tbuckley/cabot-search huggingface dataset:
Efficient Gene Silencing by Adenine Base Editor-Mediated Start Codon Mutation
Authors: Xinjie Wang, Zhiwei Liu, GuangLei Li, Lu Dang, Shisheng Huang, Lei He, Yu’e Ma, Cong Li, Ming Liu, Guang Yang, Xingxu Huang, Fei Zhou, Xiaodong Ma
Journal: Molecular Therapy (2019)

Traditional CRISPR/Cas9-based gene knockouts are generated by introducing DNA double-strand breaks (DSBs), but this may cause excessive DNA damage or cell death. CRISPR-based cytosine base editors (CBEs) and adenine base editors (ABEs) can facilitate C-to-T or A-to-G exchanges, respectively, without DSBs. CBEs have been employed in a gene knockout strategy: CRISPR-STOP or i-STOP changes single nucleotides to induce in-frame stop codons. However, this strategy is not applicable for some genes, and the unwanted mutations in CBE systems have recently been reported to be surprisingly significant. As a variant, the ABE systems mediate precise editing and have only rare unwanted mutations. In this study, we implemented a new strategy to induce gene silencing (i-Silence) with an ABE-mediated start codon mutation from ATG to GTG or ACG. Using both in vitro and in vivo model systems, we showed that the i-Silence approach is efficient and precise for producing a gene knockout. In addition, the i-Silence strategy can be employed to analyze ~17,804 human genes and can be used to mimic 147 kinds of pathogenic diseases caused by start codon mutations. Altogether, compared to other methods, the ABE-based i-Silence method is a safer gene knockout strategy, and it has promising application potential. Traditional CRISPR/Cas9-based gene knockouts are generated by introducing DNA double-strand breaks (DSBs), but this may cause excessive DNA damage or cell death. CRISPR-based cytosine base editors (CBEs) and adenine base editors (ABEs) can facilitate C-to-T or A-to-G exchanges, respectively, without DSBs. CBEs have been employed in a gene knockout strategy: CRISPR-STOP or i-STOP changes single nucleotides to induce in-frame stop codons. However, this strategy is not applicable for some genes, and the unwanted mutations in CBE systems have recently been reported to be surprisingly significant. As a variant, the ABE systems mediate precise editing and have only rare unwanted mutations. In this study, we implemented a new strategy to induce gene silencing (i-Silence) with an ABE-mediated start codon mutation from ATG to GTG or ACG. Using both in vitro and in vivo model systems, we showed that the i-Silence approach is efficient and precise for producing a gene knockout. In addition, the i-Silence strategy can be employed to analyze ~17,804 human genes and can be used to mimic 147 kinds of pathogenic diseases caused by start codon mutations. Altogether, compared to other methods, the ABE-based i-Silence method is a safer gene knockout strategy, and it has promising application potential.
Development of a Sensitive and Efficient Reporter Platform for the Detection of Chimeric Antigen Receptor T Cell Expansion, Trafficking, and Toxicity
Authors: Reona Sakemura, Lukkana Suksanpaisan, Roman H Khadka, Alysha N Newsom, Michael J. Hansen, Michelle J. Cox, Mehrdad Hefazi, Claudia Manriquez Roman, Kendall J. Schick, Erin E. Tapper, Paulina Roman Moreno, Michael W. Ruff, Sameer A. Parikh, Neil E. Kay, Kah-Whye Peng, Stephen J Russell, Saad S. Kenderian
Journal: Blood (2019)
Post-Transplantation Cyclophosphamide after Allogeneic Hematopoietic Stem Cell Transplantation: Results of the Prospective Randomized HOVON-96 Trial in Recipients of Matched Related and Unrelated Donors
Authors: Cornelis N. De Jong, Ellen Meijer, Katerina Bakunina, Erfan Nur, Marinus van Marwijk Kooij, Marco R. de Groot, Michel van Gelder, Johan A. Maertens, Jurgen H.E. Kuball, Dries Deeren, Bronno van der Holt, Jan J Cornelissen, Annoek E.C. Broers
Journal: Blood (2019)
CANOPY-A: A phase III, placebo-controlled study of canakinumab as adjuvant therapy in patients (pts) with surgically resected NSCLC
