tbuckley/cabot-search huggingface dataset:
Addressing uncertainty in genome-scale metabolic model reconstruction and analysis
Authors: David B. Bernstein, Snorre Sulheim, Eivind Almaas, Daniel Segrè
Journal: Genome biology (2021)

Abstract The reconstruction and analysis of genome-scale metabolic models constitutes a powerful systems biology approach, with applications ranging from basic understanding of genotype-phenotype mapping to solving biomedical and environmental problems. However, the biological insight obtained from these models is limited by multiple heterogeneous sources of uncertainty, which are often difficult to quantify. Here we review the major sources of uncertainty and survey existing approaches developed for representing and addressing them. A unified formal characterization of these uncertainties through probabilistic approaches and ensemble modeling will facilitate convergence towards consistent reconstruction pipelines, improved data integration algorithms, and more accurate assessment of predictive capacity.
Sex, Permanent Drug Discontinuation, and Study Retention in Clinical Trials
Authors: Emily S. Lau, Eugene Braunwald, David A. Morrow, Robert P. Giugliano, Elliott M. Antman, C. Michael Gibson, Benjamin M. Scirica, Erin A. Bohula, Stephen D. Wiviott, Deepak L. Bhatt, Marc P. Bonaca, Christopher P. Cannon, KyungAh Im, Jianping Guo, Marc S. Sabatine, Michelle L. O’Donoghue
Journal: Circulation (2021)

Women are underrepresented across cardiovascular clinical trials. Whether women are more likely than men to prematurely discontinue study drug or withdraw consent once enrolled in a clinical trial is unknown.Eleven phase 3/4 TIMI (Thrombolysis in Myocardial Infarction) trials were included (135 879 men and 51 812 women [28%]). The association between sex and premature study drug discontinuation and withdrawal of consent were examined by multivariable logistic regression after adjusting for potential confounders in each individual trial and combining the individual point estimates in random effects models.After adjusting for baseline differences, women had 22% higher odds of premature drug discontinuation (adjusted odds ratio [ORadj], 1.22 [95% CI, 1.16-1.28]; P<0.001) compared with men. Qualitatively consistent results were observed for women versus men in the placebo arms (ORadj, 1.20 [95% CI, 1.13-1.27]) and active therapy arms (ORadj, 1.23 [95% CI, 1.17-1.30)]; there was some evidence for regional heterogeneity (P interaction <0.001). Of those who stopped study drug prematurely, a similar proportion of men and women in the active arm stopped because of an adverse event (36% for both; P=0.60). Women were also more likely to withdraw consent compared with men (ORadj, 1.26 [95% CI, 1.17-1.36]; P<0.001).Women were more likely than men to prematurely discontinue study drug and withdraw consent across cardiovascular outcome trials. Premature study drug discontinuation was not explained by baseline differences by sex or a higher proportion of adverse events. Future trials should better capture reasons for drug discontinuation and withdrawal of consent to understand barriers to continued study drug use and clinical trial participation, particularly among women.
Rituximab vs Low-Dose Mycophenolate Mofetil in Recurrence of Steroid-Dependent Nephrotic Syndrome in Children and Young Adults
Authors: Pietro Ravani, Francesca Lugani, Stefania Drovandi, Gianluca Caridi, Andrea Angeletti, Gian Marco Ghiggeri
Journal: JAMA Pediatrics (2021)

This randomized clinical trial examines the superiority of a single dose of rituximab vs low-dose mycophenolate mofetil in preventing the recurrence of steroid-dependent nephrotic syndrome in children and young adults.
Intravenous ferric derisomaltose for the treatment of iron deficiency anemia
Authors: Michael Auerbach, David Henry, Thomas G. DeLoughery
Journal: American Journal of Hematology (2021)

Intravenous (IV) iron is the therapy of choice when oral iron is ineffective or poorly tolerated, yet use has been limited by fears of hypersensitivity reactions (HSRs). Newer formulations that bind iron more tightly and release it more slowly have made the risk of serious or severe HSRs very low. One such formulation, ferric derisomaltose, has been approved in the United States for delivery of 1000 mg iron in a single IV infusion. Ferric derisomaltose rapidly repletes iron parameters with low rates of serious or severe HSRs. Single-infusion iron repletion offers convenience, eliminates adherence concerns, and reduces healthcare resource utilization.
Abstract SP031: Mechanisms of therapeutic resistance in ER+ breast cancer
Authors: RB Clarke
Journal: Cancer Research (2021)

