tbuckley/cabot-search huggingface dataset:
The RECOVERY trial: cardiovascular implications of a large, simple randomized trial in COVID-19
Authors: Guilherme Pessoa-Amorim, Marion M Mafham
Journal: Cardiovascular Research (2021)

COVID-19 and the cardiovascular systemCOVID-19 primarily causes lung injury, but the disease also affects the cardiovascular system in a number of ways.First, in many countries, cardiovascular care pathways have been disrupted by the pandemic.Second, individuals with cardiovascular disease are at increased risk of hospitalization with, and death from COVID-19. 1 Last, COVID-19 causes a range of immediate cardiovascular complications, principally thrombo-embolic events (both venous and arterial), myocardial injury, and cardiac arrhythmias. 2Whether COVID-19 leads to specific longterm cardiovascular sequelae remains unclear.Generalized hyper-inflammation and multi-organ damage are the hallmark of severe COVID-19, promoted by immune cell activation and release of pro-inflammatory cytokines [such as interleukin (IL)-1, IL-6, and tumour necrosis factor-alpha], as well as D-dimers, ferritin, and C-reactive protein. 3,4The ensuing coagulopathy, Neutrophil-Extracellular-Traps(NET)osis, and platelet activation, lead to widespread vascular inflammation and dysfunction across multiple beds. 5Moreover, SARS-CoV-2 can directly infect endothelial cells through the ACE2 receptor, causing vascular damage and apoptosis. 6Indeed, localized immunothrombosis and microangiopathy are a ubiquitous finding in pulmonary COVID-19 autopsies and underlie the typical pattern of diffuse alveolar damage and hypoxia, but also the cardiac, cerebral, renal, and hepatic damage seen in severe presentations.
A Percentage of Normal B Cells from CLL Patients Express ZAP-70, Which Is Associated with Autoimmunity and Could be Responsible for Arising of Malignant Clone
Authors: Dana Ghergus, Anne-Marie Knapp, Fabien Delmotte, Mickael Martin, Sophie Jung, Jean-Nicolas Schickel, Bernard Drenou, Raoul Herbrecht, Jean-Louis Pasquali, Anne-Sophie Korganow, Laurent Daniel Vallat, Pauline Soulas-Sprauel, Eric Meffre, Thierry Martin
Journal: Blood (2017)
Improvement of a SARS-CoV-2 vaccine by enhancing the conjugation efficiency of the immunogen to self-assembled nanoparticles
Authors: Xiantao Zhang, Yaochang Yuan, Bolin Wu, Xuemei Wang, Yingtong Lin, Yuewen Luo, Rong Li, Tao Chen, Jieyi Deng, Xu Zhang, Fan Zou, Xin He, Hui Zhang
Journal: Cellular and Molecular Immunology (2021)
Transplantation of an obesity-associated human gut microbiota to mice induces vascular dysfunction and glucose intolerance
Authors: S. Raj J. Trikha, Dustin M. Lee, Kayl E. Ecton, Scott D. Wrigley, Allegra R. Vazquez, Nicole S. Litwin, Keely N. Thomas, Yuren Wei, Micah L. Battson, Sarah A. Johnson, Kristine A. Kuhn, Sean P. Colgan, Christopher L. Gentile, Tiffany L. Weir
Journal: Gut Microbes (2021)

Recent preclinical data suggest that alterations in the gut microbiota may be an important factor linking obesity to vascular dysfunction, an early sign of cardiovascular disease. The purpose of this study was to begin translation of these preclinical data by examining whether vascular phenotypes in humans are transmissible through the gut microbiota. We hypothesized that germ-free mice colonized with gut microbiota from obese individuals would display diminished vascular function compared to germ-free mice receiving microbiota from lean individuals.We transplanted fecal material from obese and lean age-and sex-matched participants with disparate vascular function to germ-free mice. Using Principle Component Analysis, the microbiota of colonized mice separated by donor group along the first principle component, accounting for between 70–93% of the total variability in the dataset. The microbiota of mice receiving transplants from lean individuals was also characterized by increased alpha diversity, as well as increased relative abundance of potentially beneficial bacteria, including Bifidobacterium, Lactobacillus, and Bacteroides ovatis. Endothelium-dependent dilation, aortic pulse wave velocity and glucose tolerance were significantly altered in mice receiving microbiota from the obese donor relative to those receiving microbiota from the lean donor or those remaining germ-free.These data indicate that the obesity-associated human gut microbiota is sufficient to alter the vascular phenotype in germ-free mice in the absence of differences in body weight or dietary manipulation, and provide justification for future clinical trials to test the efficacy of microbiota-targeted therapies in the prevention or treatment of cardiovascular disease.
Lentiviral-Driven Discovery of Cancer Drug Resistance Mutations
Authors: Paul Yenerall, Rahul K. Kollipara, Kimberley Avila, Michael Peyton, Christopher A. Eide, Daniel Bottomly, Shannon K. McWeeney, Yan Liu, Kenneth D. Westover, Brian J. Druker, John D. Minna, Ralf Kittler
Journal: Cancer Research (2021)

