tbuckley/cabot-search huggingface dataset:
Efficient In Vivo Homology-Directed Repair Within Cardiomyocytes
Authors: Yanjiang Zheng, Nathan J. VanDusen, Catalina E. Butler, Qing Ma, Justin S. King, William T. Pu
Journal: Circulation (2022)

RISPR/Cas9-based genome editing technologies provide powerful tools for genetic manipulation.Cas9 in vivo genome editing of cardiomyocytes through nonhomologous end joining efficiently creates insertion-deletion mutations at guide RNA-targeted sites. 1 However, precise addition of new genetic information, or mutation correction, requires alternate strategies.Delivery of Cas9 and a homology directed repair (HDR) template using adeno-associated virus (AAV) was recently shown to enable creation of precise genomic edits, even within postmitotic cells. 2 We studied CRISPR/Cas9 and AAV-based homology directed repair (CASAAV-HDR) in cardiomyocytes.Animal experiments were approved by the Institutional Animal Care and Use Committee and adhered to institutional guidelines.The authors will provide data, results, and reagents on reasonable request.We studied CASAAV-HDR at Myl2 (MLC2v), a highly expressed, ventricle-specific sarcomere gene.We constructed AAV9 with an Myl2-specific guide RNA and a promoterless HDR template that replaces the native stop codon with self-cleaving 2A peptide followed by mScarlet, a red fluorescent protein (Figure [A]).Subcutaneous delivery of the AAV to postnatal day 0 mice with cardiacrestricted Cas9 expression (Tnnt2Cre;Rosa26 fsCas9-P2A-GFP ) yielded strong mScarlet expression in postnatal day 7 ventricular cardiomyocytes (Figure [Bi and C]).mScarlet expression required Cas9 and Myl2 homology arms (Figure [Bii and Biii]).AAV-delivered Cas9 successfully directed mScarlet expression, albeit with reduced efficiency compared with Rosa26 fsCas9-P2A-GFP (Figure [Biv]).Guide RNAs targeting sequences on either side of
Long-term trends in the epidemiology of cardiovascular diseases in the UK: insights from the British Heart Foundation statistical compendium
Authors: Katherine Margaret Cheema, Ed Dicks, Jeremy Pearson, Nilesh J Samani
Journal: Cardiovascular Research (2022)

Abstract The British Heart Foundation’s (BHF) annual statistical compendium is a comprehensive source of accessible epidemiological data in relation to cardiovascular disease (CVD) in the UK. Using datasets with multiple years of data from the compendium we have analysed trends in mortality, morbidity, and treatment for CVD within the UK. CVD mortality in the UK has consistently declined over recent decades, from 1045 deaths per 100 000 in 1969, shortly after the BHF was founded, to 255 per 100 000 in 2019. Despite this remarkable improvement, inequalities in CVD mortality persist in the UK nations, for example in 2019 the death rate in Scotland was 326 deaths per 100 000 compared with 246 per 100 000 in England. Improvements in CVD mortality have been paralleled by increased use of primary prevention medications (anti-hypertensives and statins) and interventional procedures. In recent years, progress in mortality outcomes has stalled, probably due to a combination of factors including a rise in risk factors such as obesity and diabetes. In terms of morbidity, CVD remains a significant burden in the UK, accounting for at least 1.18 million hospital admissions and reflects the enormous economic burden of CVD, estimated at £19bn in the UK. Our results highlight the importance of accessible and comprehensive statistics in relation to the burden of CVD and the value of the BHF’s annual compendium in drawing out conclusions and opportunities for future research. One key area is to improve the data on which estimation of prevalence is based. There is also a need for ongoing work to better understand the root causes of disparity between socio-economic groups in relation to CVD. One important way to address this will be to improve the consistency of reporting of CVD health data across all nations of the UK. Understanding the causes will inform UK healthcare planning in addition to providing analytical insights that will be applicable in other countries.
Proteinases in the pathogenesis of lymphangioleiomyomatosis lung disease: nibbling or chewing up the lung?
Authors: Yael Aschner, Gregory P. Downey
Journal: European Respiratory Journal (2022)

