tbuckley/cabot-search huggingface dataset:
Mesoscale cortical dynamics reflect the interaction of sensory evidence and temporal expectation during perceptual decision-making
Authors: Ivana Orsolic, Maxime Rio, Thomas D. Mrsic-Flogel, Petr Znamenskiy
Journal: Neuron (2021)

How sensory evidence is transformed across multiple brain regions to influence behavior remains poorly understood. We trained mice in a visual change detection task designed to separate the covert antecedents of choices from activity associated with their execution. Wide-field calcium imaging across the dorsal cortex revealed fundamentally different dynamics of activity underlying these processes. Although signals related to execution of choice were widespread, fluctuations in sensory evidence in the absence of overt motor responses triggered a confined activity cascade, beginning with transient modulation of visual cortex and followed by sustained recruitment of the secondary and primary motor cortex. Activation of the motor cortex by sensory evidence was modulated by animals' expectation of when the stimulus was likely to change. These results reveal distinct activation timescales of specific cortical areas by sensory evidence during decision-making and show that recruitment of the motor cortex depends on the interaction of sensory evidence and temporal expectation.
Early double-guidewire versus repeated single-guidewire technique to facilitate selective bile duct cannulation: a randomized controlled trial
Authors: Arthur Laquière, Jocelyn Privat, Jeremie Jacques, Romain Legros, Romina Urena-Campos, Hichem Belkhodja, Clément Subtil, Leïla Kanafi, Laurence Lecomte, Christian Boustière, Maria Katsogiannou, David Karsenti
Journal: Endoscopy (2021)

Abstract Background During endoscopic retrograde cholangiopancreatography (ERCP), access to the common bile duct (CBD) can be problematic after unintentional insertion of the guidewire into the pancreatic duct. We conducted a prospective, randomized study in order to compare biliary cannulation success rates of early double-guidewire (EDG) and repeated single-guidewire (RSG) techniques in patients with inadvertent passage of the guidewire into the pancreatic duct. Methods Patients with a native papilla were randomly assigned to either the EDG or RSG groups after unintentional insertion of the guidewire into the pancreatic duct. The primary outcome was successful selective CBD cannulation within 10 minutes. The secondary outcomes were successful final selective bile duct cannulation, time to bile duct cannulation, and frequency of post-ERCP pancreatitis (PEP). Results 142 patients were randomized and selective bile duct cannulation was achieved in 57/68 patients (84 %) in the EDG group and in 37/74 patients (50 %) in the RSG group within 10 minutes (relative risk 1.34; 95 % confidence interval 1.08–6.18; P &lt; 0.001). The overall final selective bile duct cannulation rate was 99.3 %. The time to access the CBD was shorter using the EDG technique (6.0 vs. 10.4 minutes; P = 0.002). Mild PEP was not observed more frequently in the EDG group than in the RSG group. Conclusion The EDG technique significantly increased the success rate of biliary duct cannulation within 10 minutes compared with an RSG approach.
FOSL1 promotes cholangiocarcinoma via transcriptional effectors that could be therapeutically targeted
Authors: Adrián Vallejo, Oihane Erice, Rodrigo Entrialgo-Cadierno, Iker Feliu, Elizabeth Guruceaga, Maria J. Perugorria, Paula Olaizola, Alexandra Muggli, Irati Macaya, Michael O’Dell, Borja Ruiz-Fernandez de Cordoba, Sergio Ortiz-Espinosa, Aram F. Hezel, Imanol Arozarena, Fernando Lecanda, Matias A. Avila, Maite G. Fernandez-Barrena, Matthias Evert, Mariano Ponz-Sarvise, Diego F. Calvisi, Jesus M. Banales, Silve Vicent
Journal: Journal of Hepatology (2021)

