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Article ; Online: Differentiating Urgent from Elective Cases Matters in Minority Populations: Developing an Ordinal "Desirability of Outcome Ranking" to Increase Granularity and Sensitivity of Surgical Outcomes Assessment.

Jacobs, Michael A / Schmidt, Susanne / Hall, Daniel E / Stitzenberg, Karyn B / Kao, Lillian S / Wang, Chen-Pin / Manuel, Laura S / Shireman, Paula K

Journal of the American College of Surgeons

2023 Volume 237, Issue 3, Page(s) 545–555

Abstract: Background: Surgical analyses often focus on single or binary outcomes; we developed an ordinal Desirability of Outcome Ranking (DOOR) for surgery to increase granularity and sensitivity of surgical outcome assessments. Many studies also combine ... ...

Abstract	Background: Surgical analyses often focus on single or binary outcomes; we developed an ordinal Desirability of Outcome Ranking (DOOR) for surgery to increase granularity and sensitivity of surgical outcome assessments. Many studies also combine elective and urgent procedures for risk adjustment. We used DOOR to examine complex associations of race/ethnicity and presentation acuity. Study design: NSQIP (2013 to 2019) cohort study assessing DOOR outcomes across race/ethnicity groups risk-adjusted for frailty, operative stress, preoperative acute serious conditions, and elective, urgent, and emergent cases. Results: The cohort included 1,597,199 elective, 340,350 urgent, and 185,073 emergent cases with patient mean age of 60.0 ± 15.8, and 56.4% of the surgeries were performed on female patients. Minority race/ethnicity groups had increased odds of presenting with preoperative acute serious conditions (adjusted odds ratio [aORs] range 1.22 to 1.74), urgent (aOR range 1.04 to 2.21), and emergent (aOR range 1.15 to 2.18) surgeries vs the White group. Black (aOR range 1.23 to 1.34) and Native (aOR range 1.07 to 1.17) groups had increased odds of higher/worse DOOR outcomes; however, the Hispanic group had increased odds of higher/worse DOOR (aOR 1.11, CI 1.10 to 1.13), but decreased odds (aORs range 0.94 to 0.96) after adjusting for case status; the Asian group had better outcomes vs the White group. DOOR outcomes improved in minority groups when using elective vs elective/urgent cases as the reference group. Conclusions: NSQIP surgical DOOR is a new method to assess outcomes and reveals a complex interplay between race/ethnicity and presentation acuity. Combining elective and urgent cases in risk adjustment may penalize hospitals serving a higher proportion of minority populations. DOOR can be used to improve detection of health disparities and serves as a roadmap for the development of other ordinal surgical outcomes measures. Improving surgical outcomes should focus on decreasing preoperative acute serious conditions and urgent and emergent surgeries, possibly by improving access to care, especially for minority populations.
MeSH term(s)	Humans ; Female ; Minority Groups ; Cohort Studies ; Ethnicity ; Outcome Assessment, Health Care ; Postoperative Complications/epidemiology ; Retrospective Studies
Language	English
Publishing date	2023-06-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1181115-8
ISSN	1879-1190 ; 1072-7515
ISSN (online)	1879-1190
ISSN	1072-7515
DOI	10.1097/XCS.0000000000000776
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Article ; Online: Presentation Acuity and Surgical Outcomes for Patients With Health Insurance Living in Highly Deprived Neighborhoods.

Schmidt, Susanne / Jacobs, Michael A / Kim, Jeongsoo / Hall, Daniel E / Stitzenberg, Karyn B / Kao, Lillian S / Brimhall, Bradley B / Wang, Chen-Pin / Manuel, Laura S / Su, Hoah-Der / Silverstein, Jonathan C / Shireman, Paula K

JAMA surgery

2024 Volume 159, Issue 4, Page(s) 411–419

Abstract: Importance: Insurance coverage expansion has been proposed as a solution to improving health disparities, but insurance expansion alone may be insufficient to alleviate care access barriers.: Objective: To assess the association of Area Deprivation ... ...