Lymphangioleiomyomatosis (LAM) is a slowly progressive, low-grade neoplasm predominantly affecting women that originates from tuberous sclerosis complex (TSC)-deficient cells of mesenchymal lineage ("LAM cells") in the uterus or pelvis [1, 2]. These LAM cells metastasise through the lymphatics to the abdominal and retroperitoneal lymph nodes, kidneys and lung [1–5]. LAM cells have loss-of-function mutations in both alleles of either TSC1 or TSC2 that function to inhibit the mechanistic target of rapamycin complex 1 (mTORC1). In the absence of tonic inhibition, the mTORC1 pathway is active and drives proliferation and invasion of LAM cells. Drugs such as sirolimus (rapamycin) and everolimus, that inhibit mTORC1, impede LAM cell growth and invasiveness and are clinically effective in slowing the progression of LAM disease [6–8], although this effect is reversible, necessitating continued treatment with medication. There is a subset of patients who progress despite treatment and/or are unable to tolerate the drugs. At present, other than monitoring of lung function tests [9], serum levels of vascular endothelial growth factor D [10], and cyst progression by computed tomography, all of which are lagging indicators of microscopic disease progression, there is no clinically useful way to monitor disease activity/progression and response to therapy. Use of proteinase-specific nanosensors holds great promise to measure lymphangioleiomyomatosis lung disease activity and response to treatment <https://bit.ly/3uEsVhF>
Quality Healthcare Ethics Consultation: How Do We Get It and How Do We Measure It
Authors: Alexander A. Kon
Journal: The American Journal of Bioethics (2022)

This article refers to:Ethics Consultation in U.S. Hospitals: A National Follow-Up StudyEthics Consultation in U.S. Hospitals: Determinants of Consultation VolumeEthics Consultation in U.S. Hospitals: Opinions of Ethics Practitioners
The ASBH’s Obligation to Create Cost-Free Basic HEC Training
Authors: Autumn Fiester
Journal: The American Journal of Bioethics (2022)

"The ASBH’s Obligation to Create Cost-Free Basic HEC Training." The American Journal of Bioethics, 22(4), pp. 66–67This article refers to:Ethics Consultation in U.S. Hospitals: A National Follow-Up StudyEthics Consultation in U.S. Hospitals: Opinions of Ethics Practitioners Additional informationFundingThe author(s) reported there is no funding associated with the work featured in this article.
Immune correlates of clinical parameters in patients with HPV-associated malignancies treated with bintrafusp alfa
Authors: Yo-Ting Tsai, Julius Strauss, Nicole J Toney, Caroline Jochems, David J Venzon, James L Gulley, Jeffrey Schlom, Renee N Donahue
Journal: Journal for ImmunoTherapy of Cancer (2022)