Identifying resistance mutations in a drug target provides crucial information. Lentiviral transduction creates multiple types of mutations due to the error-prone nature of the HIV-1 reverse transcriptase (RT). Here we optimized and leveraged this property to identify drug resistance mutations, developing a technique we term LentiMutate. This technique was validated by identifying clinically relevant EGFR resistance mutations, then applied to two additional clinical anticancer drugs: imatinib, a BCR-ABL inhibitor, and AMG 510, a KRAS G12C inhibitor. Novel deletions in BCR-ABL1 conferred resistance to imatinib. In KRAS-G12C or wild-type KRAS, point mutations in the AMG 510 binding pocket or oncogenic non-G12C mutations conferred resistance to AMG 510. LentiMutate should prove highly valuable for clinical and preclinical cancer-drug development. SIGNIFICANCE: LentiMutate can evaluate a drug's on-target activity and can nominate resistance mutations before they occur in patients, which could accelerate and refine drug development to increase the survival of patients with cancer.
Intratumoral talimogene laherparepvec injection with concurrent preoperative radiation in patients with locally advanced soft-tissue sarcoma of the trunk and extremities: phase IB/II trial
Authors: Varun Monga, Benjamin J Miller, Munir Tanas, Sarag Boukhar, Bryan Allen, Carryn Anderson, Laura Stephens, Stacey Hartwig, Steven Varga, Jon Houtman, Lei Wang, Weizhou Zhang, Omar Jaber, Jon Thomason, David Kuehn, Maheen Rajput, Catherine Metz, K.D. Zamba, Sarah Mott, Chinemerem Abanonu, Sudershan Bhatia, Mohammed Milhem
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Soft-tissue sarcomas (STS) in the extremities and trunk treated with standard-of-care preoperative external beam radiation therapy (EBRT) followed by surgical resection are associated with local and distant relapses. In preclinical studies, oncolytic virotherapy in sarcoma has demonstrated antitumor effects via direct intratumoral oncolysis and cytotoxic T-cell–mediated immune responses. Talimogene laherparepvec (TVEC) is a replication-competent, immune-enhanced, oncolytic herpes simplex virus type 1 engineered for intratumoral injection; it has been approved by the FDA for the treatment of locally advanced and metastatic melanoma. Methods We explored a novel combination of TVEC with standard-of-care EBRT administered preoperatively in patients with locally advanced STS of the extremities and trunk in a phase IB/II clinical trial. Thirty patients with primary STS &gt;5 cm for which EBRT was indicated to achieve negative margins were enrolled. FDA-approved TVEC doses were used. Immune correlative studies in peripheral blood, biopsy and resected tumor tissues were performed. Results No dose-limiting toxicity was observed. Adverse events were similar to those reported in prior studies with TVEC. One patient with myxoid liposarcoma exhibited a partial response. Seven of the 29 (24%) evaluable patients achieved 95% pathological necrosis. None of the patients developed a herpes infection due to the treatment. Eight of the 29 (27%) patients developed postoperative wound complications, which is consistent with previous studies. None of the patients developed local recurrence after surgical resection of the primary sarcoma. 2-year progression-free and overall survival were 57% and 88%, respectively. Caspase-3 demonstrated increased expression of both in TVEC-treated tissue samples as compared with control samples treated with radiation alone. Conclusion Preoperative intratumoral TVEC with concurrent EBRT for locally advanced STS is safe and well-tolerated. This combination treatment may enhance immune responses in some cases but did not increase the proposed rate of pathological necrosis. The Caspase-3 biomarker may be associated with a positive effect of TVEC in sarcoma tumor tissue and should be explored in future studies. Trial registration number NCT02453191 .
Strong, Recent Selective Sweeps Reshape Genetic Diversity in Freshwater Bivalve<i>Megalonaias nervosa</i>
Authors: Rebekah L Rogers, Stephanie L Grizzard, Jeffrey T Garner
Journal: Molecular Biology and Evolution (2023)