Abstract ER+ breast cancer is often successfully treated with endocrine therapies and more recently CDK4/6 inhibitors. In order to discover resistance mechanisms, we studied the tumour cells that survive anti-estrogen therapies such as tamoxifen and fulvestrant. We found that tamoxifen and fulvestrant therapy-resistant cells have cancer stem cell (CSC) attributes such as aldehyde dehydrogenase (ALDH) enzyme activity, mammosphere colony formation ex vivo and tumour initiation in vivo. We established that these CSC activities are regulated by pathways downstream of JAGGED/NOTCH4 receptor, the interleukin (IL) 1beta/IL1 receptor, and IL6/STAT3 signalling. Emerging data implicate these signalling pathways in metastatic progression, and both endocrine and CDK4/6 inhibitor therapy resistance. Targeting them in combination with current therapies has the potential to improve clinical outcomes. Citation Format: RB Clarke. Mechanisms of therapeutic resistance in ER+ breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP031.
Recurrent Nodular Regenerative Hyperplasia Following Liver Transplantation in Common Variable Immunodeficiency
Authors: Julian Hercun, Esha Parikh, David E. Kleiner, Ivan Fuss, Gulbu Uzel, Warren Strober, Christopher Koh, Steven M. Holland, Theo Heller
Journal: Hepatology (2021)

Hercun, Julian; Parikh, Esha; Kleiner, David E.; Fuss, Ivan; Uzel, Gulbu; Strober, Warren; Koh, Christopher; Holland, Steven M.; Heller, Theo Author Information
Chr20q Amplification Defines a Distinct Molecular Subtype of Microsatellite Stable Colorectal Cancer
Authors: Baoyi Zhang, Kevin Yao, Emily Zhou, Lanjing Zhang, Chao Cheng
Journal: Cancer Research (2021)

Abstract Colorectal cancer is the third leading cause of cancer-related death in the United States. About 15% of colorectal cancers are associated with microsatellite instability (MSI) due to loss of function in the DNA mismatch repair pathway. This subgroup of patients has better survival rates and is more sensitive to immunotherapy. However, it remains unclear whether microsatellite stable (MSS) patients with colorectal cancer can be further stratified into subgroups with differential clinical characteristics. In this study, we analyzed The Cancer Genome Atlas data and found that Chr20q amplification is the most frequent copy number alteration that occurs specifically in colon (46%) and rectum (61%) cancer and is mutually exclusive with MSI. Importantly, MSS patients with Chr20q amplification (MSS-A) were associated with better recurrence-free survival compared with MSS patients without Chr20q amplification (MSS-N; P = 0.03). MSS-A tumors were associated with high level of chromosome instability and low immune infiltrations. In addition, MSS-A and MSS-N tumors were associated with somatic mutations in different driver genes, with high frequencies of mutated TP53 in MSS-A and mutated KRAS and BRAF in MSS-N. Our results suggest that MSS-A and MSS-N represent two subtypes of MSS colorectal cancer, and such stratification may be used to improve therapeutic treatment in an individualized manner. Significance: This study shows that chromosome 20q amplification occurs predominately in microsatellite-stable colorectal cancer and defines a distinct subtype with good prognosis, high chromosomal instability, distinct mutation profiles, and low immune infiltrations.
Abstract 14278: Empagliflozin Restores Lowered Exercise Endurance Capacity via the Activation of Skeletal Muscle Fatty Acid Oxidation in Murine Heart Failure
Authors: Hideo Nambu, Shingo Takada, Satoshi Maekawa, Naoya Kakutani, Takaaki Furihata, Akimichi Saito, Arata Fukushima, Takashi Yokota, Shintaro Kinugawa
Journal: Circulation (2019)

