tbuckley/cabot-search huggingface dataset:
Preclinical validation of a potent γ-secretase modulator for Alzheimer’s disease prevention
Authors: Kevin D. Rynearson, Moorthi Ponnusamy, Olga Prikhodko, Yuhuan Xie, Can Zhang, Phuong Nguyen, Brenda Hug, Mariko Sawa, Ann Becker, Brian Spencer, Jazmin Florio, Michael Mante, Bahar Salehi, Carlos Arias, Douglas Galasko, Brian P. Head, Graham Johnson, Jiunn H. Lin, Steven K. Duddy, Robert A. Rissman, William C. Mobley, Gopal Thinakaran, Rudolph E. Tanzi, Steven L. Wagner
Journal: The Journal of Experimental Medicine (2021)

A potent γ-secretase modulator (GSM) has been developed to circumvent problems associated with γ-secretase inhibitors (GSIs) and to potentially enable use in primary prevention of early-onset familial Alzheimer’s disease (EOFAD). Unlike GSIs, GSMs do not inhibit γ-secretase activity but rather allosterically modulate γ-secretase, reducing the net production of Aβ42 and to a lesser extent Aβ40, while concomitantly augmenting production of Aβ38 and Aβ37. This GSM demonstrated robust time- and dose-dependent efficacy in acute, subchronic, and chronic studies across multiple species, including primary and secondary prevention studies in a transgenic mouse model. The GSM displayed a &amp;gt;40-fold safety margin in rats based on a comparison of the systemic exposure (AUC) at the no observed adverse effect level (NOAEL) to the 50% effective AUC or AUCeffective, the systemic exposure required for reducing levels of Aβ42 in rat brain by 50%.
Increasing recruitment into covid-19 trials: fund nursing trials
Authors: David A Richards
Journal: BMJ (2021)

professor of mental health services research and head of nursing One can only agree wholeheartedly with Darzi and colleagues' call for better recruitment into SARS-COV-2 treatment trials. 1 Sadly, no mention is made of trials for nursing care.Patient experience of nursing care is correlated with safety, clinical effectiveness, care quality, treatment outcomes, and service use, yet no specific pandemic nursing care guidelines exist, and nurses remain in the dark as to the best way to care for SARS-COV-2 patients.In the absence of effective treatments, nursing care is the primary intervention many patients receive while waiting to recover or not.The prime minister, like many patients, highlighted nursing care and nurses as vital to his own recovery.And yet, the only UK funded trial of a nursing care intervention for non-invasively ventilated patients-the National Institute for Health Research (NIHR) UK Research and Innovation Covid-Nurse cluster randomised controlled trial-has struggled more than most to recruit sites and patient participants.While all trials are vital, better balance is required.Nurses, at the forefront of caring for patients with covid-19, deserve the highest quality evidence to deliver the finest care they can.It is frustrating for the nursing profession when externally funded and well designed attempts to gather this evidence are left so far down the pecking order when research infrastructure support is allocated that desperately needed knowledge is delayed.Darzi and colleagues would no doubt agree with us that nurses are critical to patient recovery.Would they also agree that this care should be underpinned by best evidence and that the NIHR and NHS should ensure these data are prioritised and collected as urgently as possible?
Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic<i>ROS1</i>Fusion–Positive Non–Small-Cell Lung Cancer
Authors: Rafal Dziadziuszko, Matthew G. Krebs, Filippo De Braud, Salvatore Siena, Alexander Drilon, Robert C. Doebele, Manish R. Patel, Byoung Chul Cho, Stephen V. Liu, Myung-Ju Ahn, Chao-Hua Chiu, Anna F. Farago, Chia-Chi Lin, Christos S. Karapetis, Yu-Chung Li, Bann-mo Day, David Chen, Timothy R. Wilson, Fabrice Barlesi
Journal: Journal of Clinical Oncology (2021)