Authors: B.C. Cho, G.-C. Chang, Y.-C. Kim, S. Geater, S. Saeteng, C.-T. Yang, Y. Goto, S. Lu, A. Ardizzoni, F. Barlesi, P. De Marchi, L. Paz-Ares, D.R. Spigel, M. Thomas, E.B. Garon, M. Leung, J. Baum, Z. Zewen, B. Mookerjee, J.C.-H. Yang
Journal: Annals of Oncology (2019)
The Discordance between Offsite to Onsite Testing for Von Willebrand Disease in Post-Menarchal Females: A Multi-Center Study
Authors: Julie Jaffray, Robert F. Sidonio, Jemily Malvar, Janice M Staber, Kristina M. Haley, Amy Stillings, Angela C. Weyand, Sarah H. O'Brien, Peter A. Kouides
Journal: Blood (2019)
Cancer- and Chemotherapy-Induced Anemia
Authors: George M. Rodgers, Pamela Sue Becker, Morey Blinder, David Cella, Asher Chanan-Khan, Charles Cleeland, Peter F. Coccia, Benjamin Djulbegovic, Jeffrey A. Gilreath, Eric H. Kraut, Ursula A. Matulonis, Michael M. Millenson, Denise Reinke, Joseph Rosenthal, Rowena N. Schwartz, Gerald Soff, Richard S. Stein, Gordana Vlahovic, Alva B. Weir
Journal: Journal of the National Comprehensive Cancer Network (2012)

Anemia is prevalent in 30% to 90% of patients with cancer. Anemia can be corrected through either treating the underlying cause or providing supportive care through transfusion with packed red blood cells or administration of erythropoiesis-stimulating agents (ESAs), with or without iron supplementation. Recent studies showing detrimental health effects of ESAs sparked a series of FDA label revisions and a sea change in the perception of these once commonly used agents. In light of this, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer- and Chemotherapy-Induced Anemia underwent substantial revisions this year. The purpose of these NCCN Guidelines is twofold: 1) to operationalize the evaluation and treatment of anemia in adult cancer patients, with an emphasis on those who are receiving concomitant chemotherapy, and 2) to enable patients and clinicians to individualize anemia treatment options based on patient condition.
Bone metastases and immunotherapy in patients with advanced non-small-cell lung cancer
Authors: Lorenza Landi, Federica D’Incà, Alain Gelibter, Rita Chiari, Francesco Grossi, Angelo Delmonte, Antonio Passaro, Diego Signorelli, Francesco Gelsomino, Domenico Galetta, Diana Giannarelli, Hector Soto Parra, Gabriele Minuti, Marcello Tiseo, Maria Rita Migliorino, Francesco Cognetti, Luca Toschi, Paolo Bidoli, Francovito Piantedosi, Luana Calabro’, Federico Cappuzzo
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Bone metastases (BoM) are a negative prognostic factor in non-small-cell lung cancer (NSCLC). Beyond its supportive role, bone is a hematopoietic organ actively regulating immune system. We hypothesized that BoM may influence sensitivity to immunotherapy. <h3>Methods</h3> Pretreated non-squamous (cohort A) and squamous (cohort B) NSCLCs included in the Italian Expanded Access Program were evaluated for nivolumab efficacy according to BoM. <h3>Results</h3> Cohort A accounted for 1588 patients with non-squamous NSCLC, including 626 (39%) with (BoM+) and 962 (61%) without BoM (BoM-). Cohort B accounted for 371 patients with squamous histology including 120 BoM+ (32%) and 251 (68%) BoM- cases. BoM+ had lower overall response rate (ORR; Cohort A: 12% versus 23%, <i>p</i> &lt; &nbsp;0.0001; Cohort B: 13% versus 22%, <i>p</i> = 0.04), shorter progression free survival (PFS; Cohort A: 3.0 versus 4.0 months, p &lt; &nbsp;0.0001; Cohort B: 2.7 versus 5.2 months, p &lt; &nbsp;0.0001) and overall survival (OS; Cohort A: 7.4 versus 15.3 months, p &lt; &nbsp;0.0001; Cohort B: 5.0 versus 10.9 months, <i>p</i> &lt; 0.0001). Moreover, BoM negatively affected outcome irrespective of performance status (PS; OS in both cohorts: p &lt; 0.0001) and liver metastases (OS cohort A: p &lt; 0.0001; OS Cohort B: <i>p</i> = 0.48). At multivariate analysis, BoM independently associated with higher risk of death (cohort A: HR 1.50; cohort B: HR 1.78). <h3>Conclusions</h3> BoM impairs immunotherapy efficacy. Accurate bone staging should be included in clinical trials with immunotherapy.