Cholangiocarcinoma (CCA) is a neoplasia of the biliary tract driven by genetic, epigenetic and transcriptional mechanisms. Herein, we investigated the role of the transcription factor FOSL1, as well as its downstream transcriptional effectors, in the development and progression of CCA.FOSL1 was investigated in human CCA clinical samples. Genetic inhibition of FOSL1 in human and mouse CCA cell lines was performed in in vitro and in vivo models using constitutive and inducible short-hairpin RNAs. Conditional FOSL1 ablation was done using a genetically engineered mouse (GEM) model of CCA (mutant KRAS and Trp53 knockout). Follow-up RNA and chromatin immunoprecipitation (ChIP) sequencing analyses were carried out and downstream targets were validated using genetic and pharmacological inhibition.An inter-species analysis of FOSL1 in CCA was conducted. First, FOSL1 was found to be highly upregulated in human and mouse CCA, and associated with poor patient survival. Pharmacological inhibition of different signalling pathways in CCA cells converged on the regulation of FOSL1 expression. Functional experiments showed that FOSL1 is required for cell proliferation and cell cycle progression in vitro, and for tumour growth and tumour maintenance in both orthotopic and subcutaneous xenograft models. Likewise, FOSL1 genetic abrogation in a GEM model of CCA extended mouse survival by decreasing the oncogenic potential of transformed cholangiocytes. RNA and ChIP sequencing studies identified direct and indirect transcriptional effectors such as HMGCS1 and AURKA, whose genetic and pharmacological inhibition phenocopied FOSL1 loss.Our data illustrate the functional and clinical relevance of FOSL1 in CCA and unveil potential targets amenable to pharmacological inhibition that could enable the implementation of novel therapeutic strategies.Understanding the molecular mechanisms involved in cholangiocarcinoma (bile duct cancer) development and progression stands as a critical step for the development of novel therapies. Through an inter-species approach, this study provides evidence of the clinical and functional role of the transcription factor FOSL1 in cholangiocarcinoma. Moreover, we report that downstream effectors of FOSL1 are susceptible to pharmacological inhibition, thus providing new opportunities for therapeutic intervention.
COVID-19 Mortality and Stress to the Hospital System From High Patient Load
Authors: Alessandro Soria, Giuseppe Lapadula, Paolo Bonfanti
Journal: JAMA Internal Medicine (2021)

David A. Asch, MD, MBA; Natalie E. Sheils, PhD; Md Nazmul Islam, PhD, MBA; Yong Chen, PhD; Rachel M. Werner, MD, PhD; John Buresh, BS; Jalpa A. Doshi, PhD
Targeted gene panels identify a high frequency of pathogenic germline variants in patients diagnosed with a hematological malignancy and at least one other independent cancer
Authors: Deepak Singhal, Christopher N. Hahn, Simone Feurstein, Li Yan A. Wee, Luke Moma, Monika M. Kutyna, Rakchha Chhetri, Leila Eshraghi, Andreas W. Schreiber, Jinghua Feng, Paul P-S. Wang, Milena Babic, Wendy T. Parker, Song Gao, Sarah Moore, Soma Das, David Thomas, Swetansu Pattnaik, Anna L. Brown, Richard J. D’Andrea, Nicola K. Poplawski, Daniel Thomas, Hamish S. Scott, Lucy A. Godley, Devendra K. Hiwase
Journal: Leukemia (2021)
Chemotherapy and radiotherapy in locally advanced head and neck cancer: an individual patient data network meta-analysis
Authors: Claire Petit, Benjamin Lacas, Jean-Pierre Pignon, Quynh Thu Le, Vincent Grégoire, Cai Grau, Allan Hackshaw, Björn Zackrisson, Mahesh K B Parmar, Ju-Whei Lee, Maria Grazia Ghi, Giuseppe Sanguineti, Stéphane Temam, Maurice Cheugoua-Zanetsie, Brian O'Sullivan, Marshall R Posner, Everett E Vokes, Juan J Cruz Hernandez, Zbigniew Szutkowski, Eric Lartigau, Volker Budach, Rafal Suwiński, Michael Poulsen, Shaleen Kumar, Sarbani Ghosh Laskar, Jean-Jacques Mazeron, Branislav Jeremic, John Simes, Lai-Ping Zhong, Jens Overgaard, Catherine Fortpied, Pedro Torres-Saavedra, Jean Bourhis, Anne Aupérin, Pierre Blanchard, D.J. Adelstein, J. Agarwal, M. Alfonsi, A. Argiris, A. Aupérin, A. Bacigalupo, V. Bar-Ad, H. Bartelink, B. Beadle, Y. Belkacemi, R.J. Bensadoun, J. Bernier, P. Blanchard, J. Bourhis, Å. Bratland, D. Brizel, V. Budach, W. Budach, B. Burtness, G. Calais, B. Campbell, J. Caudell, S. Chabaud, E. Chamorey, D. Chaukar, M. Cheugoua-Zanetsie, K.H. Cho, O. Choussy, J.J. Cruz Hernandez, J.W. Denham, W. Dobrowsky, M.M Dominello, C.M.L. Driessen, C. Fallai, A.A. Forastiere, C. Fortpied, G. Fountzilas, P. Garaud, A.S. Garden, B. Gery, P. Ghadjar, M.G. Ghi, S. Ghosh Laskar, P. Graff-Cailleaud, C. Grau, V. Gregoire, A. Hackshaw, E Haddad, B.G. Haffty, A. Hansen, J.H. Hay, S. Hayoz, J.C. Horiot, R. Hitt, B. Jeremic, J. Johansen, C. Jones, M. Julieron, C.A. Kristensen, S. Kumar, B. Lacas, J.A. Langendijk, M. Lapeyre, E. Lartigau, L. Licitra, Q.T. Le, J.W. Lee, P. Lee, F. Lewin, Y. Li, A. Lopes, M. Lotayef, B. Maciejewski, J.J. Mazeron, S. Mehta, W. Michalski, J. Moon, S.H. Moon, E. Moyal, M. Nankivell, P. Nilsson, P. Olmi, R. Orecchia, B. O'Sullivan, J. Overgaard, M.K.B. Parmar, C. Petit, J.P. Pignon, Y. Pointreau, M.R. Posner, M.G. Poulsen, H. Quon, S. Racadot, D.I. Rosenthal, P. Rovea, M.G. Ruo Redda, G. Sanguineti, G. Shenouda, J. Simes, A. Sharma, C. Simon, C. Sire, K. Skladowski, S. Spencer, S. Staar, P. Strojan, C. Stromberger, R. Suwinski, Z. Szutkowski, Z. Takácsi-Nagy, Y.G. Tao, S. Temam, D. Thomson, J.S. Tobias, P. Torres-Saavedra, V. Torri, L. Tripcony, A. Trotti, V. Tseroni, C. van Herpen, H. van Tinteren, J. Vermorken, C.M.P. Viegas, E.E. Vokes, J. Waldron, K.D Wernecke, J. Widder, G.T. Wolf, S.J. Wong, J.S. Wu, H. Yamazaki, B. Zaktonik, B. Zackrisson, L.P. Zhong
Journal: The Lancet Oncology (2021)
Abstract IA-022: Lysine 68 acetylation directs MnSOD as a tetrameric detoxification complex versus a monomeric tumor promoter
Authors: David Gius
Journal: Clinical Cancer Research (2021)

