Common Partner Research Articles

The natural history of fibroblast growth factor receptor (FGFR)-altered cholangiocarcinoma (CCA).

e16686 Background: Genetic alterations in the FGFR pathway are emerging as promising therapeutic targets in CCA. The clinical and molecular features of patients (pts) with CCA harboring FGFR genetic alterations are reported here. Methods: A retrospective chart review was performed in pts with CCA who were found to have an FGFR alteration on tumor molecular profiling as part of routine care between 9/2007 and 12/2019. Data on demographics, risk factors, pathology, molecular characteristics, systemic therapies, radiographical response, time on treatment, and overall survival (OS) were collected in a multi-center collaborative effort across seven academic centers. Results: Among 135 pts with FGFR-altered CCA, the median age at diagnosis was 57 years old (range = 25-92 years), and 80 (59.3%) pts were female, 129 (95.6%) had intrahepatic CCA, and 6 (5.6%) had chronic HBV. At presentation, 28.2% of pts had resectable disease, including 65.0% with Stage I-II, 22.5% with Stage III, and 5.0% with Stage IV. At the time of initial diagnosis, CA19-9 was < 35U/mL in 42.6% of pts. Bone metastases were observed in 41 (30.6%) pts with advanced disease. FGFR2 fusions were the most common FGFR alteration (68.2%), followed by FGFR2 mutations (21.5%), FGFR3 mutations (3.7%), FGFR2 rearrangements (1.5%), FGFR1 amplification (1.5%), and FGFR2 amplification (1.5%). The most common FGFR2 fusion partners were BICC1 (28.3%), SORBS1 (4.4%), POC1B (3.3%), and TACC2 (3.3%). The median lines of palliative systemic therapies received was 3 (range = 0-8), and 40/135 (29.6%) pts received a liver-directed therapy. For the 55 (59.8%) pts with FGFR2 fusions who received gemcitabine/cisplatin as first-line palliative systemic therapy, the median time on treatment was 6.2 months (95% CI: 4.1-9.3). The median OS from time of initial diagnosis was 36.1 months (95% CI: 28.3-51.6) in the FGFR2 fusion positive cohort. Among the 92 pts with FGFR2 fusions, 70 (76.1%) pts received an FGFR inhibitor on a clinical trial; 12 (17.1%) were subsequently treated with a second FGFR inhibitor, and 58.3% stayed on the second FGFR inhibitor for ≥4 months. Pts with a BICC1 fusion partner (n = 16) had an overall response rate of 42.9% on FGFR-selective inhibitors compared to 30.8% in non-BICC1 fusion partners (n = 54). Conclusions: Pts with CCA harboring FGFR alterations were found to have a high rate of normal CA19-9, high rate of bone metastases, and short median time on treatment on first-line palliative gemcitabine/cisplatin. Additional comparative studies are necessary to evaluate these findings.

Anaplastic lymphoma kinase (ALK) partners identified by next-generation sequencing in Chinese patients with solid tumors.