Purpose Bintrafusp alfa is a bifunctional agent consisting of an anti-human PD-L1 antibody linked to two TGFβRII. It is designed to act both as a checkpoint inhibitor and to ‘trap’ TGFβ in the tumor microenvironment. Phase I and II clinical studies demonstrated clinical activity in patients with a range of human papillomavirus (HPV)-associated cancers. The purpose of the studies reported here was the interrogation of various aspects of the peripheral immunome in patients with HPV-associated cancers, both prior to and early in the treatment regimen of bintrafusp alfa to better understand the mode of action of the agent and to help define which patients are more likely to benefit from bintrafusp alfa treatment. Patients and methods The peripheral immunome of patients (n=65) with HPV + malignancies was analyzed both prior to treatment with bintrafusp alfa and day 14 post-treatment for levels and changes in (1) 158 different immune cell subsets, (2) multiple plasma soluble factors including analytes reflecting immune stimulatory and inhibitory status, (3) complete blood counts, and in a subset of patients (4) TCR diversity and (5) HPV-specific T-cell responses. Results Interrogation of the peripheral immunome prior to bintrafusp alfa treatment revealed several factors that associated with clinical response, including (1) higher levels of sCD27:sCD40L ratios, (2) lower levels of TGFβ1 and 12 additional factors associated with tumor mesenchymalization, and (3) higher CD8 + T cell:MDSC ratios. Analysis at 2 weeks post bintrafusp alfa revealed that eventual clinical responders had fewer increases in IL-8 levels and the neutrophil to lymphocyte ratio, and higher levels of HPV-16 specific CD8 + T cells. This study also provided information concerning differences in the peripheral immunome for patients who were naïve versus refractory to prior checkpoint inhibition therapy. While preliminary, two multivariate models developed predicted clinical benefit with 76%–91% accuracy. Conclusions These studies add insight into the mechanism of action of bintrafusp alfa and provide evidence that the interrogation of both cellular and soluble components of the peripheral immunome of patients with HPV-associated malignancies, either prior to or early in the therapeutic regimen, can provide information as to which patients are more likely to benefit with bintrafusp alfa therapy.
Programmable Living Units for Emulating Pancreatic Tumor‐Stroma Interplay
Authors: Maria V. Monteiro, Marta Rocha, Vítor M. Gaspar, João F. Mano
Journal: Advanced Healthcare Materials (2022)

Bioengineering close-to-native in vitro models that emulate tumors bioarchitecture and microenvironment is highly appreciable for improving disease modeling toolboxes. Herein, pancreatic cancer living units-so termed cancer-on-a-bead models-are generated. Such user-programmable in vitro platforms exhibit biomimetic multicompartmentalization and tunable integration of cancer associated stromal elements. These stratified units can be rapidly assembled in-air, exhibit reproducible morphological features, tunable size, and recapitulate spatially resolved tumor-stroma extracellular matrix (ECM) niches. Compartmentalization of pancreatic cancer and stromal cells in well-defined ECM microenvironments stimulates the secretion of key biomolecular effectors including transforming growth factor β and Interleukin 1-β, closely emulating the signatures of human pancreatic tumors. Cancer-on-a-bead models also display increased drug resistance to chemotherapeutics when compared to their reductionistic counterparts, reinforcing the importance to differentially model ECM components inclusion and their spatial stratification as observed in vivo. Beyond providing a universal technology that enables spatial modularity in tumor-stroma elements bioengineering, a scalable, in-air fabrication of ECM-tunable 3D platforms that can be leveraged for recapitulating differential matrix composition occurring in other human neoplasias is provided here.
The Continuing Search for Causality between Epithelial-to-Mesenchymal Transition and the Metastatic Fitness of Carcinoma Cells
Authors: Valerie S. LeBleu, Jean Paul Thiery
Journal: Cancer Research (2022)

The epithelial-to-mesenchymal transition (EMT) is an epithelial plasticity program that is associated with embryonic development and organogenesis, and which resurfaces to a certain extent following epithelial injury caused by inflammation, fibrosis, and carcinoma progression. Carcinoma cell EMT plasticity programs superimposed on inherent genetic defects have been implicated as important for metastatic dissemination and secondary tumor formation. A careful review of data-driven facts suggests that a causal relationship between any degree of EMT program and metastasis continues to be elusive, and the steps of metastasis likely involve other mechanisms influenced by the carcinoma cell genotype and the tumor microenvironment.
Direct Oral Anticoagulant Treatment Is Associated With a Lower Prevalence of Thin-Cap Fibroatheroma
Authors: Daisuke Kinoshita, Yoshiyasu Minami, Ryota Kakizaki, Kohki Ishida, Kazuhiro Fujiyoshi, Toshimitsu Sato, Ayami Kato, Takako Nagata, Kiyoshi Asakura, Masahiro Katamine, Aritomo Katsura, Junya Ako
Journal: JACC. Cardiovascular imaging (2022)
Incorporating Ethics Consultations into Public Health Practice
Authors: Efthimios Parasidis, Amy L. Fairchild
Journal: The American Journal of Bioethics (2022)

