tbuckley/cabot-search huggingface dataset:
Neutrophil extracellular traps promote tPA-induced brain hemorrhage via cGAS in mice with stroke
Authors: Ranran Wang, Yuanbo Zhu, Zhongwang Liu, Luping Chang, Xiaofei Bai, Lijing Kang, Yongliang Cao, Xing Yang, Huilin Yu, Mei-Juan Shi, Yue Hu, Wenying Fan, Bing-Qiao Zhao
Journal: Blood (2021)

Abstract Intracerebral hemorrhage associated with thrombolytic therapy with tissue plasminogen activator (tPA) in acute ischemic stroke continues to present a major clinical problem. Here, we report that infusion of tPA resulted in a significant increase in markers of neutrophil extracellular traps (NETs) in the ischemic cortex and plasma of mice subjected to photothrombotic middle cerebral artery occlusion. Peptidylarginine deiminase 4 (PAD4), a critical enzyme for NET formation, is also significantly upregulated in the ischemic brains of tPA-treated mice. Blood–brain barrier (BBB) disruption after ischemic challenge in an in vitro model of BBB was exacerbated after exposure to NETs. Importantly, disruption of NETs by DNase I or inhibition of NET production by PAD4 deficiency restored tPA-induced loss of BBB integrity and consequently decreased tPA-associated brain hemorrhage after ischemic stroke. Furthermore, either DNase I or PAD4 deficiency reversed tPA-mediated upregulation of the DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS). Administration of cGAMP after stroke abolished DNase I–mediated downregulation of the STING pathway and type 1 interferon production and blocked the antihemorrhagic effect of DNase I in tPA-treated mice. We also show that tPA-associated brain hemorrhage after ischemic stroke was significantly reduced in cGas−/− mice. Collectively, these findings demonstrate that NETs significantly contribute to tPA-induced BBB breakdown in the ischemic brain and suggest that targeting NETs or cGAS may ameliorate thrombolytic therapy for ischemic stroke by reducing tPA-associated hemorrhage.
Allogeneic transplantation after PD-1 blockade for classic Hodgkin lymphoma
Authors: Reid W. Merryman, Luca Castagna, Laura Giordano, Vincent T. Ho, Paolo Corradini, Anna Guidetti, Beatrice Casadei, David A. Bond, Samantha Jaglowski, Michael A. Spinner, Sally Arai, Robert Lowsky, Gunjan L. Shah, Miguel-Angel Perales, Jean Marc Schiano De Colella, Didier Blaise, Alex F. Herrera, Geoffrey Shouse, Chloe Spilleboudt, Stephen M. Ansell, Yago Nieto, Talha Badar, Mehdi Hamadani, Tatyana A. Feldman, Lori Dahncke, Anurag K. Singh, Joseph P. McGuirk, Taiga Nishihori, Julio Chavez, Anthony V. Serritella, Justin Kline, Mohamad Mohty, Remy Dulery, Aspasia Stamatoulas, Roch Houot, Guillaume Manson, Marie-Pierre Moles-Moreau, Corentin Orvain, Kamal Bouabdallah, Dipenkumar Modi, Radhakrishnan Ramchandren, Lazaros Lekakis, Amer Beitinjaneh, Matthew J. Frigault, Yi-Bin Chen, Ryan C. Lynch, Stephen D. Smith, Uttam Rao, Michael Byrne, Jason T. Romancik, Jonathon B. Cohen, Sunita Nathan, Tycel Phillips, Robin M. Joyce, Maryam Rahimian, Asad Bashey, Hatcher J. Ballard, Jakub Svoboda, Valter Torri, Martina Sollini, Chiara De Philippis, Massimo Magagnoli, Armando Santoro, Philippe Armand, Pier Luigi Zinzani, Carmelo Carlo-Stella
Journal: Leukemia (2021)
Abstract PO-095: The PROState AI Cancer–Decision Support (PROSAIC-DS) pilot study: Clinical decision support technology and its role in prostate cancer MDT meetings
Authors: Vishal Santis, Deborah Enting, Vivek Patkar, Anastasia Chalkidou, John Fox, Danny Ruta, Jonathan K. Makanjuola
Journal: Clinical Cancer Research (2021)