3555 Background: Anaplastic lymphoma kinase (ALK) rearrangement is a validated therapeutic driver gene in non-small cell lung cancer (NSCLC). More than 30 different fusion partner genes of ALK in NSCLC have been reportedand most of these ALK fusions respond well to ALK inhibitors crizotinib. With the development of next-generation sequencing (NGS), more novel partners for ALK rearrangement have been identified. Here, we aimed to report the landscape of ALK rearrangement in Chinese patients with solid tumors. Methods: Tissue or blood samples were subjected to NGS in a College of American Pathologists-certified and Clinical Laboratory Improvement Amendments-accredited lab for ALK arrangement. Results: In total, we profiled more than 40,000 patients, among which 72 cases with 52 ALK fusion partner, harboring 17 reported partners and 35 novel partners. The average ALK rearrangement patients' age was 53 years (range, 17-76 years). Among all the ALK fusion cases (n = 72), lung cancer were the largest proportion with 77.8% (n = 56), colorectal cancer accounted for, 5.5% (n = 4), liver cancer accounted for 4.2% (n = 3), biliary cancer, melanoma, carcinosarcoma and inflammatory myofibroblastic tumor accounted for 2.8% (n = 2) respectively, and only one case (n = 1) was malignant peritoneal mesothelioma. The most common ALK fusion partners were KIF5B (n = 6), DCTN1 (n = 5) and STRN (n = 5). In 38 cases, 35 novel ALK fusion partners were discovered. The novel CLIP4-ALK, EHBP1-ALK, PLB1-ALK occurred twice in 6 patients, which were two lung cancer patients with CLIP4-ALK fusion, two lung cancer patients with PLB1-ALK fusion, one hepatic cellular cancer patients with EHBP1-ALK, and one melanoma patients with EHBP1-ALK. There were two special lung cancer cases with two ALK fusions. One case detected the novel LRIG1-ALK fusion and novel PLB1-ALK fusion, the other case detected novel GLI3-ALK fusion and reported HIP1-ALK fusion. Conclusions: Novel ALK fusions are detected in patients with not only NSCLC but also other solid tumors. NGS fusion assay is an optional method for screening novel fusions.

Clinical utility of comprehensive genomic pathway and integrated network analyses in personalized oncology.

e14051 Background: Adoption of next-generation sequencing (NGS) technology in routine clinical practice has enabled the detection of genetic aberrations such as single nucleotide variants, copy number alterations, and gene fusions. Pathway and network analyses (PNA) are key components for evaluation of NGS data in a clinical setting to explain findings involving thousands of altered genes and proteins with a smaller and more interpretable set of altered processes. Though PNA have been applied to identify driver genes and pathways in cohort-based analyses, its application in precision oncology remains unexplored. We investigate the potential utility of the Watson for Genomics (WfG) pathway analyses tool in interpreting complex and multiple genomic alterations in individual cancers. Methods: DNA and RNA isolated from 70 patient tumors across 30 different cancer types were processed with Illumina’s TST170 NGS platform. WfG’s feature of pathway analyses was used to identify gene variants, signaling pathways, networks, and the drugs targeting these alterations based on evidence in the clinical literature and FDA drug databases. Results: Analyses defined 5 different pathway/network models: 1) downstream therapeutic targets, 2) synthetic lethality, 3) combinatorial downstream targets + synthetic lethality, 4) two or more pathways converging to downstream targets, and 5) complex profile analyses. The five PNA models are illustrated by the following unique cases. 1) A thyroid cancer case with HRAS variant and activated RAF1 downstream pathway showed MAPK1/3 were suggestive of relevant targets. 2) An acute myeloid leukemia case with BRCA1, BRCA2 and PTEN variants, targeting a common synthetic lethal partner PARP1 was ideal for therapy. 3) A penile carcinoma case with BRAF, CDKN2A and TP53 variants, targeting the BRAF downstream pathway in combination with either CDKN2A or TP53 were the likely choice for therapy. 4) A glioma case with activated PI3K and MEK downstream pathway, targeting a common downstream marker would block both pathways. 5) A breast carcinoma case with a complex pathogenic variant profile provided relevant clinical information and levels of evidence for multiple drug targets. Conclusions: We discovered that the integrated WfG pathway analyses tool is ideal for visualization of the variants with levels of evidence from clinical literature and FDA drug databases that can help inform treatment options and provides a holistic understanding of a specific tumor profile allowing the treating clinician to select personalized targeted therapy.

The Genomic Characteristics of ALK Fusion Positive Tumors in Chinese NSCLC Patients.