This article refers to:Ethics Consultation in U.S. Hospitals: A National Follow-Up StudyEthics Consultation in U.S. Hospitals: Determinants of Consultation VolumeEthics Consultation in U.S. Hospitals: Opinions of Ethics Practitioners
Risks to the 340B Drug Pricing Program Related to Manufacturer Restrictions on Drug Availability
Authors: Ryan P. Knox, Aaron S. Kesselheim, Ameet Sarpatwari
Journal: JAMA (2022)

This Viewpoint documents the history, value, and success of the 340B Pricing Program, which is under threat from pharmaceutical corporations’ withdrawal and from a pending Supreme Court decision and offers 2 legislative fixes to address the concerns raised by the pharmaceutical companies.
Nonoperative or Surgical Treatment of Acute Achilles’ Tendon Rupture
Authors: Ståle B. Myhrvold, Espen F. Brouwer, Tor K. M. Andresen, Karin Rydevik, Madeleine Amundsen, Wolfram Grün, Faisal Butt, Morten Valberg, Svend Ulstein, Sigurd E. Hoelsbrekken
Journal: New England Journal of Medicine (2022)

Whether surgical repair of an acute Achilles' tendon rupture by an open-repair or minimally invasive approach is associated with better outcomes than nonsurgical treatment is not clear.We performed a multicenter, randomized, controlled trial that compared nonoperative treatment, open repair, and minimally invasive surgery in adults with acute Achilles' tendon rupture who presented to four trial centers. The primary outcome was the change from baseline in the Achilles' tendon Total Rupture Score (scores range from 0 to 100, with higher scores indicating better health status) at 12 months. Secondary outcomes included the incidence of tendon rerupture.A total of 554 patients underwent randomization, and 526 patients were included in the final analysis. The mean changes in the Achilles' tendon Total Rupture Score were -17.0 points in the nonoperative group, -16.0 points in the open-repair group, and -14.7 points in the minimally invasive surgery group (P = 0.57). Pairwise comparisons provided no evidence of differences between the groups. The changes from baseline in physical performance and patient-reported physical function were similar in the three groups. The number of tendon reruptures was higher in the nonoperative group (6.2%) than in the open-repair or minimally invasive surgery group (0.6% in each). There were 9 nerve injuries in the minimally invasive surgery group (in 5.2% of the patients) as compared with 5 in the open-repair group (in 2.8%) and 1 in the nonoperative group (in 0.6%).In patients with Achilles' tendon rupture, surgery (open repair or minimally invasive surgery) was not associated with better outcomes than nonoperative treatment at 12 months. (Funded by the South-Eastern Norway Regional Health Authority and Akershus University Hospital; ClinicalTrials.gov number, NCT01785264.).
The Complexity of Subtle Cardiac Tracer Uptake on Bone Scintigraphy
Authors: Christian Nitsche, Katharina Mascherbauer, Tim Wollenweber, Matthias Koschutnik, Carolina Donà, Varius Dannenberg, Felix Hofer, Kseniya Halavina, Andreas A. Kammerlander, Tatjana Traub-Weidinger, Georg Goliasch, Christian Hengstenberg, Marcus Hacker, Julia Mascherbauer
Journal: JACC. Cardiovascular imaging (2022)
Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: A randomised, open-label phase II trial
Authors: Naim Alkhouri, Robert Herring, Heidi Kabler, Zeid Kayali, Tarek Hassanein, Anita Kohli, Ryan S. Huss, Yanni Zhu, Andrew N. Billin, Lars Holm Damgaard, Kristine Buchholtz, Mette Skalshøi Kjær, Clare Balendran, Robert P. Myers, Rohit Loomba, Mazen Noureddin
Journal: Journal of Hepatology (2022)