Introduction: Exercise capacity, which is an independent predictor for poor prognosis, is attributed to markedly impaired skeletal muscle mitochondrial function along with fatty acid oxidation. Pre...
Activation of MAPK and AKT pathways by BRAF, NRAS and PIK3CA mutations in melanoma
Authors: Massimo Libra, Grazia Malaponte, Giovanni Ligresti, Pietro Gangemi, Roberta Siciliano, Salvatore Travali, Maria Mazzarino, Katia Mangano, Ferdinando Nicoletti, Ellis Wong, Linda Steelman, James McCubrey, Franca Stivala
Journal: Cancer Research (2007)

155  Malignant melanoma is an aggressive tumor of the skin with a poor prognosis for patients with advanced disease. It is resistant to current therapeutic approaches. In melanoma, both the Ras-Raf-MEK-ERK (MAPK) and the PI3K-AKT (AKT) signaling pathways are constitutively activated through multiple mechanisms. Mutation of BRAF has been proposed to contribute to melanoma development. Increased activity of the MAPK pathway prevents apoptosis and induces cell cycle progression. V600E accounts for more than 90% of BRAF mutations in melanoma. This mutation causes a substantial increase in B-Raf kinase activity. Moreover, an interaction has been recently found (Tsao et al, J. Invest. Dermatology, 2004) between the MAPK and the PI3K/AKT pathways, both activated in cutaneous melanoma. Interestingly, these studies suggest that MAPK and AKT pathways are activated in parallel. The mechanism by which AKT is activated remains unknown. Recently, mutations of PIK3CA gene have been identified in different human cancers. We screened tumor biopsy specimens from 68 patients with melanoma for PIK3CA mutations to determine whether or not PIK3CA plays a role in melanoma development. Mutations of BRAF and NRAS were also analyzed in the same tumor specimens. Activation of either the MAPK or AKT pathways were investigated by immunohistochemistry (IHC) in melanoma tissues. BRAF mutations were detected in 43 of 68 melanoma patients (61%). NRAS mutations were identified in 17 of 68 (25%) melanoma patients, while PIK3CA gene was mutated in 5 of 68 (7%) of tumor samples. In agreement with previous data, BRAF mutations occur exclusively in melanomas that were wild type for NRAS. Interestingly, one tumor sample harbouring a PIK3CA mutation was also mutated at BRAF. A total of 65/68 (95%) melanomas were mutated at BRAF, NRAS or PIK3CA. The MAPK and AKT pathways were activated in all samples having gene mutations. However, only the AKT pathway was highly expressed in the tumor tissue with both PIK3CA and BRAF mutations. These findings may explain why the AKT pathway plays an important role in melanoma development. Some PIK3CA mutations may block the MAPK pathway by activating AKT which phosphorylates and inactivates Raf. This may alter the terminal differentiation capacity of the cells. The results of the present study indicate that in melanoma both the MAPK and the AKT signaling pathways play pathogenic roles and may represent promising therapeutic targets for an otherwise devastating disease.
Reply: BAL lymphocyte percentage is as good as the company it keeps
Authors: Nicola Adderley, Christopher J. Humphreys, Hayley Barnes, Zahra A. Premji, Kerri A. Johannson
Journal: European Respiratory Journal (2021)

<b>No single value of BAL lymphocyte % in fibrotic hypersensitivity pneumonitis will be diagnostic for all, and it must be considered in the context of other clinical, radiological and histopathological features</b>https://bit.ly/3qSwUDo
Back to simplicity: a four-marker blood cell score to quantify prognostically relevant myeloid cells in melanoma patients
Authors: Veronica Huber, Lorenza Di Guardo, Luca Lalli, Daniele Giardiello, Agata Cova, Paola Squarcina, Paola Frati, Anna Maria Di Giacomo, Lorenzo Pilla, Marcella Tazzari, Chiara Camisaschi, Flavio Arienti, Chiara Castelli, Monica Rodolfo, Valeria Beretta, Massimo Di Nicola, Michele Maio, Michele Del Vecchio, Filippo de Braud, Luigi Mariani, Licia Rivoltini
Journal: Journal for ImmunoTherapy of Cancer (2021)