Anaplastic lymphoma kinase (ALK) fusion events account for ~3–7% genetic alterations in patients with non-small cell lung cancer (NSCLC). In this study, we identified the ALK fusion patterns and a novel ALK fusion partner in 44 ALK positive NSCLC patients using a customized HapOncoCDx panel, and identified ALK fusion partners. The most common partner is EML4, forming the variant 1 (v1, E13:A20, 18/44), variant 2 (v2, E20:A20, 5/44), and variant 3 (v3, E6:A20, 13/44). Moreover, we detected a new ALK fusion partner HMBOX1. At the mutation level, TP53 is the most frequently mutated gene (24%), followed by ALK (12%) and STED2 (12%). The median tumor mutation burden (TMB) of these samples is 2.29 mutations/Mb, ranging from 0.76 mut/Mb to 16.79 muts/Mb. We further elaborately portrayed the TP53 mutation sites on the peptide sequence of the encoded protein by lollipop. The mutational signature and copy number alterations (CNAs) of the samples were also analyzed. The CNA events were found in 13 (13/44) patients, and the most commonly amplified genes were MDM2 (n = 4/13) and TERT (n = 4/13). Together, these results may guide personalized clinical management of patients with ALK fusion in the era of precision medicine.

Assessment of Nine Driver Gene Mutations in Surgically Resected Samples from Patients with Non-Small-Cell Lung Cancer.

BackgroundThe mutational profile of oncogenic driver genes play an important role in non-small-cell lung cancer (NSCLC). The need of a testing panel capable of comprehensively determining patient genotypes in limited amounts of material has increased since the recent association of nine core oncogenic driver genes as tumor predictive biomarkers.MethodsSurgically resected samples from 214 NSCLC patients (168 patients with adenocarcinomas and 46 with squamous cell cancers) were included. A multiplexed PCR-based assay was developed to simultaneously test 118 hotspot mutations and fusions in nine driver genes.ResultsThe sensitivity of the kit was 1% for gene mutation and 450 copies for gene fusion. Genetic alterations were detected in 143 (66.8%) patients by the assay. The three most common alterations identified were EGFR mutations (50.9%), KRAS mutations (8.4%) and ALK fusions (4.7%). Eight (3.7%) patients harbored concurrent mutations, and the most common partners were EGFR mutations which were observed in the eight patients. No associations between survival and EGFR, KRAS, and ALK status were observed. Patients with two or more alterations exhibited shorter DFS compared to those with single mutations (P=0.032), whilst had no significant difference in OS (P=0.245). However, only TNM stage was an independent predictor of OS (HR=2.905, P<0.001) as well as DFS (HR=2.114, P<0.001) in our cohort in multivariate analysis. Furthermore, patients with the L858R mutation had longer DFS (P=0.014) compared to other sensitizing mutations and tended to have better OS but the differences were not significant (P=0.06).ConclusionThese findings suggest this multiplex gene panel testing technique can be efficiently used to detect nine driver genes in a limited number of specimens. This methodology would have the potential to save both specimens and time compared to the combination of all assays by other methods.

I-It, I-Thou, I-Robot: The Perceived Humanness of AI in Human-Machine Communication

ABSTRACT As artificial intelligence (AI) technologies become more common and capable interaction partners (human-machine communication; HMC), understanding how people perceive and interact with them becomes increasingly important to study. This essay argues that one important avenue for this study is the application of relevant interpersonal and computer-mediated communication (CMC) theories. The paper suggests that these theories are relevant because the Computers as Social Actors (CASA) approach has shown that people tend to respond to technologies as they do to other people. It summarizes some theories that may be especially useful for future study in this field. Finally, a case is made that the study of AI and HMC may also be important for greater understanding of the human-human communication process as well.