Non-alcoholic steatohepatitis (NASH) is associated with increased risk of liver-related and cardiovascular morbidity and mortality. Given the complex pathophysiology of NASH, combining therapies with complementary mechanisms may be beneficial. This trial evaluated the safety and efficacy of semaglutide, a glucagon-like peptide-1 receptor agonist, alone and in combination with the farnesoid X receptor agonist cilofexor and/or the acetyl-coenzyme A carboxylase inhibitor firsocostat in patients with NASH.This was a phase II, open-label, proof-of-concept trial in which patients with NASH (F2-F3 on biopsy, or MRI-proton density fat fraction [MRI-PDFF] ≥10% and liver stiffness by transient elastography ≥7 kPa) were randomised to 24 weeks' treatment with semaglutide 2.4 mg once weekly as monotherapy or combined with once-daily cilofexor (30 or 100 mg) and/or once-daily firsocostat 20 mg. The primary endpoint was safety. All efficacy endpoints were exploratory.A total of 108 patients were randomised to semaglutide (n = 21), semaglutide plus cilofexor 30 mg (n = 22), semaglutide plus cilofexor 100 mg (n = 22), semaglutide plus firsocostat (n = 22) or semaglutide, cilofexor 30 mg and firsocostat (n = 21). Treatments were well tolerated - the incidence of adverse events was similar across groups (73-90%) and most events were gastrointestinal in nature. Despite similar weight loss (7-10%), compared with semaglutide monotherapy, combinations resulted in greater improvements in liver steatosis measured by MRI-PDFF (least-squares mean of absolute changes: -9.8 to -11.0% vs. -8.0%), liver biochemistry, and non-invasive tests of fibrosis.In patients with mild-to-moderate fibrosis due to NASH, semaglutide with firsocostat and/or cilofexor was generally well tolerated. In exploratory efficacy analyses, treatment resulted in additional improvements in liver steatosis and biochemistry vs. semaglutide alone. Given this was a small-scale open-label trial, double-blind placebo-controlled trials with adequate patient numbers are warranted to assess the efficacy and safety of these combinations in NASH.NCT03987074.Non-alcoholic fatty liver disease and its more severe form, non-alcoholic steatohepatitis (NASH), are serious liver conditions that worsen over time if untreated. The reasons people develop NASH are complex and combining therapies that target different aspects of the disease may be more helpful than using single treatments. This trial showed that the use of 3 different types of drugs, namely semaglutide, cilofexor and firsocostat, in combination was safe and may offer additional benefits over treatment with semaglutide alone.
Novel strategies exploiting interleukin-12 in cancer immunotherapy
Authors: Assunta Cirella, Carlos Luri-Rey, Claudia Augusta Di Trani, Alvaro Teijeira, Irene Olivera, Elixabet Bolaños, Eduardo Castañón, Belen Palencia, Davide Brocco, Myriam Fernández-Sendin, Fernando Aranda, Pedro Berraondo, Ignacio Melero
Journal: Pharmacology & Therapeutics (2022)
Clinical implications of germline variations for treatment outcome and drug resistance for small molecule kinase inhibitors in patients with non-small cell lung cancer
Authors: Niels Heersche, G.D. Marijn Veerman, Mirjam de With, Sander Bins, Yehuda G. Assaraf, Anne-Marie C. Dingemans, Ron H.N. van Schaik, Ron H.J. Mathijssen, Frank G.A. Jansman
Journal: Drug Resistance Updates (2022)