Genetic rearrangements of the tyrosine receptor kinase ROS proto-oncogene 1 (ROS1) are oncogenic drivers in non-small-cell lung cancer (NSCLC). We report the results of an updated integrated analysis of three phase I or II clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2) of the ROS1 tyrosine kinase inhibitor, entrectinib, in ROS1 fusion-positive NSCLC.The efficacy-evaluable population included adults with locally advanced or metastatic ROS1 fusion-positive NSCLC with or without CNS metastases who received entrectinib ≥ 600 mg orally once per day. Co-primary end points were objective response rate (ORR) assessed by blinded independent central review and duration of response (DoR). Secondary end points included progression-free survival (PFS), overall survival (OS), intracranial ORR, intracranial DoR, intracranial PFS, and safety.In total, 161 patients with a follow-up of ≥ 6 months were evaluable. The median treatment duration was 10.7 months (IQR, 6.4-17.7). The ORR was 67.1% (n = 108, 95% CI, 59.3 to 74.3), and responses were durable (12-month DoR rate, 63%, median DoR 15.7 months). The 12-month PFS rate was 55% (median PFS 15.7 months), and the 12-month OS rate was 81% (median OS not estimable). In 24 patients with measurable baseline CNS metastases by blinded independent central review, the intracranial ORR was 79.2% (n = 19; 95% CI, 57.9 to 92.9), the median intracranial PFS was 12.0 months (95% CI, 6.2 to 19.3), and the median intracranial DoR was 12.9 months (12-month rate, 55%). The safety profile in this updated analysis was similar to that reported in the primary analysis, and no new safety signals were found.Entrectinib continued to demonstrate a high level of clinical benefit for patients with ROS1 fusion-positive NSCLC, including patients with CNS metastases.
ASSET: Alternative schedule sunitinib in metastatic renal cell carcinoma (RCC)—Cardiopulmonary exercise testing (CPET).
Authors: Michael Roger Harrison, David Bartlett, Tian Zhang, Andrew J. Armstrong, Aubrie Coburn, Brian Coyne, Monika Anand, Taofik Oyekunle, Yuan Wu, Michel Khouri, Daniel J. George
Journal: Journal of Clinical Oncology (2021)

300 Background: Sunitinib (SUN) is a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) approved for treatment of advanced RCC and high risk RCC after nephrectomy. Evidence suggests that a 2 week (wk) on, 1 wk off schedule (2/1) of SUN administration may be more tolerable than the standard 4 wk on, 2 wk off schedule (4/2). We investigated changes in cardiopulmonary function and related parameters over time in RCC patients treated with both schedules of SUN. Methods: Patients starting SUN for RCC, with KPS ≥80 and normal organ and marrow function, were enrolled and randomized 1:1 to schedule 4/2 or 2/1. Subjects were required to be able to walk and jog on a treadmill and to complete an acceptable CPET at baseline (BL). Primary endpoint was change in peak oxygen uptake (VO 2 peak) on both schedules at 12 wk from BL. Key secondary endpoints were change from BL to 12 wk in: left ventricular ejection fraction (LVEF), upper and lower body strength (1-RM), functional measures (chair stand, timed up-and-go [TUG], 6-minute walk test [6MWT], quality of life (QOL; FACT-Fatigue, FKSI-19), anxiety and depression (HADS) and exercise behavior (Godin Leisure Score). ANCOVA models controlling for baseline values were used to analyze the primary and secondary endpoints. Results: Between 11/20/2017 and 6/24/2019, 9 out of a planned 30 patients consented to participate at Duke. Two patients declined to participate and 7 patients were enrolled on study: 4 on Arm A and 3 on Arm B. All 7 patients completed the 12 wk study. Median age, BMI, and VO 2 peak were 65 yrs, 30.5 kg/m 2 , and 19.2 ml kg −1 min −1 . We observed no difference in the primary endpoint of VO 2 peak between arms (p=0.84). We report BL to 12 wk change scores for all patients starting SUN (Table). In addition, mean change scores (SE) for QOL by FACIT-Fatigue and FKSI-19 were -2.88 (1.5) and 1.2 [9.8]; anxiety and depression by HADS 1.14 (1.3); and physical activity 1.14 (1.7). Conclusions: We observed non-significant declines in most measures of physical fitness and function during the first 12 wk of treatment with SUN. To our knowledge, this is the first reported study of these parameters in patients with RCC. Given that a VEGF TKI, alone and with an immune checkpoint inhibitor, remains a standard of care for metastatic ccRCC, studies should be undertaken to examine whether exercise training can prevent declines in physical fitness and function. Clinical trial information: NCT03109015 . [Table: see text]
Efficacy of enzalutamide (ENZA) plus androgen deprivation therapy (ADT) in men with <i>de novo</i> (M1) metastatic hormone-sensitive prostate cancer (mHSPC) versus progression to mHSPC (M0): Post hoc analysis of the phase III ARCHES trial.
Authors: Arun Azad, Arnauld Villers, Boris Alekseev, Russell Zelig Szmulewitz, Antonio Alcaraz, Neal D. Shore, Daniel Peter Petrylak, Jeffrey Holzbeierlein, Francisco Gomez-Veiga, Brad Rosbrook, Fabian Zohren, Ho-Jin Lee, Gabriel P. Haas, Taro Iguchi, Arnulf Stenzl, Andrew J. Armstrong
Journal: Journal of Clinical Oncology (2021)