The efficacy of palliative radiation therapy in the treatment of recurrent and metastatic ovarian cancer.
Authors: Anish Butala, Roshal Patel, Joshua Adam Jones, Neil Taunk
Journal: Journal of Clinical Oncology (2019)

129 Background: Ovarian cancer is the 2nd most common gynecologic malignancy with surgery and platinum-based chemotherapy as the mainstay of initial treatment. However, ovarian cancer has generally high rates of recurrence and metastasis after primary therapy. For patients with progressive or symptomatic disease, radiation therapy (RT) can be utilized as an effective option for palliation. Methods: A retrospective review was conducted of patients treated with palliative RT for symptomatic or recurrent ovarian cancer between 2015-2019 at a single institution. 17 women were identified who received 20 courses of RT. Response was classified as complete response (CR), partial response (PR), and progressive disease (PD). Overall response rate (ORR) was the sum of CR and PR. Results: Median age at RT was 57 (range 36-76). Histologic subtypes were high grade serous (65%), low grade serous (12%), clear cell (12%), and other (12%). The most common indications were pain (65%), bleeding (30%), and asymptomatic progression (20%). 18 of 20 RT courses were delivered to soft tissue or nodal metastases. RT techniques included 2D/3D (60%), IMRT (30%), and SBRT (10%). Dose ranged from 20-60 Gy in 3-28 fractions. 20 Gy in 5 fractions (25%) and 30-31 Gy in 10 fractions (25%) were most common. Of the 16 RT courses for symptomatic disease, clinical ORR was 87.5% within 3 months of RT (50% PR and 37.5% CR). 3 treatments had sustained response beyond 3 months. 2 developed PD. Of 11 RT courses with follow-up imaging, radiographic ORR was 36.1% (27% PR and 9.1% CR) within 3 months of RT. 1 had sustained PR beyond 3 months. Of the 10 RT courses for symptomatic high grade serous histology, PR and CR was seen in 50% and 40% of patients within 3 months (90% ORR). Conclusions: Palliative RT offers high rates of clinical response for symptomatic patients with metastatic ovarian cancer within 3 months of treatment delivery. Rapid clinical response rates were particularly favorable for those with high grade serous histology. RT should be considered as a standard palliative option for patients with symptomatic ovarian cancer metastases. Further prospective studies are warranted to establish the optimal timing, dose, and relation to chemosensitivity in this setting.
Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study
Authors: Emmanuel S. Antonarakis, Josep M. Piulats, Marine Gross-Goupil, Jeffrey Goh, Kristiina Ojamaa, Christopher J. Hoimes, Ulka Vaishampayan, Ranaan Berger, Ahmet Sezer, Tuomo Alanko, Ronald de Wit, Chunde Li, Aurelius Omlin, Giuseppe Procopio, Satoshi Fukasawa, Ken-ichi Tabata, Se Hoon Park, Susan Feyerabend, Charles G. Drake, Haiyan Wu, Ping Qiu, Jeri Kim, Christian Poehlein, Johann Sebastian de Bono
Journal: Journal of Clinical Oncology (2019)

Pembrolizumab has previously shown antitumor activity against programmed death ligand 1 (PD-L1)-positive metastatic castration-resistant prostate cancer (mCRPC). Here, we assessed the antitumor activity and safety of pembrolizumab in three parallel cohorts of a larger mCRPC population.
Psychotherapy at the End of Life
Authors: Rebecca M. Saracino, Barry Rosenfeld, William Breitbart, Harvey Max Chochinov
Journal: The American Journal of Bioethics (2019)

Dr. Elisabeth Kübler-Ross is credited as one of the first clinicians to formalize recommendations for working with patients with advanced medical illnesses. In her seminal book, On Death and Dying, she identified a glaring gap in our understanding of how people cope with death, both on the part of the terminally ill patients that face death and as the clinicians who care for these patients. Now, 50 years later, a substantial and ever-growing body of research has identified "best practices" for end of life care and provides confirmation and support for many of the therapeutic practices originally recommended by Dr. Kübler-Ross. This paper reviews the empirical study of psychological well-being and distress at the end of life. Specifically, we review what has been learned from studies of patient desire for hastened death and the early debates around physician assisted suicide, as well as demonstrating how these studies, informed by existential principles, have led to the development of manualized psychotherapies for patients with advanced disease. The ultimate goal of these interventions has been to attenuate suffering and help terminally ill patients and their families maintain a sense of dignity, meaning, and peace as they approach the end of life. Two well-established, empirically supported psychotherapies for patients at the end of life, Dignity Therapy and Meaning Centered Psychotherapy are reviewed in detail.