Abstract	Importance: Insurance coverage expansion has been proposed as a solution to improving health disparities, but insurance expansion alone may be insufficient to alleviate care access barriers. Objective: To assess the association of Area Deprivation Index (ADI) with postsurgical textbook outcomes (TO) and presentation acuity for individuals with private insurance or Medicare. Design, setting, and participants: This cohort study used data from the National Surgical Quality Improvement Program (2013-2019) merged with electronic health record data from 3 academic health care systems. Data were analyzed from June 2022 to August 2023. Exposure: Living in a neighborhood with an ADI greater than 85. Main outcomes and measures: TO, defined as absence of unplanned reoperations, Clavien-Dindo grade 4 complications, mortality, emergency department visits/observation stays, and readmissions, and presentation acuity, defined as having preoperative acute serious conditions (PASC) and urgent or emergent cases. Results: Among a cohort of 29 924 patients, the mean (SD) age was 60.6 (15.6) years; 16 424 (54.9%) were female, and 13 500 (45.1) were male. A total of 14 306 patients had private insurance and 15 618 had Medicare. Patients in highly deprived neighborhoods (5536 patients [18.5%]), with an ADI greater than 85, had lower/worse odds of TO in both the private insurance group (adjusted odds ratio [aOR], 0.87; 95% CI, 0.76-0.99; P = .04) and Medicare group (aOR, 0.90; 95% CI, 0.82-1.00; P = .04) and higher odds of PASC and urgent or emergent cases. The association of ADIs greater than 85 with TO lost significance after adjusting for PASC and urgent/emergent cases. Differences in the probability of TO between the lowest-risk (ADI ≤85, no PASC, and elective surgery) and highest-risk (ADI >85, PASC, and urgent/emergent surgery) scenarios stratified by frailty were highest for very frail patients (Risk Analysis Index ≥40) with differences of 40.2% and 43.1% for those with private insurance and Medicare, respectively. Conclusions and relevance: This study found that patients living in highly deprived neighborhoods had lower/worse odds of TO and higher presentation acuity despite having private insurance or Medicare. These findings suggest that insurance coverage expansion alone is insufficient to overcome health care disparities, possibly due to persistent barriers to preventive care and other complex causes of health inequities.
MeSH term(s)	Humans ; Male ; Female ; Aged ; United States ; Middle Aged ; Medicare ; Cohort Studies ; Insurance, Health ; Residence Characteristics ; Acute Disease ; Treatment Outcome ; Retrospective Studies
Language	English
Publishing date	2024-02-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2701841-6
ISSN	2168-6262 ; 2168-6254
ISSN (online)	2168-6262
ISSN	2168-6254
DOI	10.1001/jamasurg.2023.7468
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Article ; Online: Rational optimization of siRNA to ensure strand bias in the interaction with the RNA-induced silencing complex.

Datta, Dhrubajyoti / Theile, Christopher S / Wassarman, Kelly / Qin, June / Racie, Tim / Schmidt, Karyn / Jiang, Yongfeng / Sigel, Rachel / Janas, Maja M / Egli, Martin / Manoharan, Muthiah

Chemical communications (Cambridge, England)

2023 Volume 59, Issue 42, Page(s) 6347–6350

Abstract: To ensure specificity of small interfering RNAs (siRNAs), the antisense strand must be selected by the RNA-induced silencing complex (RISC). We have previously demonstrated that a 5'-morpholino-modified nucleotide at the 5'-end of the sense strand ... ...

Abstract	To ensure specificity of small interfering RNAs (siRNAs), the antisense strand must be selected by the RNA-induced silencing complex (RISC). We have previously demonstrated that a 5'-morpholino-modified nucleotide at the 5'-end of the sense strand inhibits its interaction with RISC ensuring selection of the desired antisense strand. To improve this antagonizing binding property even further, a new set of morpholino-based analogues, Mo2 and Mo3, and a piperidine analogue, Pip, were designed based on the known structure of Argonaute2, the slicer enzyme component of RISC. Sense strands of siRNAs were modified with these new analogues, and the siRNAs were evaluated
MeSH term(s)	Animals ; Mice ; RNA, Small Interfering/chemistry ; RNA-Induced Silencing Complex/genetics ; RNA-Induced Silencing Complex/metabolism ; Morpholinos/chemistry
Chemical Substances	RNA, Small Interfering ; RNA-Induced Silencing Complex ; Morpholinos
Language	English
Publishing date	2023-05-23
Publishing country	England
Document type	Journal Article
ZDB-ID	1472881-3
ISSN	1364-548X ; 1359-7345 ; 0009-241X
ISSN (online)	1364-548X
ISSN	1359-7345 ; 0009-241X
DOI	10.1039/d3cc01143g
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Article ; Online: A qualitative evaluation of factors influencing Tumor Treating fields (TTFields) therapy decision making among brain tumor patients and physicians.