Abstract Freshwater Unionid bivalves have recently faced ecological upheaval through pollution, barriers to dispersal, harvesting, and changes in fish–host prevalence. Currently, over 70% of species in North America are threatened, endangered or extinct. To characterize the genetic response to recent selective pressures, we collected population genetic data for one successful bivalve species, Megalonaias nervosa. We identify megabase-sized regions that are nearly monomorphic across the population, signals of strong, recent selection reshaping diversity across 73 Mb total. These signatures of selection are greater than is commonly seen in population genetic models. We observe 102 duplicate genes with high dN/dS on terminal branches among regions with sweeps, suggesting that gene duplication is a causative mechanism of recent adaptation in M. nervosa. Genes in sweeps reflect functional classes important for Unionid survival, including anticoagulation genes important for fish host parasitization, detox genes, mitochondria management, and shell formation. We identify sweeps in regions with no known functional impacts, suggesting mechanisms of adaptation that deserve greater attention in future work on species survival. In contrast, polymorphic transposable elements (TEs) appear to be detrimental and underrepresented among regions with sweeps. TE site frequency spectra are skewed toward singleton variants, and TEs among regions with sweeps are present at low frequency. Our work suggests that duplicate genes are an essential source of genetic novelty that has helped this species succeed in environments where others have struggled. These results suggest that gene duplications deserve greater attention in non-model population genomics, especially in species that have recently faced sudden environmental challenges.
SO-13 KRAS-G12C mutations in a Nordic cohort of 1441 metastatic colorectal cancer patients
Authors: E. Osterlund, T. Muhonen, A. Ristimäki, S. Kytölä, T. Kuopio, P. Halonen, R. Kallio, L. Soveri, E. Heervä, J. Sundström, M. Keinänen, A. Ålgars, R. Ristamäki, H. Sorbye, P. Pfeiffer, K. Pulkkanen, L. Nunes, T. Salminen, A. Lamminmäki, H. Isoniemi, B. Glimelius, P. Osterlund
Journal: Annals of Oncology (2021)
Testosterone therapy and cardiovascular diseases
Authors: Antonio Cittadini, Andrea M Isidori, Andrea Salzano
Journal: Cardiovascular Research (2021)

Since it was first synthesized in 1935, testosterone (T) has been viewed as the mythical Fountain of Youth, promising rejuvenation, restoring sexual appetites, growing stronger muscles, and quicker thinking. T is endowed with direct effects on myocardial and vascular structure and function, as well as on risk factors for cardiovascular (CV) disease. Indeed, low serum T levels are a risk factor for diabetes, metabolic syndrome, inflammation, and dyslipidaemia. Moreover, many studies have shown that T deficiency per se is an independent risk factor of CV and all-cause mortality. On this background and due to direct-to-patient marketing by drug companies, we have witnessed to the widespread use of T replacement therapy without clear indications particularly in late-life onset hypogonadism. The current review will dwell upon current evidence and controversies surrounding the role of T in the pathophysiology of CV diseases, the link between circulating T levels and CV risk, and the use of replacing T as a possible adjuvant treatment in specific CV disorders. Specifically, recent findings suggest that heart failure and type 2 diabetes mellitus represent two potential targets of T therapy once that a state of hypogonadism is diagnosed. However, only if ongoing studies solve the CV safety issue the T orchid may eventually 'bloom'.
P8-3 Prognostic factors for nivolumab monotherapy in postoperative recurrence of non-small cell lung cancer
Authors: Takashi Inoue, Hiromi Ishihama, Taimei Tachibana, Nobuhiro Imamura, Yuuto Nonaka, Yoshiyuki Ito, Osamu Araki, Maeda Sumiko, Masayuki Chida
Journal: Annals of Oncology (2021)
BUSCO Update: Novel and Streamlined Workflows along with Broader and Deeper Phylogenetic Coverage for Scoring of Eukaryotic, Prokaryotic, and Viral Genomes
Authors: Mosè Manni, Matthew R Berkeley, Mathieu Seppey, Felipe A Simão, Evgeny M Zdobnov
Journal: Molecular Biology and Evolution (2021)