Sebaceous carcinoma: evidence-based clinical practice guidelines
Authors: Joshua L Owen, Nour Kibbi, Brandon Worley, Ryan C Kelm, Jordan V Wang, Christopher A Barker, Ramona Behshad, Christopher K Bichakjian, Diana Bolotin, Jeremy S Bordeaux, Scott H Bradshaw, Todd V Cartee, Sunandana Chandra, Nancy L Cho, Jennifer N Choi, M Laurin Council, Hakan Demirci, Daniel B Eisen, Bita Esmaeli, Nicholas Golda, Conway C Huang, Sherrif F Ibrahim, S Brian Jiang, John Kim, Timothy M Kuzel, Stephen Y Lai, Naomi Lawrence, Erica H Lee, Justin J Leitenberger, Ian A Maher, Margaret W Mann, Kira Minkis, Bharat B Mittal, Kishwer S Nehal, Isaac M Neuhaus, David M Ozog, Brian Petersen, Veronica Rotemberg, Sandeep Samant, Faramarz H Samie, Sabah Servaes, Carol L Shields, Thuzar M Shin, Joseph F Sobanko, Ally-Khan Somani, William G Stebbins, J Regan Thomas, Valencia D Thomas, David T Tse, Abigail H Waldman, Michael K Wong, Y Gloria Xu, Siegrid S Yu, Nathalie C Zeitouni, Timothy Ramsay, Kelly A Reynolds, Emily Poon, Murad Alam
Journal: The Lancet Oncology (2019)
A novel anti-PD-1 antibody HLX10 study led to the initiation of combination immunotherapy
Authors: T.Y. Chao, C.L. Ho, W.H. Cheng, C.L. Chang, Y.Y. Hsieh, W. Jiang, S. Liu, A. Luk, S.F. Lin, T.C. Hsieh, E. Liu
Journal: Annals of Oncology (2019)
Preliminary Results from a Phase I Trial of Pembrolizumab Plus Vorinostat in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, and Hodgkin Lymphoma
Authors: Alex F. Herrera, Lu Chen, Leslie L. Popplewell, Lihua E Budde, Matthew Mei, Saro H. Armenian, Justin Darrah, Liana Nikolaenko, Robert W. Chen, Lacolle Peters, Neena Kennedy, Steven Rosen, Stephen J Forman, Larry W Kwak
Journal: Blood (2019)
KEYNOTE-756: A randomized, double-blind, phase III study of pembrolizumab or placebo with neoadjuvant chemotherapy and adjuvant endocrine therapy for high-risk, early-stage, ER+/HER2−breast cancer
Authors: F. Cardoso, A. Bardia, F. André, D.W. Cescon, H. McArthur, M. Telli, S. Loi, J. Cortes, P. Schmid, N. Harbeck, C. Denkert, C. Jackisch, L. Jia, K. Hirshfield, V. Karantza
Journal: Annals of Oncology (2019)
Abstract 01: The Importance of Time to Cooling in Out-Of-Hospital Cardiac Arrest Patients to Influence Neurologically Intact Survival: A Sub-Analysis of the Princess Trial
Authors: Akil Awad, Fabio Silvio Taccone, Martin Jonsson, Sune Forsberg, Jacob Hollenberg, Mattias Ringh, Benjamin Abella, Lance B Becker, LeiF G Svensson, Per Nordberg
Journal: Circulation (2019)

Background: Early initiation of hypothermia has shown to be important to reduce brain injuries in experimental cardiac arrest models. The aim of this study was to investigate the association between time to initiate cooling and neurological intact survival in patients with out-of-hospital cardiac arrest (OHCA). Methods: A secondary analysis of prospectively collected data from the PRINCESS trial (NCT01400373) including 677 OHCA patients randomized to transnasal evaporative intra-arrest cooling or standard advanced life support and cooling started subsequent to hospital arrival. Time to randomization was used a proxy measurement for time to initiate cooling. An early treatment group was defined as patients randomized by the EMS &lt;20 minutes from the time of the cardiac arrest. Propensity scores were used to find matching patients in the control group. Patients with initial shockable rhythms were analyzed as a predefined subgroup. The primary outcome was good neurologic outcome, Cerebral Performance Category (CPC) 1-2 at 90 