Meşruti Rejimin Memnuniyet Ölçeği: “Kutlama Mesajları”

Meşruiyet; muktedirin iktidar iddiasını muhatabın istifadesine sunarak ve muhatabın da tepkisini tartıp muktedir iddiasının düzeyini tayin ederek düzeni ihsas ettiren dini ve beşeri ifadelere dayalı davranış biçimlerinin toplamıdır. Söz konusu toplam; kuruluştan kurumsallaşmaya, kurumsallaşmadan kuruntuya ve kuruntudan kırılmaya kadar tüm siyasal yapıların muhtaç oldukları revabıt-ı zaruretlerdendir. Meşruiyet bu hususiyetiyle muktedirlerin inisiyatiflerine mutedil bir üslup kazandırıp bunları muhatapları nezdinde onaylattıran mezkûr üslubu söylem, sembol ve seremonilerle yeniden üreten çok yönlü bir vasıtadır. Meşrutiyet; kuşatılmış bir coğrafyada esamisi esatirlere konu edilen bir ailenin kendilerini ifade etme noktasında başvurdukları kaynaklardan birisi olmuştur. Bu çok yönlü kavram, çok dinli, dilli ve mezhebi özelliklere sahip milletlerin mukadderatlarını, mezkûr ailenin müşterek paydaşları kılmış ve altı asrı aşan ve üç kıtaya yayılan siyasi bir gelenek doğurmuştur. Bu çalışma bahsedilen geleneği, meşruti rejim üzerinden güncelleyen muktedirlerin meşrulaştırımlarına, bu bağlamda ihdas edilmiş milli bayrama ve bu tür merasimlere iştirak edenlerin hissiyatını ölçen “kutlama mesajlarına” yoğunlaşmıştır.

Generation of An Endogenous FGFR2-BICC1 Gene Fusion/58 Megabase Inversion Using Single-Plasmid CRISPR/Cas9 Editing in Biliary Cells.

Fibroblast growth factor receptor 2 (FGFR2) gene fusions are bona fide oncogenic drivers in 10–15% of intrahepatic cholangiocarcinoma (CCA), yet currently there are no cell lines publically available to study endogenous FGFR2 gene fusions. The ability of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 to generate large yet precise chromosomal rearrangements has presented the possibility of engineering endogenous gene fusions for downstream studies. In this technical report, we describe the generation of an endogenous FGFR2–Bicaudal family RNA binding protein 1 (BICC1) fusion in multiple independent cholangiocarcinoma and immortalized liver cell lines using CRISPR. BICC1 is the most common FGFR2 fusion partner in CCA, and the fusion arises as a consequence of a 58-megabase-sized inversion on chromosome 10. We replicated this inversion to generate a fusion product that is identical to that seen in many human CCA. Our results demonstrate the feasibility of generating large megabase-scale inversions that faithfully reproduce human cancer aberrations.

Diversity within mutualist guilds promotes coexistence and reduces the risk of invasion from an alien mutualist.

Biodiversity is an important component of healthy ecosystems, and thus understanding the mechanisms behind species coexistence is critical in ecology and conservation biology. In particular, few studies have focused on the dynamics resulting from the co-occurrence of mutualistic and competitive interactions within a group of species. Here we build a mathematical model to study the dynamics of a guild of competitors who are also engaged in mutualistic interactions with a common partner. We show that coexistence as well as competitive exclusion can occur depending on the competition strength and on strength of the mutualistic interactions, and we formulate concrete criteria for predicting invasion success of an alien mutualist based on propagule pressure, alien traits (such as its resource exchange ability) and composition of the recipient community. We find that intra guild diversity promotes the coexistence of species that would otherwise competitively exclude each other, and makes a guild less vulnerable to invasion. Our results can serve as a useful framework to predict the consequences of species manipulation in mutualistic communities.

Genomic alterations and tumor mutational features of Chinese Xp11.2 translocation renal cell carcinoma patients.

