tbuckley/cabot-search huggingface dataset:
Abstract PO050: EphA2 signaling segregation and modulation by diverse tumor microenvironment components differentially regulates cancer cell invasion and survival
Authors: Lidia Moyano-Galceran, Pauliina S. Turunen, Nami Sugiyama, Pernilla von Nandelstadh, Erika Gucciardo, Markku Varjosalo, Kaisa Lehti
Journal: Cancer Research (2021)

Abstract The receptor tyrosine kinase EphA2 is overexpressed in many solid cancers and associated with disease aggressiveness and poor clinical outcome. EphA2 signaling mechanisms are complex, context-dependent and still not completely understood. In several cancers, EphA2-ephrinA1 interaction is associated with cell repulsion and growth suppressive signaling. Yet, this receptor can also be activated in a ligand-independent manner by crosstalk with growth factor receptors and adhesion molecules, and its signaling can be further regulated via proteolytic cleavage by the matrix metalloproteinase MT1-MMP (MMP14). Studying how such proteolytic events, duality in signaling modes and repulsive responses are co-regulated and coexist in cancer could reveal potential therapeutic opportunities. To this goal, we have here used human breast, ovarian and prostate cancer cells grown in 2D and 3D extracellular matrices (ECM), as mono- and co-cultures to mimic the confines provided by the tumor microenvironment. Our results revealed segregation of EphA2 signaling within cancer colonies, including EphA2-MMP14 co-internalization at the cancer cells confronting ephrinA1-expressing cells, in contrast to the stabilization of the receptor and induction of non-canonical signaling in the colonies. This separation of the ligand-mediated and non-canonical EphA2 signaling was dependent on MMP14 and affected platinum chemotherapy-induced apoptosis. By a mass spectroscopy-based screen for EphA2 interacting proteins in the different signaling contexts we identified regulators of proteolysis as well as endocytic pathways with differential interactions upon the ligand-dependent and independent activation states of this receptor. Our studies will help to understand the diverse EphA2 signaling modes and their impact on the regulation of cell-cell and cell-ECM communication affecting cell invasion and survival upon anti-cancer drug treatments. Citation Format: Lidia Moyano-Galceran, Pauliina S. Turunen, Nami Sugiyama, Pernilla von Nandelstadh, Erika Gucciardo, Markku Varjosalo, Kaisa Lehti. EphA2 signaling segregation and modulation by diverse tumor microenvironment components differentially regulates cancer cell invasion and survival [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 PO050.
Long-lasting analgesia via targeted in situ repression of Na <sub>V</sub> 1.7 in mice
Authors: Ana M. Moreno, Fernando Alemán, Glaucilene F. Catroli, Matthew Hunt, Michael Hu, Amir Dailamy, Andrew Pla, Sarah A. Woller, Nathan Palmer, Udit Parekh, Daniella McDonald, Amanda J. Roberts, Vanessa Goodwill, Ian Dryden, Robert F. Hevner, Lauriane Delay, Gilson Gonçalves dos Santos, Tony L. Yaksh, Prashant Mali
Journal: Science Translational Medicine (2021)

Current treatments for chronic pain rely largely on opioids despite their substantial side effects and risk of addiction. Genetic studies have identified in humans key targets pivotal to nociceptive processing. In particular, a hereditary loss-of-function mutation in Na
Kynurenine Relaxes Arteries of Normotensive Women and Those With Preeclampsia
Authors: Stephanie A. Worton, Harry A.T. Pritchard, Susan L. Greenwood, Mariam Alakrawi, Alexander E.P. Heazell, Mark Wareing, Adam Greenstein, Jenny E. Myers
Journal: Circulation Research (2021)

