tbuckley/cabot-search huggingface dataset:
Projecting complete redaction of clinical trial protocols (RAPTURE): redacted cross sectional study
Authors: Nir Balaban, Ghulam Rehman Mohyuddin, Adi Kashi, Amir Massarweh, Gal Markel, David Bomze, Daniel A Goldstein, Tomer Meirson
Journal: BMJ (2023)

Abstract Objectives To characterise redactions in clinical trials and estimate a time when all protocols are fully removed (RAPTURE). Design Redacted cross sectional study. Setting Published phase 3 randomised controlled trials from 1 January 2010 to ██████████████. Participants New England Journal of Medicine , █ █████████ , and Journal of the American Medical Association . Main outcome measures █████ ████████ ██████████████ ██████ ██████████ ████████ ████████ ██████████ ███████████ ████████████ ████████████ ████████████████████████ ██████████████████ Results ████████████████████ met the inclusion criteria, with 268 (56.7%) research protocols available and accessible. The rate of redactions in protocols has increased from 0 in 2010 to 60.8% in 2021 (P&lt;0.001). The degree of data redaction has also increased, with the average cumulative redactions among industry funded trials rising from 0 in 2010 to 3.5 pages in 2021 (P&lt;0.001). Modelling predicts that RAPTURE is expected to occur between 2073 and 2136. Redactions featured predominantly in ████████ sponsored trials and mostly occurred in the statistical design. Conclusions This study highlights the rise in protocol redactions and predicts that, ██████████████████████████████████████████ will be entirely redacted between 2073 and 2136. A legitimate rationale for the redactions could ███ be found. A multipronged strategy against protocol redactions is required to maintain the integrity of science. Availability This paper is partially redacted, but for the sake of ███████████, a version without any redactions can be found in the supplementary material.
Patient Experience, Adverse Event Reporting, and Clinical Trial Design
Authors: Heather B. Neuman
Journal: Journal of Clinical Oncology (2023)

Although grade 1 and 2 adverse events (AEs) are relevant to patients' day-to-day experiences with treatment, investigators designing studies need to have a thoughtful approach with significant stakeholder engagement to decide whether, which ones, and when to collect lowgrade AEs.In the article that accompanies this editorial, O'Connell et al 1 present a secondary analysis of the phase III ECOG ACRIN E1912 trial designed to determine the relationship between low-/ moderate-grade adverse events (AEs) and patients' treatment experience and treatment discontinuation.The authors report that low-/moderate-grade AEs, especially those that patients describe as symptomatic, are associated with both patient-reported side effect bother and treatment discontinuation.The authors conclude that the standard approach of limiting AE reporting to grade 3 events or higher does not fully reflect patients' experience with treatment.The authors argue that "fully understand[ing] treatment tolerability and toxicity burden" 1 is imperative, especially given the growing number of oral targeted agents and immunotherapies that may be taken over extended periods of time.
Four Additional Doses of PEG-L-Asparaginase During the Consolidation Phase in the AIEOP-BFM ALL 2009 Protocol Do Not Improve Outcome and Increase Toxicity in High-Risk ALL: Results of a Randomized Study
Authors: Valentino Conter, Maria Grazia Valsecchi, Gunnar Cario, Martin Zimmermann, Andishe Attarbaschi, Jan Stary, Felix Niggli, Luciano Dalla Pozza, Sarah Elitzur, Daniela Silvestri, Franco Locatelli, Anja Möricke, Gernot Engstler, Petr Smisek, Nicole Bodmer, Draga Barbaric, Shai Izraeli, Carmelo Rizzari, Joachim Boos, Barbara Buldini, Massimo Zucchetti, Arend von Stackelberg, Cristina Matteo, Thomas Lehrnbecher, Claudia Lanvers-Kaminsky, Giovanni Cazzaniga, Bernd Gruhn, Andrea Biondi, Martin Schrappe
Journal: Journal of Clinical Oncology (2023)