Abstract Manganese superoxide dismutase (MnSOD) functions as a tumor suppressor; however, once tumorigenesis occurs, clinical data suggest MnSOD levels correlate with more aggressive human tumors, implying a potential dual function of MnSOD in the regulation of metabolism. Here we show, using in vitro transformation and xenograft growth assays that the MnSOD-K68 acetylation (Ac) mimic mutant (MnSODK68Q) functions as a tumor promoter. Interestingly, in various breast cancer and primary cell types the expression of MnSODK68Q is accompanied with a change of MnSOD’s stoichiometry from a known homotetramer complex to a monomeric form. Biochemical experiments using the MnSOD-K68Q Ac-mimic, or physically K68-Ac (MnSOD-K68-Ac), suggest that these monomers function as a peroxidase, distinct from the established MnSOD superoxide dismutase activity. MnSODK68Q expressing cells exhibit resistance to tamoxifen (Tam) and cells selected for Tam resistance exhibited increased K68-Ac and monomeric MnSOD. These results suggest a MnSOD-K68-Ac metabolic pathway for Tam resistance, carcinogenesis and tumor progression. Citation Format: David Gius. Lysine 68 acetylation directs MnSOD as a tetrameric detoxification complex versus a monomeric tumor promoter [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-022.
Comparative genomics identifies thousands of candidate structured RNAs in human microbiomes
Authors: Brayon J. Fremin, Ami S. Bhatt
Journal: Genome biology (2021)

Abstract Background Structured RNAs play varied bioregulatory roles within microbes. To date, hundreds of candidate structured RNAs have been predicted using informatic approaches that search for motif structures in genomic sequence data. The human microbiome contains thousands of species and strains of microbes. Yet, much of the metagenomic data from the human microbiome remains unmined for structured RNA motifs primarily due to computational limitations. Results We sought to apply a large-scale, comparative genomics approach to these organisms to identify candidate structured RNAs. With a carefully constructed, though computationally intensive automated analysis, we identify 3161 conserved candidate structured RNAs in intergenic regions, as well as 2022 additional candidate structured RNAs that may overlap coding regions. We validate the RNA expression of 177 of these candidate structures by analyzing small fragment RNA-seq data from four human fecal samples. Conclusions This approach identifies a wide variety of candidate structured RNAs, including tmRNAs, antitoxins, and likely ribosome protein leaders, from a wide variety of taxa. Overall, our pipeline enables conservative predictions of thousands of novel candidate structured RNAs from human microbiomes.
Role of oxidative stress in calcific aortic valve disease and its therapeutic implications
Authors: Harry Z E Greenberg, Guoan Zhao, Ajay M Shah, Min Zhang
Journal: Cardiovascular Research (2021)