Rationale: Activation of the kynurenine pathway of tryptophan catabolism by infection and inflammation contributes to the development of systemic hypotension. Commercially-available kynurenine has direct vasorelaxant effects on arteries from several species and reduces systemic blood pressure when administered to normotensive or hypertensive rats. Objectives: To determine whether kynurenine promotes relaxation of human resistance arteries from normotensive and hypertensive pregnant women and to identify the vascular mechanism of its effects. Methods and Results: In isolated omental and myometrial resistance arteries from normotensive pregnant women, kynurenine (1 mmol/L) significantly reduced U46619-induced constriction (omentum N=14, P =2.4×10 −3 ; myometrium N=21–25, P =2.6×10 −4 ) and relaxed preconstricted arteries (N=53, P =1.0×10 −11 ; N=20, P =8.8×10 −3 ). Vasorelaxation persisted following endothelium removal (N=7, P =1.6×10 −4 ) but was completely prevented by inhibition of large-conductance Ca 2+ -activated K + channels (BK Ca ) channels with iberiotoxin (N=9, P =5.7×10 −4 ) or paxilline (N=10, P =2.1×10 −17 ). Accordingly, in isolated vascular smooth muscle cells from omental arteries, kynurenine increased the BK Ca current (n=5–8, P =0.022) and the amplitude of spontaneous transient outward currents (n=6, P =0.031) but did not affect spontaneous transient outward current frequency. Kynurenine also increased Ca 2+ spark frequency of pressurized omental arteries (n=8, P =0.031). Vasorelaxant effects of kynurenine persisted following inhibition of ryanodine receptors (N=7, P =0.48) but were moderately reduced by inhibition of adenylate cyclase (N=9, P =0.024). In arteries from women with preeclampsia, kynurenine similarly attenuated vasoconstriction (N=15, P =1.3×10 −5 ) and induced BK Ca -mediated vasodilation (N=16, P =2.0×10 −4 ). Vasorelaxation in response to kynurenine and a specific BK Ca activator, NS11021, was absent in fetal-derived placental resistance arteries in normal pregnancy and preeclampsia. Conclusions: Kynurenine dilates systemic arteries from multiple territories via BK Ca activation. Notably, the vasorelaxatory capacity of kynurenine is preserved in preeclampsia, suggesting this approach may have translational potential for the treatment of hypertension in pregnancy. The data warrant further investigation of the potential to exploit this endogenous vasorelaxant as a new treatment for hypertensive pathologies.
Targeting autophagy using small-molecule compounds to improve potential therapy of Parkinson's disease
Authors: Kai Zhang, Shiou Zhu, Jiamei Li, Tingting Jiang, Lu Feng, Junping Pei, Guan Wang, Liang Ouyang, Bo Liu
Journal: Acta Pharmaceutica Sinica B (2021)

Parkinson's disease (PD), known as one of the most universal neurodegenerative diseases, is a serious threat to the health of the elderly. The current treatment has been demonstrated to relieve symptoms, and the discovery of new small-molecule compounds has been regarded as a promising strategy. Of note, the homeostasis of the autolysosome pathway (ALP) is closely associated with PD, and impaired autophagy may cause the death of neurons and thereby accelerating the progress of PD. Thus, pharmacological targeting autophagy with small-molecule compounds has been drawn a rising attention so far. In this review, we focus on summarizing several autophagy-associated targets, such as AMPK, mTORC1, ULK1, IMPase, LRRK2, beclin-1, TFEB, GCase, ERRα, C-Abelson, and as well as their relevant small-molecule compounds in PD models, which will shed light on a clue on exploiting more potential targeted small-molecule drugs tracking PD treatment in the near future.
Convergent Biochemical Pathways for Xanthine Alkaloid Production in Plants Evolved from Ancestral Enzymes with Different Catalytic Properties
Authors: Andrew J. O’Donnell, Ruiqi Huang, Jessica J. Barboline, Todd J. Barkman
Journal: Molecular Biology and Evolution (2021)

Convergent evolution is widespread but the extent to which common ancestral conditions are necessary to facilitate the independent acquisition of similar traits remains unclear. In order to better understand how ancestral biosynthetic catalytic capabilities might lead to convergent evolution of similar modern-day biochemical pathways, we resurrected ancient enzymes of the caffeine synthase (CS) methyltransferases that are responsible for theobromine and caffeine production in flowering plants. Ancestral CS enzymes of Theobroma, Paullinia, and Camellia exhibited similar substrate preferences but these resulted in the formation of different sets of products. From these ancestral enzymes, descendants with similar substrate preference and product formation independently evolved after gene duplication events in Theobroma and Paullinia. Thus, it appears that the convergent modern-day pathways likely originated from ancestral pathways with different inferred flux. Subsequently, the modern-day enzymes originated independently via gene duplication and their convergent catalytic characteristics evolved to partition the multiple ancestral activities by different mutations that occurred in homologous regions of the ancestral proteins. These results show that even when modern-day pathways and recruited genes are similar, the antecedent conditions may be distinctive such that different evolutionary steps are required to generate convergence.
Specific proteome changes in platelets from individuals with GATA1-, GFI1B-, and RUNX1-linked bleeding disorders
Authors: M. G. J. M. Van Bergen, A. E. Marneth, A. J. Hoogendijk, F. P. J. Van Alphen, E. Van den Akker, B. A. P. Laros-Van Gorkom, M. Hoeks, A. Simons, S. A. De Munnik, J. J. W. M. Janssen, J. H. A. Martens, J. H. Jansen, A. B. Meijer, B. A. Van der Reijden
Journal: Blood (2021)
Researcher broke embargo to leak BMJ paper to Trump administration
Authors: Owen Dyer
Journal: BMJ (2021)