102 Background: In ARCHES (NCT02677896) ENZA + ADT reduced the risk of radiographic progression-free survival (rPFS) events, primary endpoint, and improved key secondary endpoints vs PBO + ADT in men with mHSPC (also known as metastatic castration-sensitive PC). Given the progressive nature of PC, this exploratory analysis evaluated efficacy of ENZA + ADT in patients (pts) who progressed to M1 HSPC following initial diagnosis (M0) vs pts who presented with de novo mHSPC at diagnosis (M1). Methods: mHSPC pts (n=1150) were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume and prior docetaxel use. In this post hoc analysis, pts previously centrally categorized as MX/unknown metastasis at initial diagnosis (n=213) were adjudicated as either M0 or M1 disease following review of their medical profiles; efficacy outcomes were compared according to M0 vs M1 disease at initial diagnosis. Results: In this analysis, 246 pts (ENZA n=117; PBO n=129) had M0 and 890 pts (ENZA n=448; PBO n=442) had M1 disease at initial diagnosis; metastatic status of 14 pts (ENZA n=9; PBO n=5) were unknown (data not shown). Baseline characteristics were generally comparable between treatment arms; however, a greater proportion of M1 pts had high disease volume (n=606; 68.1% vs n=116; 47.2% [M0]) and prior docetaxel (n=173, 19.4% vs n=29, 11.8% [M0]). ENZA + ADT improved rPFS vs PBO + ADT irrespective of M0 or M1 disease at diagnosis; similar improvements were observed for secondary endpoints including prostate-specific antigen (PSA) and objective responses, time to PSA progression, time to new antineoplastic therapy (Table). Safety profiles were generally similar between subgroups and the overall population; exceptions include higher fatigue in M0 ENZA and PBO treatment arms. Conclusions: This post hoc analysis demonstrates clinical benefit of ENZA + ADT vs PBO + ADT based on rPFS and secondary endpoints in men who progressed from M0 to M1 HSPC and those with de novo M1 HSPC. Clinical trial information: NCT02677896. [Table: see text]
S-Nitrosylation of Histone Deacetylase 2 by Neuronal Nitric Oxide Synthase as a Mechanism of Diastolic Dysfunction
Authors: Somy Yoon, Mira Kim, Hangyeol Lee, Gaeun Kang, Kenneth Bedi, Kenneth B. Margulies, Rajan Jain, Kwang-Il Nam, Hyun Kook, Gwang Hyeon Eom
Journal: Circulation (2021)

Background: Although the clinical importance of heart failure with preserved ejection fraction has been extensively explored, most therapeutic regimens, including nitric oxide (NO) donors, lack therapeutic benefit. Although the clinical characteristics of heart failure with preserved ejection fraction are somewhat heterogeneous, diastolic dysfunction (DD) is one of the most important features. Here we report that neuronal NO synthase (nNOS) induces DD by S-nitrosylation of HDAC2 (histone deacetylase 2). Methods: Two animal models of DD—SAUNA (SAlty drinking water/Unilateral Nephrectomy/Aldosterone) and mild transverse aortic constriction mice—as well as human heart samples from patients with left ventricular hypertrophy were used. Genetically modified mice that were either nNOS-ablated or HDAC2 S-nitrosylation–resistant were also challenged. N(ω)-propyl- L -arginine, an nNOS selective inhibitor, and dimethyl fumarate, an NRF2 (nuclear factor erythroid 2–related factor 2) inducer, were used. Molecular events were further checked in human left ventricle specimens. Results: SAUNA or mild transverse aortic constriction stress impaired diastolic function and exercise tolerance without overt systolic failure. Among the posttranslational modifications tested, S-nitrosylation was most dramatically increased in both models. Utilizing heart samples from both mice and humans, we observed increases in nNOS expression and NO production. N(ω)-propyl- L -arginine alleviated the development of DD in vivo. Similarly, nNOS knockout mice were resistant to SAUNA stress. nNOS-induced S-nitrosylation of HDAC2 was relayed by transnitrosylation of GAPDH. HDAC2 S-nitrosylation was confirmed in both DD mouse and human left ventricular hypertrophy. S-nitrosylation of HDAC2 took place at C262 and C274. When DD was induced, HDAC2 S-nitrosylation was detected in wild-type mouse, but not in HDAC2 knock-in mouse heart that expressed HDAC2 C262A/C274A. In addition, HDAC2 C262A/C274A mice maintained normal diastolic function under DD stimuli. Gene delivery with adenovirus-associated virus 9 (AAV9)–NRF2, a putative denitrosylase of HDAC2, or pharmacological intervention by dimethyl fumarate successfully induced HDAC2 denitrosylation and mitigated DD in vivo. Conclusions: Our observations are the first to demonstrate a new mechanism underlying DD pathophysiology. Our results provide theoretical and experimental evidence to explain the ineffectiveness of conventional NO enhancement trials for improving DD with heart failure symptoms. More important, our results suggest that reduction of NO or denitrosylation of HDAC2 may provide a new therapeutic platform for the treatment of refractory heart failure with preserved ejection fraction.
Response to comments on the Letter to the Editor titled “Differentiating basal cell carcinoma from intradermal nevi along the eyelid margin with dermoscopy: A case series”
Authors: Natalie M. Williams, Cristian Navarrete-Dechent, Ashfaq A. Marghoob, Álvaro Abarzua-Araya, Gabriel Salerni, Natalia Jaimes
Journal: Journal of the American Academy of Dermatology (2021)
Antibody Responses in Seropositive Persons after a Single Dose of SARS-CoV-2 mRNA Vaccine
Authors: Florian Krammer, Komal Srivastava, Hala Alshammary, Angela A. Amoako, Mahmoud H. Awawda, Katherine F. Beach, Maria C. Bermúdez-González, Dominika A. Bielak, Juan M. Carreño, Rachel L. Chernet, Lily Q. Eaker, Emily D. Ferreri, Daniel L. Floda, Charles R. Gleason, Joshua Z. Hamburger, Kaijun Jiang, Giulio Kleiner, Denise Jurczyszak, Julia C. Matthews, Wanni A. Mendez, Ismail Nabeel, Lubbertus C.F. Mulder, Ariel J. Raskin, Kayla T. Russo, Ashley-Beathrese T. Salimbangon, Miti Saksena, Amber S. Shin, Gagandeep Singh, Levy A. Sominsky, Daniel Stadlbauer, Ania Wajnberg, Viviana Simon
Journal: New England Journal of Medicine (2021)