days. Secondary outcome was complete recovery (CPC 1). Results: In total 406 patients were randomized &lt;20 minutes from the cardiac arrest and were propensity score matched (1:1). In the propensity score matched analysis the proportion of patients with CPC 1-2 was 21.7% in the intervention and 17.2% in the control group, odds ratio (OR) 1.33, 95% confidence interval (CI) 0.80-2.21, p=0.273. In patients with initial shockable rhythm (79 intervention, 79 control) the difference in CPC 1-2 was 48.1% versus 32.0%, OR 2.05, 95%CI 1.00-4.21, p=0.0498. The proportion of patients with complete neurologic recovery, CPC 1, was 19.7% in the intervention and 13.3% in the control group, OR 1.60, 95% CI 0.92-2.79, p=0.097. In patients with initial shockable rhythm the proportion with CPC 1 was 45.6% versus 24.6%, OR 2.81, 95% CI 1.23-6.42, p=0.014. Conclusions: In this ancillary study of OHCA patients receiving intra-arrest cooling, there were differences in survival with good neurologic outcome and in complete neurological recovery in favor of early intra-arrest cooling patient group compared to standard care. These differences were statistically significant in the subgroup of patients with initial shockable rhythms.
Peter Howell Schurr
Authors: Charles E Polkey
Journal: BMJ (2019)

Peter Howell Schurr, who died at 98 years of age, is probably the last survivor of those neurosurgeons who bridged the gap between neurosurgery in the interwar years. The specialty had a small number of practitioners and was still considered a sideline by many general surgeons, to the time when modern neurosurgery was beginning to develop in the 1970s. Although the professional body, the Society of British Neurological Surgeons (SBNS), was founded in 1926, the specialty began to expand after the war and the calibre and standards of these surgeons established the present stature of the neurosurgery as a recognised surgical specialty.

Peter Schurr qualified from Cambridge in 1943, joined the Royal Army Medical Corps, where he worked as a general …
Long-term impact of an educational antimicrobial stewardship programme in primary care on infections caused by extended-spectrum β-lactamase-producing Escherichia coli in the community: an interrupted time-series analysis
Authors: Germán Peñalva, Rocío Fernández-Urrusuno, José María Turmo, Rocío Hernández-Soto, Ignacio Pajares, Lucía Carrión, Inmaculada Vázquez-Cruz, Blanca Botello, Beatriz García-Robredo, Manuel Cámara-Mestres, Juan Carlos Domínguez-Camacho, Manuel María Aguilar-Carnerero, José Antonio Lepe, Marina de Cueto, María Carmen Serrano-Martino, María Carmen Domínguez-Jiménez, Ana Domínguez-Castaño, José Miguel Cisneros, Juan deDios Alcántara, Rocío Álvarez-Marín, Ana Cos-Vega, Juan Delgado-Cuesta, José María Fajardo, Joaquín Garrucho-Moreno, Elena Hevia, Aránzazu Irastorza, Ainhoa Mestraitúa-Vázquez, Jose Molina, Emilio Montero, José Luis Palma-Aguilar, Tomás Remesal, Pilar Retamar, Salomé Taboada-Prieto, Javier Toral, Joaquín Torres-Moreno
Journal: The Lancet Infectious Diseases (2019)
Neurocognitive Impairment Predicts Poor Transition Outcomes Among Patients with Sickle Cell Disease
Authors: Anjelica C. Saulsberry, Marita Partanen, Jerlym S. Porter, Pradeep S. B. Podila, Jason R. Hodges, Allison A. King, Winfred Wang, Xiwen Zhao, Guolian Kang, Lisa M. Jacola, Jane S. Hankins
Journal: Blood (2019)
High/low dose dexamethasone with physical activity for cancer-related fatigue in patients with advanced cancer: A phase II randomized double blind study.
