature detected in Lrig1+/\u2212-driven murine colonic adenomas

BackgroundThe loss of a single copy of adenomatous polyposis coli (Apc) in leucine-rich repeats and immunoglobulin-like domains 1 (Lrig1)-expressing colonic progenitor cells induces rapid growth of adenomas in mice with high penetrance and multiplicity. The tumors lack functional APC, and a genetic loss of heterozygosity of Apc was previously observed.MethodsTo identify genomic features of early tumorigenesis, and to profile intertumoral genetic heterogeneity, tumor exome DNA (n = 9 tumors) and mRNA (n = 5 tumors) sequences were compared with matched nontumoral colon tissue. Putative somatic mutations were called after stringent variant filtering. Somatic signatures of mutational processes were determined and splicing patterns were observed.ResultsThe adenomas were found to be genetically heterogeneous and unexpectedly hypermutated, displaying a strong bias toward G:C > A:T mutations. A genetic loss of heterozygosity of Apc was not observed, however, an epigenetic loss of heterozygosity was apparent in the tumor transcriptomes. Complex splicing patterns characterized by a loss of intron retention were observed uniformly across tumors.ConclusionThis study demonstrates that early tumors originating from intestinal stem cells with reduced Lrig1 and Apc expression are highly mutated and genetically heterogeneous, with an inflammation-associated mutational signature and complex splicing patterns that are uniform across tumors.

Homologous recombination deficiency (HRD) scoring in pancreatic ductal adenocarcinoma (PDAC) and response to chemotherapy.

741 Background: Whole genome sequencing (WGS) can reveal patterns of substitution base signatures and structural variation consistent with tumours deficient in homologous recombination repair. We evaluated the published HRDetect score and a novel HRD hallmark score (HS) in patients receiving combination chemotherapy (cCT) on the COMPASS trial for advanced PDAC. Methods: The HRD-HS incorporates 10 genomic characteristics of HRD-PDAC with a score ≥ 4 defining HRD. HRD-HS and an HRDetect score ≥0.7 were applied to WGS data and overall survival (OS) and response (ORR) evaluated. Sensitivity and specificity were ascertained. Results: As of 05/19, 205 eligible patients (pts) were enrolled and 186 received cCT including modified FOLFIRINOX n = 108 (58%) or cisplatin/gemcitabine n = 2 (1%) and gemcitabine/nab-paclitaxel n = 76 (41%). HRD-HS had a sensitivity of 87.5% and specificity of 100% in detecting HRD-PDAC. In contrast, HRDetect (≥0.7) had sensitivity of 51.9% and specificity of 100%; sensitivity increased to 73.7% when using a cutoff score of ≥0.99. 23/186 (12%) pts were classified as HRdetecthi and median OS was 15.3months (mo) vs 8.7mo in HRDetectlo pts (HR 0.44 95% CI 0.27-.70, p = 0.009). In platinum treated pts, median OS was 18.1mo (HRDetecthi) vs 9.3mo (HRDetectlo) (HR 0.38 95%CI 0.21-0.69, p = 0.02). HRD-HS predicted the longest median OS for platinum of 21.0mths. ORR in HRDetecthi was not different to HRDetectlo pts treated with cCT, however in those receiving platinum the ORR was 50% vs 19% respectively (p &lt; 0.001). Of the false positives by HRDetect, 46% had a non-BRCA1 tandem duplicator phenotype (TDP). The TDP group comprised 8% of all patients enrolled. HRD-PDAC was caused by inactivation of BRCA1/2, PALB2, RAD51C and XRCC2; all germline variants were pathogenic. Pathogenic ATM and CHEK2 germline variants were present in 3 pts with evidence of a second somatic hit or LOH, none of these identified as HRD by either classifier nor considered a TDP. Conclusions: HRD-HS most correctly identified HRD-PDAC however the HRDetect score classifies additional patients sensitive to cCT, especially platinum. The TDP cohort may be responsive to DNA damaging agents warranting further evaluation. Clinical trial information: NCT02750657.

Fluvial CO2 and CH4 patterns across wildfire-disturbed ecozones of subarctic Canada: Current status and implications for future change.