A medical researcher who took a political appointment with the Trump administration while working on a major international meta-analysis of potential covid-19 treatments leaked a preprint version of the research to senior government colleagues last year, documents released in a congressional investigation show.1

Paul Alexander, a former assistant professor at McMaster University in Canada who specialises in health research methods, wrote in an email to Stephen Hahn, commissioner of the Food and Drug Administration (FDA), that the research lent support to a role for hydroxychloroquine.

The FDA authorised the antimalarial on an emergency basis last April under pressure from Trump, but revoked this in June, citing the drug’s “known risks” and stating that it was “no longer reasonable to …
Next-generation Sequencing in Bone Marrow Failure Syndromes and Isolated Cytopenias: Experience of the Spanish Network on Bone Marrow Failure Syndromes
Authors: Eva Gálvez, Elena Vallespín, Elena G. Arias-Salgado, Carmen Sánchez-Valdepeñas, Yari Giménez, Susana Navarro, Paula Río, Massimo Bogliolo, Roser Pujol, Montserrat Peiró, Julián Nevado, Josune Zubicaray, Elena Sebastián, Albert Catalá, Cristina Beléndez, Cristina Díaz de Heredia, Ana Galera, Isabel Badell, Luis Madero, Rosario Perona, Leandro Sastre, Jordi Surrallés, Juan Bueren, Pablo Lapunzina, Julián Sevilla
Journal: HemaSphere (2021)

Inherited bone marrow failure syndromes (IBMFSs) are a group of congenital rare diseases characterized by bone marrow failure, congenital anomalies, high genetic heterogeneity, and predisposition to cancer. Appropriate treatment and cancer surveillance ideally depend on the identification of the mutated gene. A next-generation sequencing (NGS) panel of genes could be 1 initial genetic screening test to be carried out in a comprehensive study of IBMFSs, allowing molecular detection in affected patients. We designed 2 NGS panels of IBMFS genes: version 1 included 129 genes and version 2 involved 145 genes. The cohort included a total of 204 patients with suspected IBMFSs without molecular diagnosis. Capture-based targeted sequencing covered &gt; 99% of the target regions of 145 genes, with more than 20 independent reads. No differences were seen between the 2 versions of the panel. The NGS tool allowed a total of 91 patients to be diagnosed, with an overall molecular diagnostic rate of 44%. Among the 167 patients with classified IBMFSs, 81 patients (48%) were diagnosed. Unclassified IBMFSs involved a total of 37 patients, of whom 9 patients (24%) were diagnosed. The preexisting diagnosis of 6 clinically classified patients (6%) was amended, implying a change of therapy for some of them. Our NGS IBMFS gene panel assay is a useful tool in the molecular diagnosis of IBMFSs and a reasonable option as the first tier genetic test in these disorders.
Abstract 2327: Predictors Of Procedural Outcome In Percutaneous Coronary Intervention For Chronic Total Occlusions: Value Of Preprocedural Multislice Computed Tomographic Coronary Angiography
Authors: Mariko Ehara, Masato Kawai, Shunichi Matsushita, Osamu Kato, Yasushi Asakura, Tetsuo Matsubara, Mitsuyasu Terashima, Etsuo Tsuchikane, Yasuhisa Kinoshita, Kenya Nasu, Nobuyoshi Tanaka, Takamatsu Horisaki, Takuo Izuka, Koyo Sato, Atsuko Kodama, Takahiko Suzuki
Journal: Circulation (2007)

Purpose: Percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) is still one of the challenging procedures. Multislice computed tomographic coronary angiography (CTCA) allows re...
Tissue Homeostasis and Inflammation
Authors: Matthew L. Meizlish, Ruth A. Franklin, Xu Zhou, Ruslan Medzhitov
Journal: Annual Review of Immunology (2021)