Kumthekar, Priya / Lyleroehr, Madison / Lacson, Leilani / Lukas, Rimas V / Dixit, Karan / Stupp, Roger / Kruser, Timothy / Raizer, Jeff / Hou, Alexander / Sachdev, Sean / Schwartz, Margaret / Pa, Jessica Bajas / Lezon, Ray / Schmidt, Karyn / Amidei, Christina / Kaiser, Karen

BMC cancer

2024 Volume 24, Issue 1, Page(s) 527

Abstract: Background: Tumor Treating Fields (TTFields) Therapy is an FDA-approved therapy in the first line and recurrent setting for glioblastoma. Despite Phase 3 evidence showing improved survival with TTFields, it is not uniformly utilized. We aimed to examine ...

Abstract	Background: Tumor Treating Fields (TTFields) Therapy is an FDA-approved therapy in the first line and recurrent setting for glioblastoma. Despite Phase 3 evidence showing improved survival with TTFields, it is not uniformly utilized. We aimed to examine patient and clinician views of TTFields and factors shaping utilization of TTFields through a unique research partnership with medical neuro oncology and medical social sciences. Methods: Adult glioblastoma patients who were offered TTFields at a tertiary care academic hospital were invited to participate in a semi-structured interview about their decision to use or not use TTFields. Clinicians who prescribe TTFields were invited to participate in a semi-structured interview about TTFields. Results: Interviews were completed with 40 patients with a mean age of 53 years; 92.5% were white and 60% were male. Participants who decided against TTFields stated that head shaving, appearing sick, and inconvenience of wearing/carrying the device most influenced their decision. The most influential factors for use of TTFields were the efficacy of the device and their clinician's opinion. Clinicians (N = 9) stated that TTFields was a good option for glioblastoma patients, but some noted that their patients should consider the burdens and benefits of TTFields as it may not be the desired choice for all patients. Conclusions: This is the first study to examine patient decision making for TTFields. Findings suggest that clinician support and efficacy data are among the key decision-making factors. Properly understanding the path to patients' decision making is crucial in optimizing the use of TTFields and other therapeutic decisions for glioblastoma patients.
MeSH term(s)	Humans ; Male ; Middle Aged ; Brain Neoplasms/therapy ; Female ; Glioblastoma/therapy ; Adult ; Decision Making ; Aged ; Electric Stimulation Therapy/methods ; Qualitative Research ; Physicians/psychology ; Clinical Decision-Making
Language	English
Publishing date	2024-04-25
Publishing country	England
Document type	Journal Article
ZDB-ID	2041352-X
ISSN	1471-2407 ; 1471-2407
ISSN (online)	1471-2407
ISSN	1471-2407
DOI	10.1186/s12885-024-12042-x
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Article ; Online: A Surgical Desirability of Outcome Ranking (DOOR) Reveals Complex Relationships Between Race/Ethnicity, Insurance Type, and Neighborhood Deprivation.

Jacobs, Michael A / Schmidt, Susanne / Hall, Daniel E / Stitzenberg, Karyn B / Kao, Lillian S / Brimhall, Bradley B / Wang, Chen-Pin / Manuel, Laura S / Su, Hoah-Der / Silverstein, Jonathan C / Shireman, Paula K

Annals of surgery

2023 Volume 279, Issue 2, Page(s) 246–257

Abstract: Objective: Develop an ordinal Desirability of Outcome Ranking (DOOR) for surgical outcomes to examine complex associations of Social Determinants of Health.: Background: Studies focused on single or binary composite outcomes may not detect health ... ...

