Association of cfDNA androgen receptor amplifications with BRAF alterations in mCRPC.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 234-234
Author(s):  
Elisa M. Ledet ◽  
Joshua Schiff ◽  
Patrick Cotogno ◽  
Charlotte Manogue ◽  
Emma M. Ernst ◽  
...  
Keyword(s):  
Point Mutations ◽  
Response To Therapy ◽  
Cancer Center ◽  
Therapeutic Implications ◽  
Heterogenous Group ◽  
Somatic Alterations ◽  
The Common ◽  
The Relationship ◽  
Larger Sample ◽  
Redwood City

234 Background: Cell free DNA (cfDNA) present in plasma of cancer pts can reflect tumoral alterations. Genomic alterations in cfDNA alter prognosis and abiraterone/enzalutamide resistance in mCRPC. The goal of this evaluation was to characterize AR amplifications (Amps) and various somatic point mutations (Muts) detected in mCRPC cfDNA and to relate those changes to other common alterations in the cfDNA landscape. Methods: A heterogenous group of 46 mCRPC patients (pts) with evidence of clinical progression from Tulane Cancer Center underwent cfDNA analysis using Guardant360 test (Guardant Health, Redwood City, CA). This evaluation included full exonic coverage of 70 genes and amplifications in 18 genes. Mutations reported herein include both known pathogenic mutations as well as mutations uncharacterized for functional importance. Results: 69.5% (n = 32) of the mCRPC pts evaluated had an AR alteration. Of the pts with AR alterations, 46.8% (n = 16) had AR Amps, 43.7% (n = 14) had AR Muts, and only 6.25% (n = 2) had both. In this cohort, AR alterations were the most commonly observed aberration. In addition to amplifications, 12 different AR Muts were detected. AR Muts included: T878A (n = 9), H875Y (n = 5), W742C (n = 4), AR L702H (n = 3), and others. To better understand the relationship between AR alteration and other commonly detected cfDNA aberrations, association between BRAF (35.5%), TP53 (46.7%), and MYC (22.2%) alterations and AR were assessed. Among these genes, TP53 alterations were all Muts and MYC alterations were all Amps. BRAF alterations were predominantly Amps (N = 15) though Muts were also detected (N = 6). Neither TP53 Muts or MYC Amps were significantly associated with AR alterations. On the other hand, BRAF alterations were significantly associated with AR Amps (p = 0.041); 60% (9/15) pts with AR Amps also had BRAF alteration (Odds ratio = 7.71, 95% CI 1.284- 46.366). Conclusions: AR alterations in cfDNA impact both disease progression and response to therapy. Co-segregation of AR and BRAF alterations may have significant prognostic and therapeutic implications. Further research and larger sample size is needed to further elucidate associations between the common somatic alterations detected in mCRPC.

Comprehensive analysis of AR alterations in cell free DNA from prostate cancer patients.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 314-314
Author(s):  
Elisa Ledet ◽  
Michael B. Lilly ◽  
Guru Sonpavde ◽  
Neeraj Agarwal ◽  
Rebecca J Nagy ◽  
...  
Keyword(s):  
Point Mutations ◽  
Treatment Strategies ◽  
Comprehensive Analysis ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Somatic Alterations ◽  
The Common ◽  
Generation Sequencing ◽  
Redwood City ◽  
Gene Alterations