There is a growing interest in understanding tissue organization, homeostasis, and inflammation. However, despite an abundance of data, the organizing principles of tissue biology remain poorly defined. Here, we present a perspective on tissue organization based on the relationships between cell types and the functions that they perform. We provide a formal definition of tissue homeostasis as a collection of circuits that regulate specific variables within the tissue environment, and we describe how the functional organization of tissues allows for the maintenance of both tissue and systemic homeostasis. This leads to a natural definition of inflammation as a response to deviations from homeostasis that cannot be reversed by homeostatic mechanisms alone. We describe how inflammatory signals act on the same cellular functions involved in normal tissue organization and homeostasis in order to coordinate emergency responses to perturbations and ultimately return the system to a homeostatic state. Finally, we consider the hierarchy of homeostatic and inflammatory circuits and the implications for the development of inflammatory diseases.
Vincristine-induced peripheral neuropathy is driven by canonical NLRP3 activation and IL-1β release
Authors: Hana Starobova, Mercedes Monteleone, Christelle Adolphe, Lena Batoon, Cheyenne J. Sandrock, Bryan Tay, Jennifer R. Deuis, Alexandra V. Smith, Alexander Mueller, Evelyn Israel Nadar, Grace Pamo Lawrence, Amanda Mayor, Elissa Tolson, Jean-Pierre Levesque, Allison R. Pettit, Brandon J. Wainwright, Kate Schroder, Irina Vetter
Journal: The Journal of Experimental Medicine (2021)

Vincristine is an important component of many regimens used for pediatric and adult malignancies, but it causes a dose-limiting sensorimotor neuropathy for which there is no effective treatment. This study aimed to delineate the neuro-inflammatory mechanisms contributing to the development of mechanical allodynia and gait disturbances in a murine model of vincristine-induced neuropathy, as well as to identify novel treatment approaches. Here, we show that vincristine-induced peripheral neuropathy is driven by activation of the NLRP3 inflammasome and subsequent release of interleukin-1β from macrophages, with mechanical allodynia and gait disturbances significantly reduced in knockout mice lacking NLRP3 signaling pathway components, or after treatment with the NLRP3 inhibitor MCC950. Moreover, treatment with the IL-1 receptor antagonist anakinra prevented the development of vincristine-induced neuropathy without adversely affecting chemotherapy efficacy or tumor progression in patient-derived medulloblastoma xenograph models. These results detail the neuro-inflammatory mechanisms leading to vincristine-induced peripheral neuropathy and suggest that repurposing anakinra may be an effective co-treatment strategy to prevent vincristine-induced peripheral neuropathy.
The gut microbiota during the progression of atherosclerosis in the perimenopausal period shows specific compositional changes and significant correlations with circulating lipid metabolites
Authors: Qinghai Meng, Menghua Ma, Weiwei Zhang, Yunhui Bi, Peng Cheng, Xichao Yu, Yu Fu, Ying Chao, Tingting Ji, Jun Li, Qi Chen, Qichun Zhang, Yu Li, Jinjun Shan, Huimin Bian
Journal: Gut Microbes (2021)

Atherosclerosis (AS) is exacerbated in the perimenopausal period, which significantly increases the incidence rate of cardiovascular disease. The disruption of the gut microbiota has been associated with AS or menopause, but the specific changes of AS-associated gut microbiota in the perimenopausal period remain largely unknown. As lipid abnormalities are mainly responsible for AS, the relationship between lipid metabolism abnormalities and gut microbiota disruptions during menopause is rarely reported hitherto. In the present study, ApoE-/- mice fed with a high-fat diet (HFD) were subjected to ovariectomy and supplemented with estrogen. The ovariectomized HFD-fed ApoE-/- mice underwent significant AS damage, hepatic lipid damage, hyperlipidemia, and changes of lipid metabolism- and transport-related enzymes. There was significantly higher abundance of some lipid metabolites in the plasma of ovariectomized HFD-fed ApoE-/- mice than in non-ovariectomized ones, including cholesterol esters, triglycerides, phospholipids, and other types of lipids (free fatty acids, acylcarnitine, sphingomyelins, and ceramides). The administration of estrogen significantly reduced the contents of most lipid metabolites. The diversity and composition of gut microbiota evidently changed in ovariectomized HFD-fed ApoE-/- mice, compared to HFD-fed ApoE-/- mice without ovariectomy. In contrast, with estrogen supplementation, the diversity and composition of gut microbiota were restored to approach that of non-ovariectomized HFD-fed ApoE-/- mice, and the relative abundances of some bacteria were even like those of C57BL/6 mice fed with a normal diet. On the other hand, the transplantation of feces from C57BL/6 mice fed with normal diet to ovariectomized HFD-fed ApoE-/- mice was sufficient to correct the hyperlipidemia and AS damage, and to reverse the characteristics changing of lipid metabolomics in ovariectomized HFD-fed ApoE-/- mice. These phenomena were also been observed after transplantation of feces from estrogen-treated ovariectomized HFD-fed ApoE-/- mice to ovariectomized HFD-fed ApoE-/- mice. Moreover, the gut microbiota and lipid metabolites were significantly correlated, demonstrating that the changes of serum lipids may be associated with the gut microbiota disruptions in the perimenopausal period. In conclusion, the gut microbiota during the progression of AS in the perimenopausal period showed specific compositional changes and significant correlations with circulating lipid metabolites. Estrogen supplementation may exert beneficial effects on gut bacteria and lipid metabolism.
High-Altitude Adaptation: Mechanistic Insights from Integrated Genomics and Physiology
Authors: Jay F. Storz
Journal: Molecular Biology and Evolution (2021)