736 Background: Xp11.2 translocation renal cell carcinoma (Xp11.2 RCC) is a rare subtype of RCC which occurs predominantly in children and adolescents. Xp11.2 RCC is characterized by the gene fusions of transcription factor E3 (TFE3). Since there is a high false-positive and false-negative rate of immunohistochemistry (IHC) for TFE3 and an uncertainty of TFE3 fusion partners by fluorescence in situ hybridization (FISH), a genetic approach, such as DNA sequencing, is necessary for auxiliary diagnosis. Methods: Thirty Chinese Xp11.2 RCC patients with positive TEF3 fusion diagnosed by FISH were involved in this analysis. Formalin-fixed, paraffin-embedded (FFPE) samples were collected for a next-generation sequencing (NGS)-based 576 gene panel assay. Genomic alterations including single base substitution, copy number variations, gene fusions, and rearrangements were assessed. Tumor mutational burden (TMB) and microsatellite instability (MSI) status were also analyzed by an NGS algorithm. Results: The 30 patients in the Xp11.2 RCC cohort included 13 males and 17 females, and had a median age of 30 years. TFE3 fusions of these patients were confirmed by both FISH and NGS. Out of the 30 Xp11.2 RCC patients, 2 patients (6.7%) showed negative TFE3 IHC expression and 4 patients (13.3%) showed equivocal TFE3 IHC expression. ASPL (9/30), PRCC (5/30), PSF (5/30), and NONO (3/30) were the most common partners of TFE3 fusion in this cohort. Moreover, we identified uncommon or novel partner genes by NGS, including ZNF627 (1/30), PTPN12 (1/30), PBM10 (1/30), PARP14 (1/30), MED15 (2/30), MATR3 (1/30), LUC7L3 (1/30), KHSRP (1/30), and EWSR1 (1/30). Based on the NGS results, several actionable genomic alterations including CDKN2A, BRCA2, and ATM were found in this study. All samples were identified as microsatellite stable (MSS). The median TMB of the entire cohort was 1.35 muts/Mb (range, 0-9.2 muts/Mb). Conclusions: In summary, we identified the partner genes of TFE3 fusion in 30 Chinese Xp11.2 RCC patients by NGS. Ten uncommon or novel partner genes (33.3%) of TFE3 were identified in this study. Overall, our results provide evidence for diagnosis and therapeutic strategies for Xp11.2 RCC patients.

Hippo pathway effectors YAP1/TAZ induce an EWS-FLI1-opposing gene signature and associate with disease progression in Ewing sarcoma.

YAP1 and TAZ (WWTR1) oncoproteins are the final transducers of the Hippo tumor suppressor pathway. Deregulation of the pathway leads to YAP1/TAZ activation fostering tumorigenesis in multiple malignant tumor types, including sarcoma. However, oncogenic mutations within the core components of the Hippo pathway are uncommon. Ewing sarcoma (EwS), a pediatric cancer with low mutation rate, is characterized by a canonical fusion involving the gene EWSR1 and FLI1 as the most common partner. The fusion protein is a potent driver of oncogenesis, but secondary alterations are scarce, and little is known about other biological factors that determine the risk of relapse or progression. We have observed YAP1/TAZ expression and transcriptional activity in EwS cell lines. Analyses of 55 primary human EwS samples revealed that high YAP1/TAZ expression was associated with progression of the disease and predicted poorer outcome. We did not observe recurrent SNV or copy number gains/losses in Hippo pathway-related loci. However, differential CpG methylation of the RASSF1 locus (a regulator of the Hippo pathway) was observed in EwS cell lines compared with mesenchymal stem cells, the putative cell of origin of EwS. Hypermethylation of RASSF1 correlated with the transcriptional silencing of the tumor suppressor isoform RASFF1A, and transcriptional activation of the pro-tumorigenic isoform RASSF1C, which promotes YAP1/TAZ activation. Knockdown of YAP1/TAZ decreased proliferation and invasion abilities of EwS cells and revealed that YAP1/TAZ transcription activity is inversely correlated with the EWS-FLI1 transcriptional signature. This transcriptional antagonism could be explained partly by EWS-FLI1-mediated transcriptional repression of TAZ. Thus, YAP1/TAZ may override the transcriptional program induced by the fusion protein, contributing to the phenotypic plasticity determined by dynamic fluctuation of the fusion protein, a recently proposed model for disease dissemination in EwS. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Circulating free DNA (cfDNA) and tissue next-generation sequencing analysis in a phase II study of infigratinib (BGJ398) for cholangiocarcinoma with FGFR2 fusions.