314 Background: Somatic alterations identified in cfDNA may be associated with prognosis. Select AR alterations are associated with abiraterone/enzalutamide resistance in PCa. The goal was to characterize AR amplifications (amps) and somatic point mutations (muts) detected in cfDNA from PCa patients and to relate those changes to non-AR alterations detected in the cfDNA landscape. Methods: cfDNA data was obtained from a heterogeneous group of unique PCa pts who underwent Guardant360 testing (Guardant Health, Redwood City, CA). This assay includes next generation sequencing for full exonic coverage of 73 genes and amplifications in 18 genes. The AR amps/muts detected in cfDNA testing were reported. Results: Over 6,800 genomic alterations including AR amps/muts were identified in 892 PCa patients. Pts were a median age of 70 (range = 41-93) at testing. 49% (n = 436) had AR amp only, 32% (n = 283) had nonsynonymous (NS)-muts only, 18% (n = 165) had both amp and NS-muts; < 1% (n = 8) had synonymous AR muts only. AR amps had a mean absolute copy number of 3.3 (range = 1.2-165.2). Many patients had multiple AR muts; a total of 112 unique muts were identified in the AR gene, some of which are poorly characterized. The most prevalent AR muts were L702H (n = 220), T878A (n = 129), H875Y (n = 102), W742C (n = 75), W742L (n = 34), F877L (n = 19), and T878S (n = 14). The AR muts with the highest mutant allele fraction were H875Y, T878A, and L702H. Aside from AR, among these selected pts, amps/muts were identified in 74 other genes including TP53 50% (n = 449), MYC 34% (n = 301), BRAF 32% (n = 287), PIK3CA 29% (n = 259), MET 25% (n = 224), CDK6 26% (n = 229), EGFR 24% (n = 219), FGFR1 21% (n = 189), and APC 12% (n = 112). DNA repair gene alterations were detected in combination with AR alterations, BRCA2 8% (n = 69), BRCA1 5% (n = 42), and ATM 3% (n = 28). Conclusions: To our knowledge, this is the largest dataset ever reporting AR alterations in cfDNA. Both amps and muts, were frequently found in cfDNA from PCa pts. The common AR muts were L702H, T878A, H875Y and W742C/L, which are linked to resistance to abiraterone, enzalutamide or bicalutamide. Determining the association with other somatic cfDNA alterations and clinical outcomes may be critical for conceiving optimal treatment strategies.

Cosegregation of cfDNA AR amplifications and mutations in relation to BRAF and MYC in CRPC.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 261-261
Author(s):  
Bryce Raymon Christensen ◽  
Elisa Ledet ◽  
Marcus Marie Moses ◽  
Lynne Chapman ◽  
Peter Steinwald ◽  
...  
Keyword(s):  
Disease Progression ◽  
Demographic Data ◽  
Response To Therapy ◽  
Longitudinal Assessment ◽  
Therapeutic Implications ◽  
Somatic Alterations ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
The Relationship

261 Background: cfDNA can be utilized to evaluate androgen receptor (AR) alterations in metastatic castrate resistant prostate cancer (mCRPC) patients. Given the role of androgen receptors in the pathophysiology of PC, mutations in the AR gene can have important implications regarding prognosis and treatment. The goal of this research was to evaluate associations between certain PC treatments and AR mutations. Methods: Treatment and demographic data from 121 patients diagnosed with PC was collected including genetic data derived from the Guardant360 test (Guardant Health, Redwood City, CA). AR alterations were compared among race, treatment history, and other somatic alterations. Results: 52.9% (n = 64) of the mCRPC pts evaluated had an AR alteration. Of the pts with AR alterations, 43.8% (n = 28) had AR amplification (amps), 37.5% (n = 24) had AR mutations (muts), and 18.8% (n = 12) had both. AR muts included: T878A (n = 15), H875Y (n = 8), W742C (n = 11), AR L702H (n = 7), and others. AR alterations comprised on average about 7% of tumoral cfDNA. To better understand the relationship between AR alterations and other commonly detected cfDNA aberrations, associations between BRAF (27.3%), TP53 (44.6%), and MYC (19.0%) and AR were assessed. Among these genes, P53 alterations were all Muts. MYC (n = 21) and BRAF (n = 27) alterations were predominantly amps though muts were also detected in MYC (n = 3) and BRAF (n = 9). P53 muts were not significantly associated with AR alterations. BRAF and MYC alterations significantly associated with AR alterations (p = 0.0012 and p = 0.0223). Pts were re-tested upon disease progression; among these patients, 52.2% (n = 24) had an increase in overall mut burden. Conclusions: AR alterations in cfDNA impact both disease progression and response to therapy. Co-segregation of AR, BRAF, and MYC alterations may also have significant prognostic and therapeutic implications. Further research, a larger sample size, and longitudinal assessment are needed to further elucidate associations between disease progression and treatment response to the development of somatic alterations over time in mCRPC.