Abstract Background Multidisciplinary teams (MDT/tumour boards) were first introduced in the 1990s and have experienced little change to their methodology since. Universally used for the treatment of prostate cancer (CaP) in the UK new interventions are proposed to improve MDT efficiency and patient outcomes. Clinical practice guidelines (CPGs), designed to increase the uptake of evidence-based practice, suffer from lack of proper implementation. There is increasing evidence to suggest a gap between CPGs and actual treatment and the use of artificial intelligence an (AI) systems can help to increase the efficiency of the MDT. Methods We evaluated differences in MDT concordance with guidelines in the primary treatment of localised or locally advanced prostate cancer using the Deontics AI based custom clinical decision support software (CDSS) software. 59 paper cases were created by an expert clinician, 9 of which were excluded as they did not meet eligibility criteria. The remaining 50 cases were provided to the CDSS for evaluation. Simultaneously, two physicians assessed each patient case and provided their treatment recommendations. The results were assessed for concordance with UK, European and American guidelines, inter-rater reliability and trends in concordance based on patient variables.Results Overall clinician concordance with guidelines was 76%, while total concordance with all three guidelines was 28%. Overall concordance was highest with NICE guidelines, while total concordance was highest for NCCN guidelines. Inter-rater reliability was highest for the NCCN guidelines. Age &amp;lt; 75 (p &amp;lt;0.001; odds ratio [OR], 35.000), prostate volume &amp;lt; 46.5ml (p =0.047; OR, 4.909), and a Gleason score ≠ 8 (p =0.013; OR, 12.333), were all significantly associated with increased guideline concordance in this study. Conclusions Concordance with CPGs needs to be improved in specific patient groups. This may reflect cognitive bias, cognitive overload, or conflicting guideline recommendations and evidence base. One potential solution may be the integration of CDSS technology into the MDT setting. Citation Format: Vishal Santis, Deborah Enting, Vivek Patkar, Anastasia Chalkidou, John Fox, Danny Ruta, Jonathan K. Makanjuola. The PROState AI Cancer–Decision Support (PROSAIC-DS) pilot study: Clinical decision support technology and its role in prostate cancer MDT meetings [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 PO-095.
COVID-19 drug practices risk antimicrobial resistance evolution
Authors: Ebrahim Afshinnekoo, Chandrima Bhattacharya, Ana Burguete-García, Eduardo Castro-Nallar, Youping Deng, Christelle Desnues, Emmanuel Dias-Neto, Eran Elhaik, Gregorio Iraola, Soojin Jang, Paweł P Łabaj, Christopher E Mason, Niranjan Nagarajan, Michael Poulsen, Bharath Prithiviraj, Rania Siam, Tieliu Shi, Haruo Suzuki, Johannes Werner, Maria Mercedes Zambrano, Malay Bhattacharyya
Journal: The Lancet Microbe (2021)

Antimicrobial resistance is one of the biggest challenges facing modern medicine. Because the management of COVID-19 is increasingly becoming dependent on pharmacological interventions, there is greater risk for accelerating the evolution and spread of antimicrobial resistance. A study in a tertiary hospital environment revealed concerning colonisation patterns of microbes during extended periods.1 It also highlighted the diversity of antimicrobial resistance gene reservoirs in hospitals that could facilitate the emergence and transmission of new modes of antibiotic resistance.
Abstract LT021: Targeting AXL favors an anti-tumorigenic tumor microenvironment that enhances immunotherapy responses by decreasing HIF-1a levels in cancer cells
Authors: Marie-Anne Goyette, Jean-Philippe Gratton, Jean-François Côté
Journal: Cancer Research (2021)