Abstract	Objective: Develop an ordinal Desirability of Outcome Ranking (DOOR) for surgical outcomes to examine complex associations of Social Determinants of Health. Background: Studies focused on single or binary composite outcomes may not detect health disparities. Methods: Three health care system cohort study using NSQIP (2013-2019) linked with EHR and risk-adjusted for frailty, preoperative acute serious conditions (PASC), case status and operative stress assessing associations of multilevel Social Determinants of Health of race/ethnicity, insurance type (Private 13,957; Medicare 15,198; Medicaid 2835; Uninsured 2963) and Area Deprivation Index (ADI) on DOOR and the binary Textbook Outcomes (TO). Results: Patients living in highly deprived neighborhoods (ADI>85) had higher odds of PASC [adjusted odds ratio (aOR)=1.13, CI=1.02-1.25, P <0.001] and urgent/emergent cases (aOR=1.23, CI=1.16-1.31, P <0.001). Increased odds of higher/less desirable DOOR scores were associated with patients identifying as Black versus White and on Medicare, Medicaid or Uninsured versus Private insurance. Patients with ADI>85 had lower odds of TO (aOR=0.91, CI=0.85-0.97, P =0.006) until adjusting for insurance. In contrast, patients with ADI>85 had increased odds of higher DOOR (aOR=1.07, CI=1.01-1.14, P <0.021) after adjusting for insurance but similar odds after adjusting for PASC and urgent/emergent cases. Conclusions: DOOR revealed complex interactions between race/ethnicity, insurance type and neighborhood deprivation. ADI>85 was associated with higher odds of worse DOOR outcomes while TO failed to capture the effect of ADI. Our results suggest that presentation acuity is a critical determinant of worse outcomes in patients in highly deprived neighborhoods and without insurance. Including risk adjustment for living in deprived neighborhoods and urgent/emergent surgeries could improve the accuracy of quality metrics.
MeSH term(s)	Aged ; Humans ; United States ; Ethnicity ; Medicare ; Cohort Studies ; Insurance Coverage ; Medicaid ; Retrospective Studies
Language	English
Publishing date	2023-07-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	340-2
ISSN	1528-1140 ; 0003-4932
ISSN (online)	1528-1140
ISSN	0003-4932
DOI	10.1097/SLA.0000000000005994
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Article ; Online: Independent Associations of Neighborhood Deprivation and Patient-level Social Determinants of Health with Textbook Outcomes after Inpatient Surgery.

Schmidt, Susanne / Kim, Jeongsoo / Jacobs, Michael A / Hall, Daniel E / Stitzenberg, Karyn B / Kao, Lillian S / Brimhall, Bradley B / Wang, Chen-Pin / Manuel, Laura S / Su, Hoah-Der / Silverstein, Jonathan C / Shireman, Paula K

Annals of surgery open : perspectives of surgical history, education, and clinical approaches

2023 Volume 4, Issue 1

Abstract: Objective: Assess associations of Social Determinants of Health (SDoH) using Area Deprivation Index (ADI), race/ethnicity and insurance type with Textbook Outcomes (TO).: Summary background data: Individual- and contextual-level SDoH affect health ... ...

Abstract	Objective: Assess associations of Social Determinants of Health (SDoH) using Area Deprivation Index (ADI), race/ethnicity and insurance type with Textbook Outcomes (TO). Summary background data: Individual- and contextual-level SDoH affect health outcomes, but only one SDoH level is usually included. Methods: Three healthcare system cohort study using National Surgical Quality Improvement Program (2013-2019) linked with ADI risk-adjusted for frailty, case status and operative stress examining TO/TO components (unplanned reoperations, complications, mortality, Emergency Department/Observation Stays and readmissions). Results: Cohort (34,251 cases) mean age 58.3 [SD=16.0], 54.8% females, 14.1% Hispanics, 11.6% Non-Hispanic Blacks, 21.6% with ADI>85, and 81.8% TO. Racial and ethnic minorities, non-Private insurance, and ADI>85 patients had increased odds of urgent/emergent surgeries (aORs range: 1.17-2.83, all P<.001). Non-Hispanic Black patients, ADI>85 and non-Private insurances had lower TO odds (aORs range: 0.55-0.93, all P<.04), but ADI>85 lost significance after including case status. Urgent/emergent versus elective had lower TO odds (aOR=0.51, P<.001). ADI>85 patients had higher complication and mortality odds. Estimated reduction in TO probability was 9.9% (CI=7.2%-12.6%) for urgent/emergent cases, 7.0% (CI=4.6%-9.3%) for Medicaid, and 1.6% (CI=0.2%-3.0%) for non-Hispanic Black patients. TO probability difference for lowest-risk (White-Private-ADI≤85-elective) to highest-risk (Black-Medicaid-ADI>85-urgent/emergent) was 29.8% for very frail patients. Conclusion: Multi-level SDoH had independent effects on TO, predominately affecting outcomes through increased rates/odds of urgent/emergent surgeries driving complications and worse outcomes. Lowest-risk versus highest-risk scenarios demonstrated the magnitude of intersecting SDoH variables. Combination of insurance type and ADI should be used to identify high-risk patients to redesign care pathways to improve outcomes. Risk adjustment including contextual neighborhood deprivation and patient-level SDoH could reduce unintended consequences of value-based programs.
Language	English
Publishing date	2023-02-21
Publishing country	United States
Document type	Journal Article
ISSN	2691-3593
ISSN (online)	2691-3593
DOI	10.1097/as9.0000000000000237
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Article ; Online: Mechanical Resonances of Mobile Impurities in a One-Dimensional Quantum Fluid.