Elements of Pathological Love Relationships

1983 ◽  
Vol 53 (1) ◽  
pp. 83-92 ◽  
Author(s):  
John M. Curtis
Keyword(s):  
Present Discussion ◽  
Therapeutic Implications ◽  
Love Relationships ◽  
The Common ◽  
The Stability ◽  
The Relationship ◽  
Qualitative Changes

The present discussion specifies a number of elements which seem to be involved in functional and pathological relationships. Since the stability of such relationships may be attributable to the manner in which “love” is transacted and interchanged, it seems advisable for the clinician to utilize a more precise set of criteria against which both adaptive and maladaptive relationships may be appraised and therapeutically managed. In this context, the judicious expression of the following elements of adaptive love relationships were identified: (a) needing, (b) giving, (c) romance, and (d) companionship. Similarly, the common determinants of maladaptive love relationships, i.e., (a) power, (b) possession, (c) protection, (d) pity, and (e) perversion, were also labeled and discussed together with therapeutic implications. With these specific elements the therapist may be more able to assess counter-productive patterns and promote the conditions under which qualitative changes in the relationship might be accomplished with improved speed and consistency.

Copper transporter CTR1 expression and tissue platinum concentration in NSCLC.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2601-2601
Author(s):  
Deepak Kilari ◽  
XiMing Tang ◽  
Chi-Wan Chow ◽  
Junya Fujimoto ◽  
Neda Kalhor ◽  
...  
Keyword(s):  
Tumor Response ◽  
Causative Factor ◽  
Cancer Center ◽  
Nsclc Tissue ◽  
Copper Transporter ◽  
Md Anderson ◽  
Nsclc Patients ◽  
The Relationship ◽  
Larger Sample ◽  
Expression Score

2601 Background: Platinum (Pt) resistance is a major limitation in the treatment of advanced non-small cell lung cancer (NSCLC). We previously demonstrated that low tissue Pt concentration in NSCLC tumor specimens was significantly associated with reduced tumor response and worse survival. Furthermore, low expression of the copper transporter CTR1, a transporter of Pt uptake is reported to be associated with poor clinical outcome following Pt-based therapy in NSCLC patients. However, a defect in CTR1expression as a causative factor in reduced Pt accumulation in NSCLC tissues is not well-established. We investigated the relationship between tissue Pt concentrations and CTR1 expression in NSCLC specimens. Methods: We identified paraffin-embedded NSCLC tissue blocks from 30 patients who underwent neoadjuvant Pt-based chemotherapy with known tissue Pt concentrations at MD Anderson Cancer Center. Expression of CTR1 was determined by immunohistochemistry with adequate controls; 0 = undetectable; 1+ = barely detectable staining; 2+ = readily appreciable staining; and 3+ = dark brown staining. Pt concentration was compared between different CTR1 expression groups. Results: Tissue Pt concentration significantly correlated with tumor response in 30 patients who received neoadjuvant Pt-based chemotherapy (P<0.001). There was an uneven distribution of CTR1 expression scores with a majority of specimens demonstrating scores of 2+ (N=15, 50%). There were 2 specimens with no detectable CTR1 expression (score of 0) and 6 patients with a score of 3+. Patients with undetectable CTR1 expression in their tumors had significantly lower Pt concentrations compared to those with scores of 3+ (P=0.014). Furthermore, those with undetectable CTR1 expression had reduced tumor response compared to those with scores of 3+ following Pt-based chemotherapy (P=0.039). Conclusions: To the best of our knowledge, this is the first study to correlate CTR1 expression in clinical specimens to both tumor Pt uptake and response. Patients with undetectable CTR1 expression in their tumors had significantly lower Pt concentration and reduced tumor response. Further evaluation with a larger sample size is required. (Supported by 2012 ASCO Young Investigator Award)