Abstract Breast cancer-related deaths are predominantly associated to complications arising from metastases. Hypoxia is an important biological process that fuels metastasis and contributes to deregulate the tumor microenvironment (TME) of solid tumors. Hypoxia also promotes resistance to therapies by a plethora of mechanisms including enhancing tumoral angiogenesis, metabolic reprogramming, epithelial-to-mesenchymal transition (EMT) and immune evasion. The expression of the receptor tyrosine kinase AXL, a hypoxia-induced gene, is associated with poor clinical prognosis and metastasis in various cancers, including breast cancer. Here, we hypothesize that genetic or pharmacological interference of AXL may alter hypoxic responses and associated modulation of the TME offering an ideal setting for immunotherapy. In a HER2 mouse model of breast cancer (MMTV-NIC), we found that the mammary gland epithelial cells specific deletion of AXL led to a reduction of lung metastases and improved the TME by reducing the hypoxic response in tumor cells. When breast cancer cells were subjected to hypoxic conditions, we found that AXL inhibition reduced the levels of the hypoxia transcription factor HIF-1a which resulted in an altered hypoxic response. Specifically, AXL deletion led to a reduction of hypoxia-induced EMT and invasion, and a reduction of the secretion of key cytokines for macrophages recruitment and polarization. We demonstrate in vivo that AXL pharmacological inhibition in the MMTV-NIC breast cancer model generated an anti-inflammatory TME that enhanced an anti-PD-1 immune checkpoint blockade response and decreased the metastatic burden. Collectively, these results suggest that targeting AXL could be a powerful approach to improve immunotherapy response by generating an anti-tumoral microenvironment therefore limiting the metastatic burden of breast cancer. Citation Format: Marie-Anne Goyette, Jean-Philippe Gratton, Jean-François Côté. Targeting AXL favors an anti-tumorigenic tumor microenvironment that enhances immunotherapy responses by decreasing HIF-1a levels in cancer cells [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT021.
Improved wire-guided basket for intrahepatic stone extraction in a patient after pancreatoduodenectomy
Authors: Wenxia Ding, Yan Chen, Ting Yang, Jie Chen
Journal: Endoscopy (2021)

A 61-year-old man with symptoms of chills and high fever had undergone pancreatoduodenectomy in 2009 because of pancreatic serous cystadenoma. Magnetic resonance cholangiopancreatography suggested stones in the common and left hepatic duct ([Fig. 1]). The type of the gastrointestinal reconstruction was ascertained from surgical records, and we used a cap-assisted colonoscope (PCF-PQ260; Olympus Medical Systems, Tokyo, Japan) for endoscopic retrograde cholangiopancreatography (ERCP). The removal of the common hepatic duct stones followed the ERCP sequence: intubation to the afferent limb, biliary cannulation, balloon dilation of the distal bile duct, and balloon-assisted stone extraction. When the left intrahepatic duct stones could not be removed using to this method, we carried out wire-guided cannulation using an improved single-lumen stone extraction basket, in which a hole was made with the tip of a needle ([Fig. 2]) to allow it to be advanced over the guidewire ([Fig. 3]) into the desired segmental duct ([Fig. 4]). The stones were engaged and dragged into the intestinal tract without removing the guidewire ([Video 1]). This process was repeated until complete removal of the stones was accomplished. The patient was discharged on the 2nd day after the operation. During the following 3 weeks, there were no abnormal symptoms.
Deep-sea microbes as tools to refine the rules of innate immune pattern recognition
Authors: Anna E. Gauthier, Courtney E. Chandler, Valentina Poli, Francesca M. Gardner, Aranteiti Tekiau, Richard Smith, Kevin S. Bonham, Erik E. Cordes, Timothy M. Shank, Ivan Zanoni, David R. Goodlett, Steven J. Biller, Robert K. Ernst, Randi D. Rotjan, Jonathan C. Kagan
Journal: Science Immunology (2021)