Despite occupying a small fraction of the landscape, fluvial networks are disproportionately large emitters of CO2 and CH4 , with the potential to offset terrestrial carbon sinks. Yet the extent of this offset remains uncertain, because current estimates of fluvial emissions often do not integrate beyond individual river reaches and over the entire fluvial network in complex landscapes. Here we studied broad patterns of concentrations and isotopic signatures of CO2 and CH4 in 50 streams in the western boreal biome of Canada, across an area of 250,000km2 . Our study watersheds differ starkly in their geology (sedimentary and shield), permafrost extent (sporadic to extensive discontinuous) and land cover (large variability in lake and wetland extents). We also investigated the effect of wildfire, as half of our study streams drained watersheds affected by megafires that occurred 3years prior. Similar to other boreal regions, we found that stream CO2 concentrations were primarily associated with greater terrestrial productivity and warmer climates, and decreased downstream within the fluvial network. No effects of recent wildfire, bedrock geology or land cover composition were found. The isotopic signatures suggested dominance of biogenic CO2 sources, despite dominant carbonate bedrock in parts of the study region. Fluvial CH4 concentrations had a high variability which could not be explained by any landscape factors. Estimated fluvial CO2 emissions were 0.63 (0.09-6.06, 95% CI) and 0.29 (0.17-0.44, 95% CI) g C m-2 year-1 at the landscape scale using a stream network modelling and a mass balance approach, respectively, a small but potentially important component of the landscape C balance. These fluvial CO2 emissions are lower than in other northern regions, likely due to a drier climate. Overall, our study suggests that fluvial CO2 emissions are unlikely to be sensitive to altered fire regimes, but that warming and permafrost thaw will increase emissions significantly.

Characterizing Magnetic Reconnection Regions Using Gaussian Mixture Models on Particle Velocity Distributions

Abstract We present a method based on unsupervised machine learning to identify and characterize regions of interest using particle velocity distributions as a signature pattern. An automatic density estimation technique is applied to particle distributions provided by particle-in-cell simulations to study magnetic reconnection regions. Its application to magnetic reconnection is new. The key components of the method involve (i) a Gaussian mixture model determining the presence of a given number of subpopulations within an overall population, and (ii) a model selection technique with a Bayesian information criterion to estimate the appropriate number of subpopulations. Thus, this method automatically identifies the presence of complex distributions, such as beams or other non-Maxwellian features, and can be used as a detection algorithm able to identify reconnection regions. The approach is demonstrated for a specific double Harris sheet simulation, but it can in principle be applied to any other type of simulation data on the particle distribution function.

Multi-scale observations of the co-evolution of sea ice thermophysical properties and microwave brightness temperatures during the summer melt period in Hudson Bay

Monitoring the trend of sea ice breakup and formation in Hudson Bay is vital for maritime operations, such as local hunting or shipping, particularly in response to the lengthening of the ice-free period in the Bay driven by climate change. Satellite passive microwave sea ice concentration products are commonly used for large-scale sea ice monitoring and predictive modelling; however, these product algorithms are known to underperform during the summer melt period due to the changes in sea ice thermophysical properties. This study investigates the evolution of in situ and satellite-retrieved brightness temperature (TB) throughout the melt season using a combination of in situ passive microwave measurements, thermophysical sampling, unmanned aerial vehicle (UAV) surveys, and satellite-retrieved TB. In situ data revealed a strong positive correlation between the presence of liquid water in the snow matrix and in situ TB in the 37 and 89 GHz frequencies. When considering TB ratios utilized by popular sea ice concentration algorithms (e.g., NASA Team 2), liquid water presence in the snow matrix was shown to increase the in situ TB gradient ratio of 37/19V. In situ gradient ratios of 89/19V and 89/19H were shown to correlate positively with UAV-derived melt pond coverage across the ice surface. Multi-scale comparison between in situ TB measurements and satellite-retrieved TB (by Advanced Microwave Scanning Radiometer 2) showed a distinct pattern of passive microwave TB signature at different stages of melt, confirmed by data from in situ thermophysical measurements. This pattern allowed for both in situ and satellite-retrieved TB to be partitioned into three discrete stages of sea ice melt: late spring, early melt and advanced melt. The results of this study thus advance the goal of achieving more accurate modeled predictions of the sea ice cover during the critical navigation and breakup period in Hudson Bay.

A new metabolic signature contributes to disease progression and predicts worse survival in melanoma

ABSTRACT Metabolic reprogramming is a common hallmark of tumor cells and is a crucial mediator of resistance toward anticancer therapies. The pattern of a metabolism-related signature in melanoma remains unknown. Here, we explored the role of a multi-metabolism-related gene signature in melanoma.We used the training and validation sets to develop a multi-metabolism-related gene signature. Cox regression analysis and the least absolute shrinkage and selection operator (LASSO) method were used for constructing a model. The predictive role of the metabolic signature with clinicopathological features of melanoma was also analyzed. Functional analysis of this metabolic signature was also investigated.A ten metabolism-related gene signature was identified and can stratify melanoma into high- and low- risk groups. The signature was correlated with progressive T stage, Breslow thickness, Clark level, and worse survival (all Ps< 0.01). This metabolic signature was shown as an independent prognostic factor and was also a predictive indicator for worse survival in various clinical and molecular features of melanoma. Furthermore, the metabolic signature was implicated in immune responses such as the regulation of T cell activation and cytokine activity. The metabolic signaturewas associated with the progression and worse survival of melanoma. Our study offered a valuable metabolism-targeted therapy approach for melanoma.