PERSOALAN KEHIDUPAN KONTEMPORER: MENGGAGAS KAJIAN SACHEDINA TENTANG THEOLOGI PLURALISME

EMPIRISMA ◽  
2017 ◽  
Vol 26 (1) ◽  
Author(s):  
Limas Dodi
Keyword(s):  
Religious Pluralism ◽  
Main Argument ◽  
Religious Groups ◽  
Common View ◽  
The Public ◽  
The People ◽  
Muslim Majority ◽  
The Common ◽  
The Relationship ◽  
Religious Differences

According to Abdulaziz Sachedina, the main argument of religious pluralism in the Qur’an based on the relationship between private belief (personal) and public projection of Islam in society. By regarding to private faith, the Qur’an being noninterventionist (for example, all forms of human authority should not be disturb the inner beliefs of individuals). While the public projection of faith, the Qur’an attitude based on the principle of coexistence. There is the willingness of the dominant race provide the freedom for people of other faiths with their own rules. Rules could shape how to run their affairs and to live side by side with the Muslims. Thus, based on the principle that the people of Indonesia are Muslim majority, it should be a mirror of a societie’s recognizion, respects and execution of religious pluralism. Abdul Aziz Sachedina called for Muslims to rediscover the moral concerns of public Islam in peace. The call for peace seemed to indicate that the existence of increasingly weakened in the religious sense of the Muslims and hence need to be reaffi rmed. Sachedina also like to emphasize that the position of peace in Islam is parallel with a variety of other doctrines, such as: prayer, fasting, pilgrimage and so on. Sachedina also tried to show the argument that the common view among religious groups is only one religion and traditions of other false and worthless. “Antipluralist” argument comes amid the reality of human religious differences. Keywords: Theology, Pluralism, Abdulaziz Sachedina

Migraine: Genetic Variants and Clinical Phenotypes

2019 ◽  
Vol 26 (34) ◽  
pp. 6207-6221 ◽  
Author(s):  
Innocenzo Rainero ◽  
Alessandro Vacca ◽  
Flora Govone ◽  
Annalisa Gai ◽  
Lorenzo Pinessi ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Association Studies ◽  
Mthfr Gene ◽  
Genome Wide Association Studies ◽  
Clinical Phenotypes ◽  
Network Analyses ◽  
Genome Wide ◽  
Genomic Studies ◽  
The Common ◽  
The Relationship

Migraine is a common, chronic neurovascular disorder caused by a complex interaction between genetic and environmental risk factors. In the last two decades, molecular genetics of migraine have been intensively investigated. In a few cases, migraine is transmitted as a monogenic disorder, and the disease phenotype cosegregates with mutations in different genes like CACNA1A, ATP1A2, SCN1A, KCNK18, and NOTCH3. In the common forms of migraine, candidate genes as well as genome-wide association studies have shown that a large number of genetic variants may increase the risk of developing migraine. At present, few studies investigated the genotype-phenotype correlation in patients with migraine. The purpose of this review was to discuss recent studies investigating the relationship between different genetic variants and the clinical characteristics of migraine. Analysis of genotype-phenotype correlations in migraineurs is complicated by several confounding factors and, to date, only polymorphisms of the MTHFR gene have been shown to have an effect on migraine phenotype. Additional genomic studies and network analyses are needed to clarify the complex pathways underlying migraine and its clinical phenotypes.

The Trade Mark, Other Product Designations, and Goodwill

2017 ◽  
Author(s):  
Justine Pila
Keyword(s):  
Subject Matter ◽  
Common Law ◽  
Trade Mark ◽  
Geographical Indication ◽  
Passing Off ◽  
Rights Protection ◽  
Essential Properties ◽  
The Subject ◽  
The Common ◽  
The Relationship

This chapter considers the meaning of the terms that appropriately denote the subject matter protectable by registered trade mark and allied rights, including the common law action of passing off. Drawing on the earlier analyses of the objects protectable by patent and copyright, it defines the trade mark, designation of origin, and geographical indication in their current European and UK conception as hybrid inventions/works in the form of purpose-limited expressive objects. It also considers the relationship between the different requirements for trade mark and allied rights protection, and related principles of entitlement. In its conclusion, the legal understandings of trade mark and allied rights subject matter are presented as answers to the questions identified in Chapter 3 concerning the categories and essential properties of the subject matter in question, their method of individuation, and the relationship between and method of establishing their and their tokens’ existence.