579 Background: Fibroblast growth factor receptor 2 (FGFR2) alterations occur in 11% of cholangiocarcinomas, 85% of which are fusions. A multicenter, open-label, phase II study is currently evaluating the efficacy of infigratinib, a selective FGFR1–3 tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma containing FGFR2 fusions. We report detailed biomarker analyses from this study. Methods: Patients with advanced or metastatic cholangiocarcinoma containing FGFR2 fusions whose disease had progressed following cisplatin- or gemcitabine-based therapy were eligible. Patients received oral infigratinib 125 mg once daily on days 1–21 every 28 days. Comprehensive genomic profiling (CGP) was performed on tumor tissue and cfDNA collected prior to the start of therapy. The primary endpoint was investigator-assessed overall response rate (ORR) [RECIST version 1.1]. Data cut-off (prespecified): August 8, 2018. Trial registration: NCT02150967. Results: At data cut-off, 71 patients with FGFR2 fusions were included (62% women; median age 53 years; 55% received ≥2 prior lines of therapy). Median duration of treatment was 5.5 months. ORR (confirmed and unconfirmed) was 31.0% (95% CI 20.5–43.1%) and confirmed ORR was 26.9% (95% CI 16.8–39.1%). 33 unique FGFR2 fusion genes were identified in 71 enrolled patients. The most common fusion gene partner was BICC1 (32%; 23/71). Pathogenic variants in 9 other druggable genes were identified in 32% of patients (13/37) who underwent CGP. FGFR2 fusions were concordant in 67% (8/12) of patients with tumor tissue and cfDNA at screening. Conclusions: The large assortment of FGFR2 fusion genes identified in this study underscores the diversity of FGFR2 rearrangements that may drive cholangiocarcinoma. Although cfDNA analysis was performed in a minority, these preliminary data suggest that cfDNA analysis may be valuable for the identification of FGFR2 fusions and to study intratumoral heterogeneity. Clinical trial information: NCT02150967.

Selectivity and Specificity in WW Domain-PPxY Interactions

WW domain-PPxY (where x is any amino acid) interactions play multiple roles in regulating cell growth. A puzzling aspect of these interactions is how the same PPxY motif protein selects between diverse WW domain proteins. Using recombinant PPxY motif proteins Angiomotin-Like 1 (AMOTL1) and Large tumor suppressor 1 (LATS1) and their common WW domain partners Yes-associated protein (YAP) and the kidney and brain protein KIBRA, we demonstrated by isothermal titration calorimetry and nuclear magnetic resonance spectroscopy that selectivity is achieved via simultaneous interactions as well as mutually exclusive binding. AMOTL1, a primarily disordered protein with three PPxY motifs, simultaneously interacts with YAP and KIBRA via the first and third PPxY motifs respectively. On the contrary, binding of YAP and KIBRA to the two PPxY motif of LATS1 is mutually exclusive, with preferential formation of the YAP-LATS1 complex when all three proteins are present. These discoveries provide exciting new insights into the complex mechanisms that regulate cell growth.

Addressing Challenges to Coordinating the Implementation of Place-Based Chronic Disease Prevention Interventions in Los Angeles.