LPS immune detection strategies are tailored for host-microbe interactions that are possible in nature.
Four childhood atopic dermatitis subtypes identified from trajectory and severity of disease and internally validated in a large UK birth cohort
Authors: A.R. Mulick, K.E. Mansfield, R.J. Silverwood, A. Budu‐Aggrey, A. Roberts, A. Custovic, N. Pearce, A.D. Irvine, L. Smeeth, K. Abuabara, S.M. Langan
Journal: British Journal of Dermatology (2021)

Atopic dermatitis (AD) disease activity and severity is highly variable during childhood. Early attempts to identify subtypes based on disease trajectory have assessed AD presence over time without incorporating severity.To identify childhood AD subtypes from symptom severity and trajectories, and determine associations with genetic risk factors, comorbidities and demographic and environmental variables.We split data from children in the Avon Longitudinal Study of Parents and Children birth cohort into development and validation sets. To identify subtypes, we ran latent class analyses in the development set on AD symptom reports up to age 14 years. We regressed identified subtypes on nongenetic variables in mutually adjusted, multiply imputed (genetic: unadjusted, complete case) multinomial regression analyses. We repeated analyses in the validation set and report confirmed results.There were 11 866 children who contributed to analyses. We identified one Unaffected/Rare class (66% of children) and four AD subtypes: Severe-Frequent (4%), Moderate-Frequent (7%), Moderate-Declining (11%) and Mild-Intermittent (12%). Symptom patterns within the first two subtypes appeared more homogeneous than the last two. Filaggrin (FLG) null mutations, an AD polygenic risk score (PRS), being female, parental AD and comorbid asthma were associated with higher risk for some or all subtypes; FLG, AD-PRS and asthma associations were stronger along a subtype gradient arranged by increasing severity and frequency; FLG and AD-PRS further differentiated some phenotypes from each other.Considering severity and AD trajectories leads to four well-defined and recognizable subtypes. The differential associations of risk factors among and between subtypes is novel and requires further research.
23P Prediction of response to atezolizumab plus nab-paclitaxel in unresectable locally advanced triple-negative breast cancer (TNBC): The clinical usefulness of PD-L1 mRNA expression in plasma-derived exosomes
Authors: L. Raimondi, F.M. Raimondi, R. Lazzeroni, L. Di Benedetto, G. Cimino, G.P. Spinelli
Journal: Annals of Oncology (2021)
Avadomide Induces Degradation of ZMYM2 Fusion Oncoproteins in Hematologic Malignancies
Authors: Aline Renneville, Jessica A. Gasser, Daniel E. Grinshpun, Pierre M. Jean Beltran, Namrata D. Udeshi, Mary E. Matyskiela, Thomas Clayton, Marie McConkey, Kaushik Viswanathan, Alexander Tepper, Andrew A. Guirguis, Rob S. Sellar, Sophie Cotteret, Christophe Marzac, Véronique Saada, Stéphane De Botton, Jean-Jacques Kiladjian, Jean-Michel Cayuela, Mark Rolfe, Philip P. Chamberlain, Steven A. Carr, Benjamin L. Ebert
Journal: Blood Cancer Discovery (2021)