A comparison of the changes in the patterns of the usage and categorization of the classifier ‘ben 本’ in Korean, Chinese, and Japanese

2021 ◽  
Vol 5 (1) ◽  
pp. 43-51
Author(s):  
Jeong-A Jo
Keyword(s):  
Cultural Differences ◽  
Chinese Character ◽  
Chinese Characters ◽  
Common Features ◽  
The World ◽  
The Common ◽  
Korean Chinese ◽  
The Relationship

This study aims to examine the common features and differences in how the Chinese-character classifier ‘ ben 本’ is used in Chinese, Korean, and Japanese, and will explore the factors that have affected the categorization processes and patterns of the classifier ‘ ben 本.’ Consideration of the differences in the patterns of usage and categorization of the same Chinese classifier in different languages enables us to look into the perception of the world and the socio cultural differences inherent in each language, the differences in the perception of Chinese characters, and the relationship between classifiers.

Pensare Dio. Spunti di riflessione in dialogo con Anca Vasiliu

Elenchos ◽  
2020 ◽  
Vol 41 (1) ◽  
pp. 181-194
Author(s):  
Angela Longo
Keyword(s):  
Late Antiquity ◽  
Human Being ◽  
Common Thread ◽  
Critical Issues ◽  
Relevant Topic ◽  
The Common ◽  
The One ◽  
Relationship Of ◽  
The Relationship ◽  
The Trinity

AbstractThe following work features elements to ponder and an in-depth explanation taken on the Anca Vasiliu’s study about the possibilities and ways of thinking of God by a rational entity, such as the human being. This is an ever relevant topic that, however, takes place in relation to Platonic authors and texts, especially in Late Antiquity. The common thread is that the human being is a God’s creature who resembles him and who is image of. Nevertheless, this also applies within the Christian Trinity according to which, not without problems, the Son is the image of the Father. Lastly, also the relationship of the Spirit with the Father and the Son, always within the Trinity, can be considered as a relationship of similarity, but again not without critical issues between the similarity of attributes, on the one hand, and the identity of nature, on the other.

scholarly journals Evangelical and Catholic Timespace in Work: An Argument against a Homeless Eschatology

Religions ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 199
Author(s):  
Maria Ledstam
Keyword(s):  
Empirical Study ◽  
Common Good ◽  
Ethnographic Study ◽  
The Other ◽  
Faith Based ◽  
Business As Mission ◽  
Achievable Goal ◽  
The Common ◽  
The One ◽  
The Relationship

This article engages with how religion and economy relate to each other in faith-based businesses. It also elaborates on a recurrent idea in theological literature that reflections on different visions of time can advance theological analyses of the relationship between Christianity and capitalism. More specifically, this article brings results from an ethnographic study of two faith-based businesses into conversation with the ethicist Luke Bretherton’s presentation of different understandings of the relationship between Christianity and capitalism. Using Theodore Schatzki’s theory of timespace, the article examines how time and space are constituted in two small faith-based businesses that are part of the two networks Business as Mission (evangelical) and Economy of Communion (catholic) and how the different timespaces affect the religious-economic configurations in the two cases and with what moral implications. The overall findings suggest that the timespace in the Catholic business was characterized by struggling caused by a tension between certain ideals on how religion and economy should relate to each other on the one hand and how the practice evolved on the other hand. Furthermore, the timespace in the evangelical business was characterized by confidence, caused by the business having a rather distinct and achievable goal when it came to how they wanted to be different and how religion should relate to economy. There are, however, nuances and important resemblances between the cases that cannot be explained by the businesses’ confessional and theological affiliations. Rather, there seems to be something about the phenomenon of tension-filled and confident faith-based businesses that causes a drive in the practices towards the common good. After mapping the results of the empirical study, I discuss some contributions that I argue this study brings to Bretherton’s presentation of the relationship between Christianity and capitalism.

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