Calcific aortic valve disease (CAVD) is the end result of active cellular processes that lead to the progressive fibrosis and calcification of aortic valve leaflets. In western populations, CAVD is a significant cause of cardiovascular morbidity and mortality, and in the absence of effective drugs, it will likely represent an increasing disease burden as populations age. As there are currently no pharmacological therapies available for preventing, treating, or slowing the development of CAVD, understanding the mechanisms underlying the initiation and progression of the disease is important for identifying novel therapeutic targets. Recent evidence has emerged of an important causative role for reactive oxygen species (ROS)-mediated oxidative stress in the pathophysiology of CAVD, inducing the differentiation of valve interstitial cells into myofibroblasts and then osteoblasts. In this review, we focus on the roles and sources of ROS driving CAVD and consider their potential as novel therapeutic targets for this debilitating condition.
Direct optogenetic stimulation of smooth muscle cells to control gastric contractility
Authors: Markus Vogt, Benjamin Schulz, Ahmed Wagdi, Jan Lebert, Gijsbert J. van Belle, Jan Christoph, Tobias Bruegmann, Robert Patejdl
Journal: Theranostics (2021)

Rationale: Antral peristalsis is responsible for gastric emptying. Its failure is called gastroparesis and often caused by dysfunction of enteric neurons and interstitial cells of Cajal (ICC). Current treatment options, including gastric electrical stimulation, are non-satisfying and may improve symptoms but commonly fail to restore gastric emptying. Herein, we explore direct optogenetic stimulation of smooth muscle cells (SMC) via the light-gated non-selective cation channel Channelrhodopsin2 (ChR2) to control gastric motor function. Methods: We used a transgenic mouse model expressing ChR2 in fusion with eYFP under the control of the chicken-β-actin promoter. We performed patch clamp experiments to quantify light-induced currents in isolated SMC, Ca2+ imaging and isometric force measurements of antral smooth muscle strips as well as pressure recordings of intact stomachs to evaluate contractile responses. Light-induced propulsion of gastric contents from the isolated stomach preparation was quantified in video recordings. We furthermore tested optogenetic stimulation in a gastroparesis model induced by neuronal- and ICC-specific damage through methylene blue photo-toxicity. Results: In the stomachs, eYFP signals were restricted to SMC in which blue light (460 nm) induced inward currents typical for ChR2. These depolarizing currents led to contractions in antral smooth muscle strips that were stronger than those triggered by supramaximal electrical field stimulation and comparable to those evoked by global depolarization with high K+ concentration. In the intact stomach, panoramic illumination efficiently increased intragastric pressure achieving 239±46% (n=6) of the pressure induced by electrical field stimulation and triggered gastric transport. Within the gastroparesis model, electric field stimulation completely failed but light still efficiently generated pressure waves. Conclusions: We demonstrate direct optogenetic stimulation of SMC to control gastric contractility. This completely new approach could allow for the restoration of motility in gastroparesis in the future.
Dasiglucagon—A Next-Generation Glucagon Analog for Rapid and Effective Treatment of Severe Hypoglycemia: Results of Phase 3 Randomized Double-Blind Clinical Trial
Authors: Thomas R. Pieber, Ronnie Aronson, Ulrike Hövelmann, Julie Willard, Leona Plum-Mörschel, Kim M. Knudsen, Benedikte Bandak, Ramin Tehranchi
Journal: Diabetes Care (2021)

OBJECTIVE To evaluate the efficacy and safety of dasiglucagon, a ready-to-use, next-generation glucagon analog in aqueous formulation for subcutaneous dosing, for treatment of severe hypoglycemia in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS This randomized, double-blind trial included 170 adult participants with type 1 diabetes, each randomly assigned to receive a single subcutaneous dose of 0.6 mg dasiglucagon, placebo, or 1 mg reconstituted glucagon (2:1:1 randomization) during controlled insulin-induced hypoglycemia. The primary end point was time to plasma glucose recovery, defined as an increase of ≥20 mg/dL from baseline without rescue intravenous glucose. The primary comparison was dasiglucagon versus placebo; reconstituted lyophilized glucagon was included as reference. RESULTS Median (95% CI) time to recovery was 10 (10, 10) minutes for dasiglucagon compared with 40 (30, 40) minutes for placebo (P &amp;lt; 0.001); the corresponding result for reconstituted glucagon was 12 (10, 12) minutes. In the dasiglucagon group, plasma glucose recovery was achieved within 15 min in all but one participant (99%), superior to placebo (2%; P &amp;lt; 0.001) and similar to glucagon (95%). Similar outcomes were observed for the other investigated time points at 10, 20, and 30 min after dosing. The most frequent adverse effects were nausea and vomiting, as expected with glucagon treatment. CONCLUSIONS Dasiglucagon provided rapid and effective reversal of hypoglycemia in adults with type 1 diabetes, with safety and tolerability similar to those reported for reconstituted glucagon injection. The ready-to-use, aqueous formulation of dasiglucagon offers the potential to provide rapid and reliable treatment of severe hypoglycemia.
Tissue inhibitor of metalloproteinases-2 (TIMP-2) inhibits tumorigenesis and tumor growth in Wnt-1-induced mammary carcinogenesis.
Authors: Laurence Blavier, Alisa Lazaryev, Gregory M. Shackleford, Yves A. De Clerck
Journal: Cancer Research (2004)