Authors: Sriram Yennu, Vicente Valero, Bora Lim, Daniel J. Booser, Carolina Diaz Hernandez, Zhanni Lu, Diane D. Liu, Naifa Lamki Busaidy, James M. Reuben, Janet L. Williams, Kenneth R. Hess, Karen Basen-Engquist, Eduardo Bruera
Journal: Journal of Clinical Oncology (2019)

110 Background: Cancer-related-fatigue (CRF) is the most debilitating symptom in patients with advanced cancer. Physical activity (PA) improves CRF with lower adherence in advanced cancer. Dexamethasone (Dex) improves CRF but has long-term side effects. The purpose of the study was to determine whether a brief course of Dex improves adherence to PA for CRF management. Methods: Advanced cancer patients with CRF ≥ 4/10 on Edmonton Symptom Assessment Scale (ESAS) were eligible. Patients were randomized to either 4mg of Dex (LoDex) or 8mg of Dex (HiDex) orally BID for 7 days Plus standardized aerobic and resistance exercise for 4 weeks. Change in the Functional Assessment of Chronic Illness-Fatigue (FACIT-F) fatigue subscale from baseline to Day 8 (primary outcome) and Day 29 were assessed. Secondary outcomes included changes in fatigue (ESAS, PROMIS, MFSI), Sleep Quality (PSQI), fasting blood glucose, and myopathy. Results: Total evaluable patients were 60 (31 LoDex and 29 HiDex arms). The study was feasible (N = 60/67 were evaluable); 84% and 65% LoDex, and 96% and 68% Hi Dex were adherent to aerobic and resistance exercise, respectively [All Patients were adherent to study medication]. There was no significant difference in grade 3+ AE’s between the two arms (P = 0. 92). The FACIT fatigue subscale Cohen’s d in Lo Dex was 0.90 (P &lt; 0.001) and 0.94(P &lt; 0.001); and Hi Dex was 0.86(P &lt; 0.001); and 1.05(P &lt; 0.001) at Day 8 and Day 29, respectively. Similar improvement was found for ESAS Fatigue (P &lt; 0.001), MFSI total (P = 0.005), and PROMIS –fatigue total (P = 0.005). Mixed model analysis showed significant improvement in FACIT-F fatigue scores at Day 8 (P = 0.0006), Day 15 (P = 0.0002), and D (P = 0.0018). There was no significant difference between the two arms at Day 8 and Day 29 in fatigue scores, myopathy, fasting blood glucose levels, symptom distress, and sleep quality scores. Conclusions: Short course of dexamethasone Plus physical activity resulted in sustained and robust improvement in CRF outcomes for upto 3 weeks after discontinuation of steroids suggesting possible priming effects of steroids helped to sustain physical activity. Further larger studies are justified. Clinical trial information: NCT02491632.
Effective and Accurate Gene Silencing by a Recombinant AAV-Compatible MicroRNA Scaffold
Authors: Jun Xie, Phillip W.L. Tai, Alexander Brown, Shoufang Gong, Sha Zhu, Yi Wang, Chengjian Li, Cansu Colpan, Qin Su, Ran He, Hong Ma, Jia Li, Hanqing Ye, Jihye Ko, Phillip D. Zamore, Guangping Gao
Journal: Molecular Therapy (2019)

Short hairpin RNAs that are delivered by recombinant adeno-associated virus (rAAV) have the potential to elicit long-term RNAi therapy for human disease. However, the discovery that short hairpin sequences can cause truncation of the rAAV genome calls into question the efficiency and gene-silencing specificity of this strategy in humans. Here, we report that embedding the guide strand of a small silencing RNA into an artificial microRNA (miRNA) scaffold derived from mouse miRNA-33 ensures rAAV genomic integrity and reduces off-targeting by 10-fold, while maintaining effective in vivo target gene repression in mice. Short hairpin RNAs that are delivered by recombinant adeno-associated virus (rAAV) have the potential to elicit long-term RNAi therapy for human disease. However, the discovery that short hairpin sequences can cause truncation of the rAAV genome calls into question the efficiency and gene-silencing specificity of this strategy in humans. Here, we report that embedding the guide strand of a small silencing RNA into an artificial microRNA (miRNA) scaffold derived from mouse miRNA-33 ensures rAAV genomic integrity and reduces off-targeting by 10-fold, while maintaining effective in vivo target gene repression in mice.