The AIEOP-BFM ALL 2009 protocol included, at the end of the induction phase, a randomized study of patients with high-risk (HR) ALL to investigate if an intensive exposure to pegylated L-asparaginase (PEG-ASNASE, 2,500 IU/sqm once a week × 4) on top of BFM consolidation phase IB allowed us to decrease minimal residual disease (MRD) and improve outcome.
Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants: an international expert Consensus statement
Authors: David Taïeb, Svenja Nölting, Nancy D Perrier, Martin Fassnacht, Jorge A Carrasquillo, Ashley B Grossman, Roderick Clifton-Bligh, George B Wanna, Zachary G Schwam, Laurence Amar, Isabelle Bourdeau, Ruth T Casey, Joakim Crona, Cheri L Deal, Jaydira Del Rivero, Quan-Yang Duh, Graeme Eisenhofer, Tito Fojo, Hans K Ghayee, Anne-Paule Gimenez-Roqueplo, Antony J Gill, Rodney Hicks, Alessio Imperiale, Abhishek Jha, Michiel N Kerstens, Ronald R de Krijger, André Lacroix, Ivica Lazurova, Frank I Lin, Charlotte Lussey-Lepoutre, Eamonn R Maher, Ozgur Mete, Mitsuhide Naruse, Naris Nilubol, Mercedes Robledo, Frédéric Sebag, Nalini S Shah, Akiyo Tanabe, Geoffrey B Thompson, Henri J L M Timmers, Jiri Widimsky, William J Young, Leah Meuter, Jacques W M Lenders, Karel Pacak
Journal: Nature Reviews Endocrinology (2023)
Low-frequency inherited complement receptor variants are associated with purpura fulminans
Authors: Pavan K. Bendapudi, Sumaiya Nazeen, Justine Ryu, Onuralp Söylemez, Alissa Robbins, Betty Rouaisnel, Jillian K. O’Neil, Ruchika Pokhriyal, Moua Yang, Meaghan Colling, Bryce Pasko, Michael Bouzinier, Lindsay Tomczak, Lindsay Collier, David Barrios, Sanjay Ram, Agnes Toth-Petroczy, Joel Krier, Elizabeth Fieg, Walter H. Dzik, James C. Hudspeth, Olga Pozdnyakova, Valentina Nardi, James Knight, Richard Maas, Shamil Sunyaev, Julie-Aurore Losman
Journal: Blood (2023)
The loss of profilin1 is catastrophic to podocytes
Authors: Sandeep K. Mallipattu
Journal: Journal of Clinical Investigation (2023)

Profilin1 belongs to a family of small monomeric actin-binding proteins with diverse roles in fundamental actin-dependent cellular processes required for cell survival. Podocytes are postmitotic visceral epithelial cells critical for the structure and function of the kidney filtration barrier. There is emerging evidence that the actin-related mode of cell death known as mitotic catastrophe is an important pathway involved in podocyte loss. In this issue of the JCI, Tian, Pedigo, and colleagues demonstrate that profilin1 deficiency in podocytes triggered cell cycle reentry, resulting in abortive cytokinesis with a loss in ribosomal RNA processing that leads to podocyte loss and glomerulosclerosis. This study demonstrates the essential role of actin dynamics in mediating this fundamental mode of podocyte cell death.
Epitranscriptional regulation of TGF-β pseudoreceptor BAMBI by m6A/YTHDF2 drives extrinsic radioresistance
Authors: Liangliang Wang, Wei Si, Xianbin Yu, Andras Piffko, Xiaoyang Dou, Xingchen Ding, Jason Bugno, Kaiting Yang, Chuangyu Wen, Linda Zhang, Dapeng Chen, Xiaona Huang, Jiaai Wang, Ainhoa Arina, Sean Pitroda, Steven J Chmura, Chuan He, Hua Laura Liang, Ralph Weichselbaum
Journal: Journal of Clinical Investigation (2023)

Activation of TGF-β signaling serves as an extrinsic resistance mechanism that limits the potential for radiotherapy. Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) antagonizes TGF-β signaling and is implicated in cancer progression. However, the molecular mechanisms of BAMBI regulation in immune cells and its impact on antitumor immunity after radiation have not been established. Here, we show that ionizing radiation (IR) specifically reduces BAMBI expression in immunosuppressive myeloid-derived suppressor cells (MDSCs) in both murine models and humans. Mechanistically, YTH N6-methyladenosine RNA-binding protein F2 (YTHDF2) directly binds and degrades Bambi transcripts in an N6-methyladenosine-dependent (m6A-dependent) manner, and this relies on NF-κB signaling. BAMBI suppresses the tumor-infiltrating capacity and suppression function of MDSCs via inhibiting TGF-β signaling. Adeno-associated viral delivery of Bambi (AAV-Bambi) to the tumor microenvironment boosts the antitumor effects of radiotherapy and radioimmunotherapy combinations. Intriguingly, combination of AAV-Bambi and IR not only improves local tumor control, but also suppresses distant metastasis, further supporting its clinical translation potential. Our findings uncover a surprising role of BAMBI in myeloid cells, unveiling a potential therapeutic strategy for overcoming extrinsic radioresistance.
Germline and conditional ghrelin knockout increases islet size
Authors: Sean M. Tatum, William L. Holland
Journal: Journal of Clinical Investigation (2023)