2289  Epithelial mesenchymal transition (EMT) occurs in the early stages of malignant transformation in epithelial cancer. Here we have used Wnt-1-induced EMT in C57MG murine mammary epithelial cells to study the role of Matrix Metalloproteinases (MMPs) in EMT and its control by MMP inhibitors. Following transfection with Wnt-1, C57MG cells went through EMT, showing changes in cell morphology and redistribution of β-catenin expression from the cell membrane to the cytoplasm and nucleus. These changes, also associated with increased cell proliferation and cell motility, were reversed upon incubation of the cells with MMP inhibitors such as AG3340 or tissue inhibitor of metalloproteinase-2. Analysis of the conditioned media of these cells by zymographies and Western blot revealed an increase in MMP-3 expression upon transformation with Wnt-1, whereas there was no change in the expression of MMP-2, TIMP-1, and TIMP-2, and no expression of MMP-9. MMTV-Wnt-1 transgenic mice which develop spontaneous mammary tumors were then used to study the cooperation between Wnt-1 and MMPs in mammary adenocarcinoma. All MMTV-Wnt-1 mice (n=25) developed tumors at a median time of 15 weeks. Tumor extracts showed an abundant expression of MMP-9 and MMP-2, and low levels of MMP-3, TIMP-1 and TIMP-2 expression. We generated MMTV-TIMP-2 transgenic mice that overexpressed TIMP-2 in the mammary gland which were crossed with MMTV-Wnt-1 mice to generate double transgenic MMTV-Wnt-1/TIMP-2 mice. Multiparous females in each transgenic line were monitored for tumor incidence and growth. MMTV-TIMP-2 mice never developed tumors (n>50). MMTV-Wnt-1/TIMP-2 mice expressing low levels of TIMP-2 (line 8) (n=15) developed tumors at a median time of 14 weeks of age, comparable to MMTV-Wnt-1 mice (p=0.567). In contrast, in MMTV-Wnt-1/TIMP-2 mice expressing high levels of TIMP-2 (line 1), only 11 mice out of 19 have developed tumors and the median time for tumor detection was 24 weeks (p=0.0013). Whereas MMTV-Wnt-1 mice grew large tumors at an accelerated rate, most tumors in MMTV-Wnt-1/TIMP-2 line 1 mice grew slower, with some maintaining a state of dormancy for 45 to 98 days. These tumors contained higher levels of functional TIMP-2, but levels of MMP-2 and MMP-9 similar to tumors in MMTV-Wnt-1 mice. Interestingly these tumors significantly differed from MMTV-Wnt-1 tumors by the presence of abundant collagen and smaller CD31-positive microvessels. Altogether, our data indicate that there is a specific temporal expression of MMPs during Wnt-1 induced mammary tumorigenesis, with MMP-3 being involved during the early stages of EMT and MMP-9 playing a more prominent role in angiogenesis and growth. The data further suggest that MMP inhibition may play a role in the prevention of mammary cancers.
Enhanced tumour penetration and prolonged circulation in blood of polyzwitterion–drug conjugates with cell-membrane affinity
Authors: Siqin Chen, Yin Zhong, Wufa Fan, Jiajia Xiang, Guowei Wang, Quan Zhou, Jinqiang Wang, Yu Geng, Rui Sun, Zhen Zhang, Ying Piao, Jianguo Wang, Jianyong Zhuo, Hailin Cong, Haiping Jiang, Jun Ling, Zichen Li, Dingding Yang, Xin Yao, Xiao Xu, Zhuxian Zhou, Jianbin Tang, Youqing Shen
Journal: Nature Biomedical Engineering (2021)