Responses of Seropositive Persons to a Single SARS-CoV-2 Vaccine Some persons who have recovered from Covid-19 have antibodies to the spike protein of SARS-CoV-2. In 43 such persons who had receive...
Macrophage SR-BI modulates autophagy via VPS34 complex and PPARα transcription of Tfeb in atherosclerosis
Authors: Huan Tao, Patricia G. Yancey, John L. Blakemore, Youmin Zhang, Lei Ding, W. Gray Jerome, Jonathan D. Brown, Kasey C. Vickers, MacRae F. Linton
Journal: Journal of Clinical Investigation (2021)

Autophagy modulates lipid turnover, cell survival, inflammation, and atherogenesis. Scavenger receptor class B type I (SR-BI) plays a crucial role in lysosome function. Here, we demonstrate that SR-BI regulates autophagy in atherosclerosis. SR-BI deletion attenuated lipid-induced expression of autophagy mediators in macrophages and atherosclerotic aortas. Consequently, SR-BI deletion resulted in 1.8- and 2.5-fold increases in foam cell formation and apoptosis, respectively, and increased oxidized LDL-induced inflammatory cytokine expression. Pharmacological activation of autophagy failed to reduce lipid content or apoptosis in Sr-b1-/- macrophages. SR-BI deletion reduced both basal and inducible levels of transcription factor EB (TFEB), a master regulator of autophagy, causing decreased expression of autophagy genes encoding VPS34 and Beclin-1. Notably, SR-BI regulated Tfeb expression by enhancing PPARα activation. Moreover, intracellular macrophage SR-BI localized to autophagosomes, where it formed cholesterol domains resulting in enhanced association of Barkor and recruitment of the VPS34-Beclin-1 complex. Thus, SR-BI deficiency led to lower VPS34 activity in macrophages and in atherosclerotic aortic tissues. Overexpression of Tfeb or Vps34 rescued the defective autophagy in Sr-b1-/- macrophages. Taken together, our results show that macrophage SR-BI regulates autophagy via Tfeb expression and recruitment of the VPS34-Beclin-1 complex, thus identifying previously unrecognized roles for SR-BI and potentially novel targets for the treatment of atherosclerosis.
What is the balance of benefits and harms for lung cancer screening with low-dose computed tomography?
Authors: Stephen H Bradley, Bethany Shinkins, Martyn PT Kennedy
Journal: Journal of the Royal Society of Medicine (2021)