Towards precision medicine: defining and characterizing adipose tissue dysfunction to identify early immunometabolic risk in symptom-free adults from the GEMM family study

ABSTRACT Interactions between macrophages and adipocytes are early molecular factors influencing adipose tissue (AT) dysfunction, resulting in high leptin, low adiponectin circulating levels and low-grade metaflammation, leading to insulin resistance (IR) with increased cardiovascular risk. We report the characterization of AT dysfunction through measurements of the adiponectin/leptin ratio (ALR), the adipo-insulin resistance index (Adipo-IRi), fasting/postprandial (F/P) immunometabolic phenotyping and direct F/P differential gene expression in AT biopsies obtained from symptom-free adults from the GEMM family study. AT dysfunction was evaluated through associations of the ALR with F/P insulin-glucose axis, lipid-lipoprotein metabolism, and inflammatory markers. A relevant pattern of negative associations between decreased ALR and markers of systemic low-grade metaflammation, HOMA, and postprandial cardiovascular risk hyperinsulinemic, triglyceride and GLP-1 curves was found. We also analysed their plasma non-coding microRNAs and shotgun lipidomics profiles finding trends that may reflect a pattern of adipose tissue dysfunction in the fed and fasted state. Direct gene differential expression data showed initial patterns of AT molecular signatures of key immunometabolic genes involved in AT expansion, angiogenic remodelling and immune cell migration. These data reinforce the central, early role of AT dysfunction at the molecular and systemic level in the pathogenesis of IR and immunometabolic disorders.

Integrated Genome-Wide DNA Methylation and RNAseq Analysis of Hippocampal Specimens Identifies Potential Candidate Genes and Aberrant Signalling Pathways in Patients with Hippocampal Sclerosis

DNA methylation and demethylation play a crucial role in the regulation of gene expression, though their interplay during pathogenesis of hippocampal scelerosis (HS) remains elusive. The present study was designed to investigate the DNA methylation regulated changes in expression of HS patients. We performed integrative analysis of genome-wide CpG-DNA methylation profiling and RNA sequencing to profile global changes in promoter methylation and gene expression in HS patients. Real time PCR was performed to validate the findings of methylation and RNA sequencing. A total of 16040 sites showed altered DNA methylation in all the CpG islands. Of these, 3185 sites were in the promoter regions, of which 66 genes showed an inverse correlation between methylation and expression. These genes are largely related to pathways predicted to participate in axon guidance by semaphorins, MAPK, ionotropic glutamate receptor pathway, notch signaling, regulatory activities related to TFAP2A and immune response, with the most distinct ones included TFAP2A, NRP1, SEMA3B, CACNG2, MAP3K11, and ADAM17. We performed integrated analysis of genomic methylation signature and differential gene expression patterns of hippocampal tissues resected from patients with HS for the first time. Collectively, our findings implicate DNA methylation as a critical regulator of the pathogenic mechanisms of epileptogenesis associated with HS.

First record of Ditrupa gracillima (Annelida, Polychaeta) from the late Pliocene of Andaman and Nicobar Basin: insights on the ultrastructure, stable isotopic signature and distribution pattern

In the present study from the late Pliocene of Neill West Coast Formation, Neil Island, serpulid tubes assignable to Ditrupa gracillima Grube have been identified with the help of tube morphological (light microscopy) and ultrastructural (SEM) studies. This is the first record of the species from the late Pliocene of India. The outer layer of D. gracillima is entirely different from other invertebrates, and the presence of Ridged Prismatic Structure (RRP) exclusively characterises this particular species. The mineralogical analysis (Raman spectroscopy and EDS) reveals a Mg-Ca skeletal for D. gracillima. Isotopic analysis indicates that there is a narrow range of variation in the delta 18 O values of D. gracillima The delta 13 C of D. gracillima shows significant variation and displays the most 13 C depleted values. Based on isotopic analysis it has been inferred that the deposition of sediments took place in a shallow marine environment and D. gracillima thrived in the proximity of hydrocarbon seepages. The present day distributional pattern of D. gracillima indicates that they are mainly confined in the Indo-Pacific region.