Chronic disease prevention initiatives have traditionally been structured to address a single disease, potentially limiting the scope of health impacts. In the past decade, initiatives have increasingly adopted a coordinated approach, in which multiple interventions are intended to work synergistically-often in a bounded geographic area-to address interrelated risk factors and diseases. However, despite increased interest in this coordinated approach, few examples exist of how coordination has been operationalized in local public health practice. In 2014, the Los Angeles County Department of Public Health launched the 4-year Chronic Disease Prevention Strategy (CDPS). Through CDPS, the Los Angeles County Department of Public Health implemented a range of environmental, lifestyle change, and health system interventions intended to collectively reduce chronic disease among adults in Los Angeles, with concentrated implementation occurring in 1 high-need neighborhood. This case study examined the activities undertaken to coordinate across CDPS interventions and documented challenges to these efforts. Data were collected via a document review of programmatic materials and structured conversations with staff leading implementation of CDPS interventions. Document review and structured conversations with staff identified 3 primary coordination activities: (1) collaborating on outreach materials to unify messaging, (2) developing a network of common partners, and (3) investing in shared data collection. Operational challenges identified were disparate short-term objectives across interventions, minimal alignment between clinical practice and CDPS goals, restrictions around bidirectional referrals between organizations, and limited bandwidth among new partners to engage with multiple CDPS interventions. Contextual challenges identified were competing social and political issues, and geographic fluidity regarding where community members sought health resources. Developing an initiative-specific coordination plan prior to implementation may help reduce challenges to coordination. Modifications in how health initiatives are funded and structured may be needed: greater flexibility in how funding is administered, and the inclusion of coordination-specific metrics, may enable more robust coordination.

Chemotyping of terrestrial Nostoc-like isolates from alkali grassland areas by non-targeted peptide analysis

The Nostoc genus is a well-known heterocytous, filamentous cyanobacterium which can be found all over the world. The size of terrestrial and/or freshwater colonies can be microscopic and macroscopic as well. In addition, Nostoc species are one of the most common photosynthetic cyanobacterial partners in symbiotic interactions. Terrestrial cyanobacterial colonies were collected and isolated in this study from various alkali grassland habitats (Great Hungarian Plain). Altogether 133 colonies were isolated from the 65 collected samples. The peptide patterns of the Nostoc-like strains were examined using HPLC-ESI-MS/MS and 41 peptides were identified from 45 isolated Nostoc-like strains; these compounds belonged to 4 different peptide classes. Twelve nostoginin/microginin, 16 anabaenopeptin, 12 banyaside/suomilide variants were identified. 37% of our isolated Nostoc-like strains produced some of the peptide metabolites we tested. These strains showed distinct chemotypes according to their peptide patterns, and can be divided into 4 groups based on their metabolisms. Strains either contained: (1) nostoginins/microginins, (2) anabaenopeptins, (3) anabaenopeptins and banyasides or (4) banyasides as major compounds. Banyasides were present in many of our strains and showed very high intensity in some cases. A number of previously unknown banyaside variants have been identified.

Common Individual Auditors and Analyst Forecast Performance

We examine the importance of analysts covering firms with common audit partners to analyst earnings forecast performance (hereafter, we term the analyst, auditor, and the firm as being “common”). We find that analysts issue more accurate and less optimistically biased earnings forecasts for firms with common audit partners than other analysts following the same firm without common audit partners. Consistent with expectations, we identify auditors’ style in making audit judgments as the channel through which analysts accumulate better information from covering firms with common audit partners. In a series of cross-sectional analyses, we find that this result is stronger when: (1) analysts suffer from poor direct access to firm-specific information from managers; (2) the information value from common auditors is higher, evident in their clients having more opaque operations, more difficult-to-forecast earnings, and greater stock price synchronicity; and (3) the quality of information that analysts elicit from auditors is higher, evident in auditors belonging to a large audit firm. Our results are robust to different approaches for addressing the potential endogeneity of analysts’ coverage decisions.

Telehealth: An Opportunity for State and Territorial Health Agencies to Improve Access to Needed Health Services.

Telehealth: An Opportunity for State and Territorial Health Agencies to Improve Access to Needed Health Services.