After the National Lung Screening Trial (NLST)1 demonstrated improved lung cancer mortality almost a decade ago, hopes have been raised that low-dose computed tomography could be used to detect lung cancer in asymptomatic populations and improve outcomes by reducing the number of people diagnosed with advanced disease. The publication of the long-awaited Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON) trial last year2 has provided further evidence of a lung cancer mortality benefit and has provoked further calls to implement national population-based screening programmes, but the case for lung cancer screening remains controversial.
Compare and contrast: Detecting mammographic soft-tissue lesions with C<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" altimg="si1.svg"><mml:msup><mml:mrow /><mml:mn>2</mml:mn></mml:msup></mml:math>-Net
Authors: Yuhang Liu, Changsheng Zhou, Fandong Zhang, Qianyi Zhang, Siwen Wang, Juan Zhou, Fugeng Sheng, Xiaoqi Wang, Wanhua Liu, Yizhou Wang, Yizhou Yu, Guangming Lu
Journal: Medical Image Analysis (2021)
Progressive immune dysfunction with advancing disease stage in renal cell carcinoma
Authors: David A. Braun, Kelly Street, Kelly P. Burke, David L. Cookmeyer, Thomas Denize, Christina B. Pedersen, Satyen H. Gohil, Nicholas Schindler, Lucas Pomerance, Laure Hirsch, Ziad Bakouny, Yue Hou, Juliet Forman, Teddy Huang, Shuqiang Li, Ang Cui, Derin B. Keskin, John Steinharter, Gabrielle Bouchard, Maxine Sun, Erica M. Pimenta, Wenxin Xu, Kathleen M. Mahoney, Bradley A. McGregor, Michelle S. Hirsch, Steven L. Chang, Kenneth J. Livak, David F. McDermott, Sachet A. Shukla, Lars R. Olsen, Sabina Signoretti, Arlene H. Sharpe, Rafael A. Irizarry, Toni K. Choueiri, Catherine J. Wu
Journal: Cancer Cell (2021)
Abstract IA-09: Mapping cell structure across scales by fusing protein images and interactions
Authors: Trey Ideker
Journal: Clinical Cancer Research (2021)

Abstract Cancer cells are multi-scale structures with modular organization across at least four orders of magnitude. Two central approaches for mapping this structure – protein fluorescent imaging and protein interaction – each generate extensive datasets but of distinct qualities and resolutions that are typically treated separately. Here, I will describe ongoing efforts to reconcile the large-scale data emerging from protein imaging and protein affinity purification interaction screens to create unified maps of cancer cells. The core concept is to use machine learning to compute a suitable embedding for each dataset, then to use these data embeddings to produce a general measure of protein distance calibrated against cellular components of known size. The evolving map, called the Multi-Scale Integrated Cell (MuSIC 1.0), currently resolves 69 subcellular systems of which approximately half are undocumented. Based on these findings we have performed 134 additional affinity purifications, validating close subunit associations for the majority of systems. I will also discuss how these cell maps can be used to identify protein complexes, and larger-scale systems such as organelles, that are under significant selective pressure for somatic mutations in different tumor types. In many of these cases, the mutation burden of the complex is far more substantial than the mutation frequency of any of the individual genes that encode it. By integration across scales, MuSIC substantially increases the mapping resolution obtained from imaging while giving protein interactions a spatial dimension, paving the way to incorporate many molecular data types in proteome-wide maps of cells. This work is a collaboration between the Cancer Cell Mapping Initiative (CCMI), the Human Protein Atlas (HPA), and the BioPlex Resource. Citation Format: Trey Ideker. Mapping cell structure across scales by fusing protein images and interactions [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr IA-09.
Joseph Berke: counterculture revolutionary
Authors: John Illman
Journal: BMJ (2021)

Photo credit: Family photograph

The American born doctor and psychotherapist Joseph (“Joe”) Berke was a close ally of R D Laing, one of the 20th century’s most controversial psychiatrists. Berke took up a traineeship with Laing, who aspired to lead a revolution in the diagnosis and treatment of mental illness.

Laing, a Scot, commandeered a former community centre in east London for his most radical “anti-psychiatry” experiment. The sprawling Kingsley Hall became an asylum in the original Greek meaning of the word: a refuge or safe haven for mentally ill people. Residents were free to come and go as they chose. There were no locks on the doors and no anti-psychotic drugs.

It was no surprise that Laing and Berke got on so well. Berke maintained that the old “Bedlam” system of incarcerating people with mental illness and treating them with anti-psychotic drugs and electroconvulsive therapy exacerbated their suffering. He dismissed pharmaceutical treatments as “chemical restraints,” but had a big appetite for non-prescription drugs. He took lysergide with the one-time Harvard psychologist Timothy Leary, an evangelist for the mind expanding potential of psychedelic drugs.

Berke’s first patient at Kingsley Hall was its …