Abstract Thalidomide analogues exert their therapeutic effects by binding to the CRL4CRBN E3 ubiquitin ligase, promoting ubiquitination and subsequent proteasomal degradation of specific protein substrates. Drug-induced degradation of IKZF1 and IKZF3 in B-cell malignancies demonstrates the clinical utility of targeting disease-relevant transcription factors for degradation. Here, we found that avadomide (CC-122) induces CRBN-dependent ubiquitination and proteasomal degradation of ZMYM2 (ZNF198), a transcription factor involved in balanced chromosomal rearrangements with FGFR1 and FLT3 in aggressive forms of hematologic malignancies. The minimal drug-responsive element of ZMYM2 is a zinc-chelating MYM domain and is contained in the N-terminal portion of ZMYM2 that is universally included in the derived fusion proteins. We demonstrate that avadomide has the ability to induce proteasomal degradation of ZMYM2–FGFR1 and ZMYM2–FLT3 chimeric oncoproteins, both in vitro and in vivo. Our findings suggest that patients with hematologic malignancies harboring these ZMYM2 fusion proteins may benefit from avadomide treatment. Significance: We extend the potential clinical scope of thalidomide analogues by the identification of a novel avadomide-dependent CRL4CRBN substrate, ZMYM2. Avadomide induces ubiquitination and degradation of ZMYM2–FGFR1 and ZMYM2–FLT3, two chimeric oncoproteins involved in hematologic malignancies, providing a proof of concept for drug-induced degradation of transcription factor fusion proteins by thalidomide analogues.
Trends over time in survival in patients with urothelial carcinoma in the real-world: A multicenter analysis.
Authors: Sunil Samnani, Zachary William Neil Veitch, Jeenan Kaiser, Carlos Stecca, Husam Alqaisi, Scott A. North, Srikala S. Sridhar, Nimira S. Alimohamed
Journal: Journal of Clinical Oncology (2021)

412 Background: Patients with muscle-invasive bladder cancer (MIBC) historically have poor long-term outcomes, with nearly 50% developing metastatic disease. Similarly, patients with metastatic urothelial carcinoma (mUC) have had median overall survivals of less than 2 years. Novel therapies have been implemented over time in attempts to improve outcomes. This study evaluates trends in survival over time in patients with MIBC and mUC treated in the real-world setting. Methods: Retrospective data was collected from two major cancer centres in Alberta and the Princess Margaret Cancer Centre in Ontario, Canada. Consecutive patients treated with platinum-based chemotherapy between 01/2005 and 01/2018 who had confirmed MIBC or mUC were evaluated. Patients were excluded if they had been treated as part of a clinical trial in the first-line setting. Patients were categorized based on year of diagnosis at presentation: time period 1 (T1) diagnosed between 01/2005 and 12/2011, and time period 2 (T2) diagnosed between 01/2012 and 12/2018. The co-primary endpoints were disease-free survival (DFS) for MIBC, progression-free survival (PFS) for mUC, and overall survival (OS) for both. Results: 572 patients were included, 196 (78% male; median age 63.8 years) had MIBC and 376 (76% male; median age 68.4 years) were treated for mUC. Amongst patients with MIBC, 33% (65) were treated in T1 and 67% (131) in T2. Median DFS and OS were significantly improved in T2 compared to T1 for patients with MIBC (Table). On multivariate analysis, earlier year of diagnosis and ECOG status ≥2 was independently associated with poor outcomes (p=0.016 and p=0.008, respectively). Amongst patients with mUC, 205 (55%) were treated in T1 and 171 (45%) in T2. Median PFS and OS did not significantly improve over time in patients with mUC from T1 to T2 (Table). Conclusions: In this real-world analysis, outcomes for patients with MIBC have significantly improved over time. This is likely attributed to standardization of perioperative chemotherapy protocols and improvements in surgical techniques. Similar improvements have not yet been demonstrated for patients with mUC during the two time periods. However, novel therapies (eg. immunotherapy) were only approved in 2017. Future analysis may explore the reasons for improvement in patients with MIBC and will evaluate outcomes in mUC patients treated from 2017 onwards. CI= confidence interval, HR= hazard ratio. [Table: see text]
Sixty seconds on . . . twins
Authors: Zosia Kmietowicz
Journal: BMJ (2021)

Very probably. The chances of seeing twins are higher now than ever. Since the 1980s the twinning rate has increased by a third from 9 to 12 per 1000 deliveries, says a global overview in Human Reproduction .1 About 1.6 million twins are born each year worldwide—that’s one in every 42 newborns.