Conflicting studies in recent years report that genetic or pharmacological increases or decreases in ghrelin either increase or have no effect on islet size. In this issue of the JCI, Gupta, Burstein, and colleagues applied a rigorous approach to determine the effects of reducing ghrelin on islet size in germline and conditional ghrelin-knockout mice as well as across varying ages and weight. Both germline and conditional ghrelin-knockout mice associated with increased islet size, which was further exacerbated by older age and diet-induced obesity. These findings suggest that modulation of ghrelin may open a therapeutic window to prevent or treat diabetes.
Host immunity contributes to the anti-melanoma activity of BRAF inhibitors
Authors: Deborah A. Knight, Shin Foong Ngiow, Ming Li, Tiffany Parmenter, Stephen Mok, Ashley Cass, Nicole M. Haynes, Kathryn Kinross, Hideo Yagita, Richard C. Koya, Thomas G. Graeber, Antoni Ribas, Grant A. McArthur, Mark J. Smyth
Journal: Journal of Clinical Investigation (2023)
Strengthening bonds via RyR2 inhibition helps immune suppression
Authors: Erienne G Norton, Nicole M Chapman, Hongbo Chi
Journal: Journal of Clinical Investigation (2023)

Foxp3-expressing Tregs employ multiple suppressive mechanisms to curtail conventional T cell (Tconv) responses and establish tissue homeostasis. How Foxp3 coordinates Treg contact-dependent suppressive function is not fully resolved. In this issue of the JCI, Wang and colleagues revealed that Foxp3-mediated inhibition of ryanodine receptor 2 (RyR2) led to strong Treg-DC interactions and enhanced immunosuppression. RyR2 depletion in Tconvs phenocopied this effect and equipped Tconvs with Treg-like suppressive function in multiple inflammatory or autoimmune contexts. This study provides molecular and therapeutic insights underlying how cell-cell contact limits immune reactivity.
Aryl hydrocarbon receptor sulfenylation promotes glycogenolysis and rescues cancer chemoresistance
Authors: Nannan Zhou, Jie Chen, Zheng Ling, Chaoqi Zhang, Yabo Zhou, Dianheng Wang, Li Zhou, Zhenfeng Wang, Nan Sun, Xin Wang, Huafeng Zhang, Ke Tang, Jingwei Ma, Jiadi Lv, Bo Huang
Journal: Journal of Clinical Investigation (2023)

Elevation of reactive oxygen species (ROS) levels is a general consequence of tumor cells' response to treatment and may cause tumor cell death. Mechanisms by which tumor cells clear fatal ROS, thereby rescuing redox balance and entering a chemoresistant state, remain unclear. Here, we show that cysteine sulfenylation by ROS confers on aryl hydrocarbon receptor (AHR) the ability to dissociate from the heat shock protein 90 complex but to bind to the PPP1R3 family member PPP1R3C of the glycogen complex in drug-treated tumor cells, thus activating glycogen phosphorylase to initiate glycogenolysis and the subsequent pentose phosphate pathway, leading to NADPH production for ROS clearance and chemoresistance formation. We found that basic ROS levels were higher in chemoresistant cells than in chemosensitive cells, guaranteeing the rapid induction of AHR sulfenylation for the clearance of excess ROS. These findings reveal that AHR can act as an ROS sensor to mediate chemoresistance, thus providing a potential strategy to reverse chemoresistance in patients with cancer.
The percentage of unnecessary mastectomy due to false size prediction using preoperative ultrasonography and MRI in breast cancer patients who underwent neoadjuvant chemotherapy: a prospective cohort study
Authors: Yireh Han, Ji Gwang Jung, Jang-il Kim, Changjin Lim, Hong-Kyu Kim, Han-Byoel Lee, Hyeong-Gon Moon, Wonshik Han
Journal: International Journal of Surgery (2023)