Myeloid-derived suppressor cells (MDSC), a cornerstone of cancer-related immunosuppression, influence response to therapy and disease outcomes in melanoma patients. Nevertheless, their quantification is far from being integrated into routine clinical practice mostly because of the complex and still evolving phenotypic signatures applied to define the cell subsets. Here, we used a multistep downsizing process to verify whether a core of few markers could be sufficient to capture the prognostic potential of myeloid cells in peripheral blood mononuclear cells (PBMC) of metastatic melanoma patients. In baseline frozen PBMC from a total of 143 stage IIIc to IV melanoma patients, we first assessed the relevant or redundant expression of myeloid and MDSC-related markers by flow cytometry (screening set, n=23 patients). Subsequently, we applied the identified panel to the development set samples (n=59 patients undergoing first/second-line therapy) to obtain prognostic variables associated with overall survival (OS) and progression-free survival (PFS) by machine learning adaptive index modeling. Finally, the identified score was confirmed in a validation set (n=61) and compared with standard clinical prognostic factors to assess its additive value in patient prognostication. This selection process led to the identification of what we defined myeloid index score (MIS), which is composed by four cell subsets (CD14+, CD14+HLA-DRneg, CD14+PD-L1+ and CD15+ cells), whose frequencies above cut-offs stratified melanoma patients according to progressively worse prognosis. Patients with a MIS=0, showing no over-threshold value of MIS subsets, had the best clinical outcome, with a median survival of >33.6 months, while in patients with MIS 1→3, OS deteriorated from 10.9 to 6.8 and 6.0 months as the MIS increased (p<0.0001, c-index=0.745). MIS clustered patients into risk groups also according to PFS (p<0.0001). The inverse correlation between MIS and survival was confirmed in the validation set, was independent of the type of therapy and was not interfered by clinical prognostic factors. MIS HR was remarkably superior to that of lactate dehydrogenase, tumor burden and neutrophil-to-lymphocyte ratio. The MIS >0 identifies melanoma patients with a more aggressive disease, thus acting as a simple blood biomarker that can help tailoring therapeutic choices in real-life oncology.
Publisher Correction: Transcriptome-scale spatial gene expression in the human dorsolateral prefrontal cortex
Authors: Kristen R. Maynard, Leonardo Collado-Torres, Lukas M. Weber, Cedric Uytingco, Brianna K. Barry, Stephen R. Williams, Joseph L. Catallini, Matthew N. Tran, Zachary Besich, Madhavi Tippani, Jennifer Chew, Yifeng Yin, Joel E. Kleinman, Thomas M. Hyde, Nikhil Rao, Stephanie C. Hicks, Keri Martinowich, Andrew E. Jaffe
Journal: Nature Neuroscience (2021)
Genetic polymorphisms of hepatic lipase and cholesteryl ester transfer protein, intermediate phenotypes, and coronary risk: Do they add up yet?**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Jeffrey L Anderson, John F Carlquist
Journal: Journal of the American College of Cardiology (2003)
TGFβ1 neutralization displays therapeutic efficacy through both an immunomodulatory and a non-immune tumor-intrinsic mechanism
Authors: Stefania Canè, Jacques Van Snick, Catherine Uyttenhove, Luc Pilotte, Benoit J Van den Eynde
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Transforming growth factor-β (TGFβ) is emerging as a promising target for cancer therapy, given its ability to promote progression of advanced tumors and to suppress anti-tumor immune responses. However, TGFβ also plays multiple roles in normal tissues, particularly during organogenesis, raising toxicity concerns about TGFβ blockade. Dose-limiting cardiovascular toxicity was observed, possibly due to the blockade of all three TGFβ isoforms. The dominant isoform in tumors is TGFβ1, while TGFβ2 and TGFβ3 seem to be more involved in cardiovascular development. Recent data indicated that selective targeting of TGFβ1 promoted the efficacy of checkpoint inhibitor anti-PD1 in transplanted preclinical tumor models, without cardiovascular toxicity. Methods To further explore the therapeutic potential of isoform-specific TGFβ blockade, we developed neutralizing mAbs targeting mature TGFβ1 or TGFβ3, and tested them, in parallel with anti-panTGFβ mAb 1D11, in two preclinical models: the transplanted colon cancer model CT26, and the autochthonous melanoma model TiRP. Results We observed that the blockade of TGFβ1, but not that of TGFβ3, increased the efficacy of a prophylactic cellular vaccine against colon cancer CT26. This effect was similar to pan-TGFβ blockade, and was associated with increased infiltration of activated CD8 T cells in the tumor, and reduced levels of regulatory T cells and myeloid-derived suppressor cells. In contrast, in the autochthonous TiRP melanoma model, we observed therapeutic efficacy of the TGFβ1-specific mAb as a single agent, while the TGFβ3 mAb was inactive. In this model, the anti-tumor effect of TGFβ1 blockade was tumor intrinsic rather than immune mediated, as it was also observed in T-cell depleted mice. Mechanistically, TGFβ1 blockade increased mouse survival by delaying the phenotype switch, akin to epithelial-to-mesenchymal transition (EMT), which transforms initially pigmented tumors into highly aggressive unpigmented tumors. Conclusions Our results confirm TGFβ1 as the relevant isoform to target for cancer therapy, not only in combination with checkpoint inhibitors, but also with other immunotherapies such as cancer vaccines. Moreover, TGFβ1 blockade can also act as a monotherapy, through a tumor-intrinsic effect blocking the EMT-like transition. Because human melanomas that resist therapy often express a gene signature that links TGFβ1 with EMT-related genes, these results support the clinical development of TGFβ1-specific mAbs in melanoma.
Bio-culturally grounded: why separation and connection may not be the same around the world
Authors: Albert Lee, Gianluca Esposito
Journal: Behavioral and Brain Sciences (2021)