Substrate specificity of thioredoxins and glutaredoxins – towards a functional classification

The spatio-temporal reduction and oxidation of protein thiols is an essential mechanism in signal transduction in all kingdoms of life. Thioredoxin (Trx) family proteins efficiently catalyze thiol-disulfide exchange reactions and the proteins are widely recognized for their importance in the operation of thiol switches. Trx family proteins have a broad and at the same time very distinct substrate specificity – a prerequisite for redox switching. Despite of multiple efforts, the true nature for this specificity is still under debate. Here, we comprehensively compare the classification/clustering of various redoxins from all domains of life based on their similarity in amino acid sequence, tertiary structure, and their electrostatic properties. We correlate these similarities to the existence of common interaction partners, identified in various previous studies and suggested by proteomic screenings. These analyses confirm that primary and tertiary structure similarity, and thereby all common classification systems, do not correlate to the target specificity of the proteins as thiol-disulfide oxidoreductases. Instead, a number of examples clearly demonstrate the importance of electrostatic similarity for their target specificity, independent of their belonging to the Trx or glutaredoxin subfamilies.

Uniones de hecho: estudio de derecho comparado entre España y Paraguay

Este trabajo se propone comparar el régimen jurídico de las parejas de hecho en Paraguay y España. En Paraguay las uniones concubinarias están contempladas en el artículo 52 de la Constitución de 1992 y en la Ley de Reforma Parcial del Código Civil, también de 1992. Contrariamente, España carece de una ley aplicable a nivel nacional, y son las leyes autonómicas las que han regulado las uniones estables con un contenido muy distinto. Ello ha generado una clara situación de desigualdad entre los derechos y obligaciones atribuidos a los miembros de una pareja estable en función de la ley autonómica que les resulte aplicable. Para poner fin a esta ruptura del principio de igualdad se podrían arbitrar soluciones de distinta naturaleza: propiciar una armonización de la legislación autonómica, continuar realizando modificaciones puntuales de nuestro ordenamiento jurídico que dote de determinados efectos jurídicos a la convivencia y, finalmente, aprobar una ley general aplicable a todo el territorio nacional.

Integrated transcriptomic and epigenetic data analysis identifiesaberrant expression of genes in acute myeloid leukemia with MLL‑AF9 translocation.

Rearrangement of the mixed lineage leukemia (MLL; also known as lysine methyltransferase 2A) gene is a recurrent genomic aberration in acute myeloid leukemia (AML). MLLT3, super elongation complex subunit (AF9) is one of the most common MLL fusion partners in AML. The present study aimed to explore the aberrant expression of genes associated with the MLL-AF9 translocation and identified potential new targets for the therapy of AML with MLL-AF9 translocation. The transcriptomic and epigenetic datasets were downloaded from National Center of Biotechnology Information Gene Expression Omnibus (GEO) database. Differentially expressed genes were obtained from two independent datasets (GSE68643 and GSE73457). Gene Ontology biological process and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was performed using the Database for Annotation, Visualization and Integrated Discovery. MLL-AF9-associated chromatin immunoprecipitation sequencing (ChIP-Seq) data was analyzed and identified binding sites for MLL-AF9 and wild type MLL (MLL WT). The ChIP-Seq of histone modification data was downloaded from the GEO database, including histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 79 dimethylation (H3K79me2) and histone 3 lysine 27 acetylation (H3K27ac), was used for comparing histone modification marks between the MLL-AF9 leukemia cells and normal hematopoietic cells at MLL-AF9 and MLL WT binding sites. The differentially expressed genes with the same trend in H3K79me2, H3K27ac and H3K4me3 alteration were identified as potential MLL-AF9 direct target genes. Upon validation using RNA-Seq data from the Therapeutically Applicable Research to Generate Effective Treatments AML project, eight potential direct target genes of MLL-AF9 were identified and further confirmed in MLL-AF9 mouse model using reverse transcription-quantitative polymerase chain reaction. These genes may have a critical role in AML with MLL-AF9 translocation.