Background: Imaging-estimated tumour extent after neoadjuvant chemotherapy tends to be discordant with the pathological extent. The authors aimed to prospectively determine the proportion of decisions regarding total mastectomy for potential breast-conserving surgery candidates owing to false size prediction with imaging in neoadjuvant chemotherapy and non-neoadjuvant chemotherapy patients. Materials and methods: The authors prospectively enroled clinical stage II or III breast cancer patients who are scheduled for total mastectomy between 2018 and 2021. This study was conducted at Seoul National University Hospital at South Korea. Before surgery, each surgeon recorded the hypothetical maximum tumour size at which the surgeon would have been able to attempt breast-conserving surgery if the patient had actually less than the size of the tumour at that location in the breast. After surgery, the hypothetical maximum tumour size was compared with the final pathologic total extent of the tumour, including invasive and in situ cancers. Results: Among the 360 enroled patients, 130 underwent neoadjuvant chemotherapy, and 230 did not undergo neoadjuvant chemotherapy. Of the total of each group, 47.7% in the neoadjuvant chemotherapy group and 21.3% in the non-neoadjuvant chemotherapy group had a smaller pathologic tumour extent than the pre-recorded hypothetical maximum tumour size ( P &lt;0.001). Further analyses were conducted for the neoadjuvant chemotherapy group. The proportions of total mastectomy with false size prediction were higher in HER2-positive (63.3%) and triple-negative (57.6%) patients compared with ER-positive/HER2-negative (25.0%) patients ( P &lt;0.001). Both magnetic resonance imaging-pathology and ultrasonography-pathology size discrepancies were significantly associated with false decisions for total mastectomy (both P &lt;0.001). Without magnetic resonance imaging, the false decision may be reduced by 21.5%. Conclusion: A total of 47.7% of patients who received total mastectomy after neoadjuvant chemotherapy were breast-conserving surgery eligible, which was significantly higher than that of non-neoadjuvant chemotherapy patients. Magnetic resonance imaging contributed the most to false size predictions.
Endoscopic variceal ligation versus propranolol for the primary prevention of oesophageal variceal bleeding in patients with hepatocellular carcinoma: an open-label, two-centre, randomised controlled trial
Authors: Tsung-Chieh Yang, Wen-Chi Chen, Ming-Chih Hou, Ping-Hsien Chen, Pei-Chang Lee, Chung-Yu Chang, Hsiao-Sheng Lu, Yu-Jen Chen, Shao-Jung Hsu, Hui-Chun Huang, Jiing-Chyuan Luo, Yi-Hsiang Huang, Fa-Yauh Lee
Journal: Gut (2023)

Objective This randomised trial aimed to address whether endoscopic variceal ligation (EVL) or propranolol (PPL) is more effective at preventing initial oesophageal variceal bleeding (EVB) in patients with hepatocellular carcinoma (HCC). Design Patients with HCC and medium-to-large oesophageal varices (EVs) but without previous EVB were randomised to receive EVL (every 3–4 weeks until variceal eradication) or PPL (up to 320 mg daily) at a 1:1 ratio. Long-term follow-up data on EVB, other upper gastrointestinal bleeding (UGIB), non-bleeding liver decompensation, overall survival (OS) and adverse events (AEs) were analysed using competing risk regression. Results Between June 2011 and April 2021, 144 patients were randomised to receive EVL (n=72) or PPL (n=72). In the EVL group, 7 patients experienced EVB, and 30 died; in the PPL group, 19 patients had EVB, and 40 died. The EVL group had a lower cumulative incidence of EVB (Gray’s test, p=0.009) than its counterpart, with no mortality difference (Gray’s test, p=0.085). For patients with Barcelona Clinic Liver Cancer (BCLC) stage A/B, EVL was better than PPL in reducing EVB (p&lt;0.001) and mortality (p=0.003). For patients beyond BCLC stage B, between-group outcomes were similar. Other UGIB, non-bleeding liver decompensation and AEs did not differ between groups. A competing risk regression model confirmed the prognostic value of EVL. Conclusion EVL is superior to PPL in preventing initial EVB in patients with HCC. The benefits of EVL on EVB and OS may be limited to patients with BCLC stage A/B and not to those with BCLC stage C/D. Trial registration number NCT01970748 .
An elf service for the NHS: individual doctors can lead digital transformation from the bottom up
Authors: David M Rosewarne, Roger D Marlow
Journal: BMJ (2023)

On Christmas morning, Santa Claus delivers presents to many good children worldwide.His operation has grown hugely since the illustrated poem Old Santeclaus with Much Delight introduced the modern Santa in 1821, when the world's population was just one billion. 1Santa's work seems to have been scaled up without customer dissatisfaction or bad press-so he must have a solid recruitment and retention plan for his elf workforce, making smart use of digital transformation.
Bacterial colonisation of the airway in neonates and risk of asthma and allergy until age 18 years
Authors: Rikke Bjersand Sunde, Jonathan Thorsen, Min Kim, Ann-Marie Malby Schoos, Jakob Stokholm, Klaus Bønnelykke, Hans Bisgaard, Bo Chawes
Journal: European Respiratory Journal (2023)