Schmidt, Thomas L / Dolcetto, Giacomo / Pedder, Christopher J / Le Hur, Karyn / Orth, Peter P

Physical review letters

2019 Volume 123, Issue 7, Page(s) 75302

Abstract: We study a one-dimensional interacting quantum liquid hosting a pair of mobile impurities causing backscattering. We determine the effective retarded interaction between the two impurities mediated by the liquid. We show that for strong backscattering ... ...

Abstract	We study a one-dimensional interacting quantum liquid hosting a pair of mobile impurities causing backscattering. We determine the effective retarded interaction between the two impurities mediated by the liquid. We show that for strong backscattering this interaction gives rise to resonances and antiresonances in the finite-frequency mobility of the impurity pair. At the antiresonances, the two impurities remain at rest even when driven by a (small) external force. At the resonances, their synchronous motion follows the external drive in phase and reaches maximum amplitude. Using a perturbative renormalization group analysis in quantum tunneling across the impurities, we study the range of validity of our model. We predict that these mechanical antiresonances are observable in experiments on ultracold atom gases confined to one dimension.
Language	English
Publishing date	2019-09-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	208853-8
ISSN	1079-7114 ; 0031-9007
ISSN (online)	1079-7114
ISSN	0031-9007
DOI	10.1103/PhysRevLett.123.075302
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Article ; Online: Nuclear RNA surveillance: role of TRAMP in controlling exosome specificity.

Schmidt, Karyn / Butler, J Scott

Wiley interdisciplinary reviews. RNA

2013 Volume 4, Issue 2, Page(s) 217–231

Abstract: The advent of high-throughput sequencing technologies has revealed that pervasive transcription generates RNAs from nearly all regions of eukaryotic genomes. Normally, these transcripts undergo rapid degradation by a nuclear RNA surveillance system ... ...

Abstract	The advent of high-throughput sequencing technologies has revealed that pervasive transcription generates RNAs from nearly all regions of eukaryotic genomes. Normally, these transcripts undergo rapid degradation by a nuclear RNA surveillance system primarily featuring the RNA exosome. This multimeric protein complex plays a critical role in the efficient turnover and processing of a vast array of RNAs in the nucleus. Despite its initial discovery over a decade ago, important questions remain concerning the mechanisms that recruit and activate the nuclear exosome. Specificity and modulation of exosome activity requires additional protein cofactors, including the conserved TRAMP polyadenylation complex. Recent studies suggest that helicase and RNA-binding subunits of TRAMP direct RNA substrates for polyadenylation, which enhances their degradation by Dis3/Rrp44 and Rrp6, the two exosome-associated ribonucleases. These findings indicate that the exosome and TRAMP have evolved highly flexible functions that allow recognition of a wide range of RNA substrates. This flexibility provides the nuclear RNA surveillance system with the ability to regulate the levels of a broad range of coding and noncoding RNAs, which results in profound effects on gene expression, cellular development, gene silencing, and heterochromatin formation. This review summarizes recent findings on the nuclear RNA surveillance complexes, and speculates upon possible mechanisms for TRAMP-mediated substrate recognition and exosome activation.
MeSH term(s)	Exosomes/genetics ; Exosomes/metabolism ; Humans ; Multiprotein Complexes/genetics ; Multiprotein Complexes/metabolism ; RNA, Nuclear/genetics ; RNA, Nuclear/metabolism ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Species Specificity
Chemical Substances	Multiprotein Complexes ; RNA, Nuclear ; Saccharomyces cerevisiae Proteins
Language	English
Publishing date	2013-02-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	2634714-3
ISSN	1757-7012 ; 1757-7004
ISSN (online)	1757-7012
ISSN	1757-7004
DOI	10.1002/wrna.1155
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Article ; Online: RNAi-mediated rheostat for dynamic control of AAV-delivered transgenes.