Small-molecule kinase inhibitors (SMKIs) represent the cornerstone in the treatment of non-small cell lung cancer (NSCLC) patients harboring genetic driver mutations. Because of the introduction of SMKIs in the last decades, treatment outcomes have drastically improved. Their treatment efficacy, the development of drug resistance as well as untoward toxicity, all suffer from large patient variability. This variability can be explained, at least in part, by their oral route of administration, which leads to a large inter- and intra-patient variation in bioavailability based on differences in absorption. Additionally, drug-drug and food-drug interactions are frequently reported. These interactions could modulate SMKI efficacy and/or untoward toxicity. Furthermore, the large patient variability could be explained by the presence of germline variations in target receptor domains, metabolizing enzymes, and drug efflux transporters. Knowledge about these predictor variations is crucial for handling SMKIs in clinical practice, and for selecting the most optimal therapy. In the current review, the literature search included all SMKIs registered for locally-advanced and metastatic NSCLC by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) until March 24th, 2022. The BIM deletion showed a significantly decreased PFS and OS for East-Asian patients treated with gefitinib, and has the potential to be clinically relevant for other SMKIs as well. Furthermore, we expect most relevance from the ABCG2 34 G>A and CYP1A1 variations during erlotinib and gefitinib treatment. Pre-emptive CYP2D6 testing before starting gefitinib treatment can also be considered to prevent severe drug-related toxicity. These and other germline variations are summarized and discussed, in order to provide clear recommendations for clinical practice.
Reconstructed glycosylase base editors GBE2.0 with enhanced C-to-G base editing efficiency and purity
Authors: Naxin Sun, Dongdong Zhao, Siwei Li, Ziteng Zhang, Changhao Bi, Xueli Zhang
Journal: Molecular Therapy (2022)

Base editing techniques were developed for precise base conversion on cellular genomic DNA, which has great potential for the treatment of human genetic diseases. The glycosylase base editor (GBE) recently developed in our lab was used to perform C-to-G transversions in mammalian cells. To improve the application prospects of GBE, it is necessary to further increase its performance. With this aim, we replaced the human Ung in GBE with Ung1 from Saccharomyces cerevisiae. The resulting editor APOBEC-nCas9-Ung1 was tested at 17 chromosomal loci and was found to have an increased C-to-G editing efficiency ranging from 2.63% to 52.3%, with an average of 23.48%, which was a significant improvement over GBE, with an average efficiency of 15.54%, but with a decreased purity. For further improvement, we constructed APOBEC(R33A)-nCas9-Rad51-Ung1 with two beneficial modifications adapted from previous reports. This base editor was able to achieve even higher editing efficiency ranging from 8.70% to 72.1%, averaging 30.88%, while also exhibiting high C-to-G purity ranging from 35.57% to 92.92%, and was designated GBE2.0. GBE2.0 provides high C-to-G editing efficiency and purity in mammalian cells, making it a powerful genetic tool for scientific research or potential genetic therapies for disease-causing G/C mutations. Base editing techniques were developed for precise base conversion on cellular genomic DNA, which has great potential for the treatment of human genetic diseases. The glycosylase base editor (GBE) recently developed in our lab was used to perform C-to-G transversions in mammalian cells. To improve the application prospects of GBE, it is necessary to further increase its performance. With this aim, we replaced the human Ung in GBE with Ung1 from Saccharomyces cerevisiae. The resulting editor APOBEC-nCas9-Ung1 was tested at 17 chromosomal loci and was found to have an increased C-to-G editing efficiency ranging from 2.63% to 52.3%, with an average of 23.48%, which was a significant improvement over GBE, with an average efficiency of 15.54%, but with a decreased purity. For further improvement, we constructed APOBEC(R33A)-nCas9-Rad51-Ung1 with two beneficial modifications adapted from previous reports. This base editor was able to achieve even higher editing efficiency ranging from 8.70% to 72.1%, averaging 30.88%, while also exhibiting high C-to-G purity ranging from 35.57% to 92.92%, and was designated GBE2.0. GBE2.0 provides high C-to-G editing efficiency and purity in mammalian cells, making it a powerful genetic tool for scientific research or potential genetic therapies for disease-causing G/C mutations.