A major reason is the growth in medically assisted reproduction including in vitro fertilisation (IVF), as well as ovarian stimulation and artificial insemination. They started in wealthier countries in …
Liver Involvement and d FLC Level Affect Survival of Patients with Non-Cardiac Light Chain Amyloidosis: A European Study of 334 Patients
Authors: Giovanni Palladini, Ute Hegenbart, Paolo Milani, Marco Basset, Christoph Kimmich, Francesca Russo, Tilman Bochtler, Andrea Foli, Giampaolo Merlini, Stefan Schönland
Journal: Blood (2017)
How easy will it really be to replicate the success of the covid-19 vaccine with neglected infectious diseases?
Authors: Ramandeep Sahota
Journal: BMJ (2021)

The inferior colliculus (IC) is an obligatory relay for ascending auditory inputs from the brainstem and receives descending input from the auditory cortex. The IC comprises a central nucleus (CNIC), surrounded by several shell regions, but the internal organization of this midbrain nucleus remains incompletely understood. We used two-photon calcium imaging to study the functional microarchitecture of both neurons in the mouse dorsal IC and corticocollicular axons that terminate there. In contrast to previous electrophysiological studies, our approach revealed a clear functional distinction between the CNIC and the dorsal cortex of the IC (DCIC), suggesting that the mouse midbrain is more similar to that of other mammals than previously thought. We found that the DCIC comprises a thin sheet of neurons, sometimes extending barely 100 μm below the pial surface. The sound frequency representation in the DCIC approximated the mouse9s full hearing range, whereas dorsal CNIC neurons almost exclusively preferred low frequencies. The response properties of neurons in these two regions were otherwise surprisingly similar, and the frequency tuning of DCIC neurons was only slightly broader than that of CNIC neurons. In several animals, frequency gradients were observed in the DCIC, and a comparable tonotopic arrangement was observed across the boutons of the corticocollicular axons, which form a dense mesh beneath the dorsal surface of the IC. Nevertheless, acoustically responsive corticocollicular boutons were sparse, produced unreliable responses, and were more broadly tuned than DCIC neurons, suggesting that they have a largely modulatory rather than driving influence on auditory midbrain neurons. <b>SIGNIFICANCE STATEMENT</b> Due to its genetic tractability, the mouse is fast becoming the most popular animal model for sensory neuroscience. Nevertheless, many aspects of its neural architecture are still poorly understood. Here, we image the dorsal auditory midbrain and its inputs from the cortex, revealing a hitherto hidden level of organization and paving the way for the direct observation of corticocollicular interactions. We show that a precise functional organization exists in the mouse auditory midbrain, which has been missed by previous, more macroscopic approaches. The fine-scale distribution of sound-frequency tuning suggests that the mouse midbrain is more similar to that of other mammals than previously thought and contrasts with the more heterogeneous organization reported in imaging studies of auditory cortex.
Abstract 16613: Serial High-Sensitivity Troponin T and Cardiovascular Outcomes in Patients in the IMPROVE-IT Trial
Authors: Arman Qamar, Robert P Giugliano, Michael A Blazing, Jeong G Park, Sabina A Murphy, Christopher P Cannon, Eugene Braunwald, David A Morrow
Journal: Circulation (2017)

Introduction: Stable patients (pts) with previous acute coronary syndrome (ACS) vary significantly in their risk of recurrent cardiovascular (CV) events. We evaluated the prognostic implications of...
Abstract 10766: Oral Administration of Synthetic Prostacyclin Agonist ONO-1301 Improves Survival Rate With Prevention in Deteriorated Pathophysiology of Dilated Cardiomyopathy Model Hamsters
Authors: Naoki Okuda, Shigeru Miyagawa, Takuji Kawamura, Akima Harada, Yoshiki Sakai, Takayoshi Ueno, Yoshiki Sawa
Journal: Circulation (2019)

Introduction: Dilated cardiomyopathy (DCM) is one of the most critical intractable diseases. It has been already reported that synthetic prostacyclin agonist (ONO-1301), Prostaglandin IP receptor a...