Subramanian, Megha / McIninch, James / Zlatev, Ivan / Schlegel, Mark K / Kaittanis, Charalambos / Nguyen, Tuyen / Agarwal, Saket / Racie, Timothy / Alvarado, Martha Arbaiza / Wassarman, Kelly / Collins, Thomas S / Chickering, Tyler / Brown, Christopher R / Schmidt, Karyn / Castoreno, Adam B / Shulga-Morskaya, Svetlana / Stamenova, Elena / Buckowing, Kira / Berman, Daniel /

Barry, Joseph D / Bisbe, Anna / Maier, Martin A / Fitzgerald, Kevin / Jadhav, Vasant

Nature communications

2023 Volume 14, Issue 1, Page(s) 1970

Abstract: Adeno-associated virus (AAV)-based gene therapy could be facilitated by the development of molecular switches to control the magnitude and timing of expression of therapeutic transgenes. RNA interference (RNAi)-based approaches hold unique potential as a ...

Abstract	Adeno-associated virus (AAV)-based gene therapy could be facilitated by the development of molecular switches to control the magnitude and timing of expression of therapeutic transgenes. RNA interference (RNAi)-based approaches hold unique potential as a clinically proven modality to pharmacologically regulate AAV gene dosage in a sequence-specific manner. We present a generalizable RNAi-based rheostat wherein hepatocyte-directed AAV transgene expression is silenced using the clinically validated modality of chemically modified small interfering RNA (siRNA) conjugates or vectorized co-expression of short hairpin RNA (shRNA). For transgene induction, we employ REVERSIR technology, a synthetic high-affinity oligonucleotide complementary to the siRNA or shRNA guide strand to reverse RNAi activity and rapidly recover transgene expression. For potential clinical development, we report potent and specific siRNA sequences that may allow selective regulation of transgenes while minimizing unintended off-target effects. Our results establish a conceptual framework for RNAi-based regulatory switches with potential for infrequent dosing in clinical settings to dynamically modulate expression of virally-delivered gene therapies.
MeSH term(s)	RNA Interference ; Dependovirus/genetics ; Dependovirus/metabolism ; RNA, Small Interfering/metabolism ; Transgenes ; Genetic Therapy ; RNA, Double-Stranded ; Genetic Vectors/genetics
Chemical Substances	RNA, Small Interfering ; RNA, Double-Stranded
Language	English
Publishing date	2023-04-08
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-37774-5
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Article ; Online: Targeting the Oncogenic Long Non-coding RNA SLNCR1 by Blocking Its Sequence-Specific Binding to the Androgen Receptor.

Schmidt, Karyn / Weidmann, Chase A / Hilimire, Thomas A / Yee, Elaine / Hatfield, Breanne M / Schneekloth, John S / Weeks, Kevin M / Novina, Carl D

Cell reports

2020 Volume 30, Issue 2, Page(s) 541–554.e5

Abstract: Long non-coding RNAs (lncRNAs) are critical regulators of numerous physiological processes and diseases, especially cancers. However, development of lncRNA-based therapies is limited because the mechanisms of many lncRNAs are obscure, and interactions ... ...

Abstract	Long non-coding RNAs (lncRNAs) are critical regulators of numerous physiological processes and diseases, especially cancers. However, development of lncRNA-based therapies is limited because the mechanisms of many lncRNAs are obscure, and interactions with functional partners, including proteins, remain uncharacterized. The lncRNA SLNCR1 binds to and regulates the androgen receptor (AR) to mediate melanoma invasion and proliferation in an androgen-independent manner. Here, we use biochemical analyses coupled with selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) RNA structure probing to show that the N-terminal domain of AR binds a pyrimidine-rich motif in an unstructured region of SLNCR1. This motif is predictive of AR binding, as we identify an AR-binding motif in lncRNA HOXA11-AS-203. Oligonucleotides that bind either the AR N-terminal domain or the AR RNA motif block the SLNCR1-AR interaction and reduce SLNCR1-mediated melanoma invasion. Delivery of oligos that block SLNCR1-AR interaction thus represent a plausible therapeutic strategy.
MeSH term(s)	Base Sequence ; Cell Line, Tumor ; Cell Proliferation/physiology ; Female ; HEK293 Cells ; Humans ; Male ; Melanoma/genetics ; Melanoma/metabolism ; Melanoma/pathology ; Neoplasm Invasiveness ; Protein Domains ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism ; RNA, Neoplasm/genetics ; RNA, Neoplasm/metabolism ; Receptors, Androgen/genetics ; Receptors, Androgen/metabolism
Chemical Substances	AR protein, human ; RNA, Long Noncoding ; RNA, Neoplasm ; Receptors, Androgen ; long non-coding RNA SLNCR1, human
Language	English
Publishing date	2020-01-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2019.12.011
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