Abstract Central to the account of grounded procedures is the premise that mental experiences are grounded in physical actions. We complement this account by incorporating frameworks in cultural psychology and developmental neuroscience, with new predictions. Through the examples of vicarious experiences and demerit transfer, we discuss why, and how, separation and connection may operate somewhat differently across cultures.
Syed Safdar Raza
Authors: Syed Ahsan Raza
Journal: BMJ (2021)

Syed Safdar Raza was born in Chapra, Bihar, India. His life was a trial from the beginning: his mother died when he was 11months old, and his father when he was only 6 years. Brought up by his auntie, he used to recall fondly walking to school in bare feet as they were poor. He passed his exams and was admitted to …
Phase I Assessment of Safety and Therapeutic Activity of BAY1436032 in Patients with IDH1-Mutant Solid Tumors
Authors: Antje Wick, Oliver Bähr, Martin Schuler, Kristoffer Rohrberg, Sant P. Chawla, Filip Janku, David Schiff, Volker Heinemann, Yoshitaka Narita, Heinz-Josef Lenz, Masafumi Ikeda, Yuichi Ando, Wolfgang Wick, Joachim P. Steinbach, Michael C. Burger, Katharina Wenger, Ulrik Lassen, Kamalesh K. Sankhala, Cristiana Roggia, Isabelle Genvresse, Catya Munhoz, Christine Rentzsch, Susanne Reschke, Simon Langer, Markus Wagner, Stefan Kaulfuss, Charles Cai, Eleni Lagkadinou, Michael Jeffers, Carol Peña, Ghazaleh Tabatabai
Journal: Clinical Cancer Research (2021)

Abstract Purpose: BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics of BAY1436032, and to evaluate its potential pharmacodynamics and antitumor effects. Patients and Methods: The study comprised of dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily on a continuous basis in subjects with mIDH1 solid tumors. Results: In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across five doses (150–1,500 mg twice daily). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2-hydroxyglutarate levels of 76%. BAY1436032 was well tolerated and an MTD was not identified. A dose of 1,500 mg twice daily was selected for dose expansion, where 52 subjects were treated in cohorts representing four different tumor types [lower grade glioma (LGG), glioblastoma, intrahepatic cholangiocarcinoma, and a basket cohort of other tumor types]. The best clinical outcomes were in subjects with LGG (n = 35), with an objective response rate of 11% (one complete response and three partial responses) and stable disease in 43%. As of August 2020, four of these subjects were in treatment for &amp;gt;2 years and still ongoing. Objective responses were observed only in LGG. Conclusions: BAY1436032 was well tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG.
Fructose-functionalized polymers to enhance therapeutic potential of p-boronophenylalanine for neutron capture therapy
Authors: Takahiro Nomoto, Ying Yao, Yukiya Inoue, Minoru Suzuki, Kaito Kanamori, Hiroyasu Takemoto, Makoto Matsui, Keishiro Tomoda, Nobuhiro Nishiyama
Journal: Journal of Controlled Release (2021)