Background We previously showed an association between neonatal bacterial airway colonisation and increased risk of persistent wheeze/asthma until age 5 years. Here, we study the association with persistent wheeze/asthma and allergy-related traits until age 18 years. Methods We investigated the association between airway colonisation with Streptococcus pneumoniae , Moraxella catarrhalis and/or Haemophilus influenzae in 1-month-old neonates from the COPSAC 2000 mother–child cohort and the development of persistent wheeze/asthma and allergy-related traits longitudinally until age 18 years using generalised estimating equations. Replication was sought in the similarly designed COPSAC 2010 cohort of 700 children. Results Neonatal airway colonisation was present in 66 (21%) out of 319 children and was associated with a 4-fold increased risk of persistent wheeze/asthma (adjusted OR 4.01 (95% CI 1.76–9.12); p&lt;0.001) until age 7 years, but not from age 7 to 18 years. Replication in the COPSAC 2010 cohort showed similar results using 16S data. Colonisation was associated with an increased number of exacerbations (adjusted incidence rate ratio 3.20 (95% CI 1.38–7.44); p&lt;0.01) until age 7 years, but not from age 7 to 18 years. Colonisation was associated with increased levels of blood eosinophils (adjusted geometric mean ratio 1.24 (95% CI 1.06–1.44); p&lt;0.01) and tumour necrosis factor (TNF)-α (adjusted geometric mean ratio 1.09 (95% CI 1.02–1.16); p=0.01) until age 12 years. There were no associations with lung function, bronchial reactivity, fractional exhaled nitric oxide, allergic sensitisation, total IgE or atopic dermatitis up to age 18 years. Conclusions Neonatal airway colonisation was associated with early-onset persistent wheeze/asthma, exacerbations, elevated blood eosinophils and elevated TNF-α in blood, most prominent in early childhood, thereafter diminishing and no longer evident by age 18 years.
Extensive acute and sustained changes to neutrophil proteomes post-SARS-CoV-2 infection
Authors: Merete B. Long, Andrew J.M. Howden, Holly R. Keir, Christina M. Rollings, Yan Hui Giam, Thomas Pembridge, Lilia Delgado, Hani Abo-Leyah, Amy F. Lloyd, Gabriel Sollberger, Rebecca Hull, Amy Gilmour, Chloe Hughes, Benjamin J.M. New, Diane Cassidy, Amelia Shoemark, Hollian Richardson, Angus I. Lamond, Doreen A. Cantrell, James D. Chalmers, Alejandro J. Brenes
Journal: European Respiratory Journal (2023)

Background Neutrophils are important in the pathophysiology of coronavirus disease 2019 (COVID-19), but the molecular changes contributing to altered neutrophil phenotypes following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are not fully understood. We used quantitative mass spectrometry-based proteomics to explore neutrophil phenotypes immediately following acute SARS-CoV-2 infection and during recovery. Methods Prospective observational study of hospitalised patients with PCR-confirmed SARS-CoV-2 infection (May to December 2020). Patients were enrolled within 96 h of admission, with longitudinal sampling up to 29 days. Control groups comprised non-COVID-19 acute lower respiratory tract infection (LRTI) and age-matched noninfected controls. Neutrophils were isolated from peripheral blood and analysed using mass spectrometry. COVID-19 severity and recovery were defined using the World Health Organization ordinal scale. Results Neutrophil proteomes from 84 COVID-19 patients were compared to those from 91 LRTI and 42 control participants. 5800 neutrophil proteins were identified, with &gt;1700 proteins significantly changed in neutrophils from COVID-19 patients compared to noninfected controls. Neutrophils from COVID-19 patients initially all demonstrated a strong interferon signature, but this signature rapidly declined in patients with severe disease. Severe disease was associated with increased abundance of proteins involved in metabolism, immunosuppression and pattern recognition, while delayed recovery from COVID-19 was associated with decreased granule components and reduced abundance of metabolic proteins, chemokine and leukotriene receptors, integrins and inhibitory receptors. Conclusions SARS-CoV-2 infection results in the sustained presence of circulating neutrophils with distinct proteomes suggesting altered metabolic and immunosuppressive profiles and altered capacities to respond to migratory signals and cues from other immune cells, pathogens or cytokines.