Abstract Population genomic analyses of high-altitude humans and other vertebrates have identified numerous candidate genes for hypoxia adaptation, and the physiological pathways implicated by such analyses suggest testable hypotheses about underlying mechanisms. Studies of highland natives that integrate genomic data with experimental measures of physiological performance capacities and subordinate traits are revealing associations between genotypes (e.g., hypoxia-inducible factor gene variants) and hypoxia-responsive phenotypes. The subsequent search for causal mechanisms is complicated by the fact that observed genotypic associations with hypoxia-induced phenotypes may reflect second-order consequences of selection-mediated changes in other (unmeasured) traits that are coupled with the focal trait via feedback regulation. Manipulative experiments to decipher circuits of feedback control and patterns of phenotypic integration can help identify causal relationships that underlie observed genotype–phenotype associations. Such experiments are critical for correct inferences about phenotypic targets of selection and mechanisms of adaptation.
Ability to assess the effects of test substances on HsRAD51 promoter activity may help predict oncogenic potential
Authors: Robert C. Bertheau, Masood A. Shammas, Vidit Munshi, Frank Desarnaud, Nikhil C. Munshi
Journal: Cancer Research (2006)

798  The molecular basis for the generation of genetic diversity in cancer cells has emerged as an important focus of investigation. We have previously shown that homologous recombination (HR), required for a variety of normal cellular processes, is dysregulated in cancers and leads to the progressive accumulation of genetic variation over time. Moreover the inhibition or stimulation of HR activity in cancer cells, by altering components of the HR pathway, concordantly affects the acquisition of new genetic. Consistent with this, an elevated frequency of cancer is observed in patients whose cells have elevated rate of recombination. A dysregulated expression of HsRAD51 recombinase, a key player in HR can cause an increase in HR activity, leading to increased rate of mutations, telomere elongation, and development of cancer. We have previously demonstrated that siRNAs targeting hsRAD51 can completely inhibit acquisition of new mutation in cancer cells. Based on these data, we hypothesized that hsRAD51 promoter activity may be a target of carcinogenic agents and ability to measure the hsRAD51 promoter activity may provide a method to assess carcinogenic potential of a test agent. To this end we constructed a mammalian expression vector containing firefly luciferase gene downstream of hsRAD51 promoter. This plasmid was introduced into normal human diploid fibroblasts and 24 hrs later the transfected cells were exposed to carcinogens or the control vehicle. Following 2 hrs exposure, cells are lysed and luciferase activity assayed. Although exposure to a non-carcinogen, Sodium azide did not induce hsRAD51 promoter activity or HR activity in normal fibroblasts, exposure to agents with known transforming ability, Mitomycin C and Nickel chloride, led to a significant induction of hsRAD51 promoter activity (2.5 and 3.5-fold respectively) in normal fibroblast. In these cells we have also confirmed an associated elevation in HR activity following treatment with these chemicals. These agents were also able to further induce hsRAD51 promoter in myeloma cells, with known over-expression of hsRAD51. We have further evaluated the effects of anti-oxidants on hsRAD51 promoter activity. In myeloma cells with elevated hsRAD51 expression, the anti-oxidant tocopherol and cannabinol were able to reduce hsRAD51 promoter activity by 3- and 8-fold respectively while vitamin C and Selenium had minimal effects. These preliminary results provide us with an ability to measure potential of known carcinogens to induce HR. Validation of this test is underway prior to its application to screen agents with ability to transform cells or inhibit HR activity.