Abstract Methods for evaluating the quality of genomic and metagenomic data are essential to aid genome assembly procedures and to correctly interpret the results of subsequent analyses. BUSCO estimates the completeness and redundancy of processed genomic data based on universal single-copy orthologs. Here, we present new functionalities and major improvements of the BUSCO software, as well as the renewal and expansion of the underlying data sets in sync with the OrthoDB v10 release. Among the major novelties, BUSCO now enables phylogenetic placement of the input sequence to automatically select the most appropriate BUSCO data set for the assessment, allowing the analysis of metagenome-assembled genomes of unknown origin. A newly introduced genome workflow increases the efficiency and runtimes especially on large eukaryotic genomes. BUSCO is the only tool capable of assessing both eukaryotic and prokaryotic species, and can be applied to various data types, from genome assemblies and metagenomic bins, to transcriptomes and gene sets.
Newly defined allergens in the WHO/IUIS Allergen Nomenclature Database during 01/2019‐03/2021
Authors: Srinidhi Sudharson, Tanja Kalic, Christine Hafner, Heimo Breiteneder
Journal: Allergy (2021)

The WHO/IUIS Allergen Nomenclature Database (http://allergen.org) provides up-to-date expert-reviewed data on newly discovered allergens and their unambiguous nomenclature to allergen researchers worldwide. This review discusses the 106 allergens that were accepted by the Allergen Nomenclature Sub-Committee between 01/2019 and 03/2021. Information about protein family membership, patient cohorts, and assays used for allergen characterization is summarized. A first allergenic fungal triosephosphate isomerase, Asp t 36, was discovered in Aspergillus terreus. Plant allergens contained 1 contact, 38 respiratory, and 16 food allergens. Can s 4 from Indian hemp was identified as the first allergenic oxygen-evolving enhancer protein 2 and Cic a 1 from chickpeas as the first allergenic group 4 late embryogenesis abundant protein. Among the animal allergens were 19 respiratory, 28 food, and 3 venom allergens. Important discoveries include Rap v 2, an allergenic paramyosin in molluscs, and Sal s 4 and Pan h 4, allergenic fish tropomyosins. Paramyosins and tropomyosins were previously known mainly as arthropod allergens. Collagens from barramundi, Lat c 6, and salmon, Sal s 6, were the first members from the collagen superfamily added to the database. In summary, the addition of 106 new allergens to the previously listed 930 allergens reflects the continuous linear growth of the allergen database. In addition, 17 newly described allergen sources were included.
Long covid—mechanisms, risk factors, and management
Authors: Harry Crook, Sanara Raza, Joseph Nowell, Megan Young, Paul Edison
Journal: BMJ (2021)

Since its emergence in Wuhan, China, covid-19 has spread and had a profound effect on the lives and health of people around the globe. As of 4 July 2021, more than 183 million confirmed cases of covid-19 had been recorded worldwide, and 3.97 million deaths. Recent evidence has shown that a range of persistent symptoms can remain long after the acute SARS-CoV-2 infection, and this condition is now coined long covid by recognized research institutes. Studies have shown that long covid can affect the whole spectrum of people with covid-19, from those with very mild acute disease to the most severe forms. Like acute covid-19, long covid can involve multiple organs and can affect many systems including, but not limited to, the respiratory, cardiovascular, neurological, gastrointestinal, and musculoskeletal systems. The symptoms of long covid include fatigue, dyspnea, cardiac abnormalities, cognitive impairment, sleep disturbances, symptoms of post-traumatic stress disorder, muscle pain, concentration problems, and headache. This review summarizes studies of the long term effects of covid-19 in hospitalized and non-hospitalized patients and describes the persistent symptoms they endure. Risk factors for acute covid-19 and long covid and possible therapeutic options are also discussed.
CCDC65 as a new potential tumor suppressor induced by metformin inhibits activation of AKT1 via ubiquitination of ENO1 in gastric cancer
Authors: Tongyuan Deng, Peng Shen, Aimin Li, Ziyan Zhang, Huiling Yang, Xiaojie Deng, Xuemei Peng, Zhe Hu, Zibo Tang, Jiahao Liu, Rentao Hou, Zhen Liu, Weiyi Fang
Journal: Theranostics (2021)

The coiled-coil domain containing protein members have been well documented for their roles in many diseases including cancers. However, the function of the coiled-coil domain containing 65 (CCDC65) remains unknown in tumorigenesis including gastric cancer. Methods: CCDC65 expression and its correlation with clinical features and prognosis of gastric cancer were analyzed in tissue. The biological role and molecular basis of CCDC65 were performed via in vitro and in vivo assays and a various of experimental methods including co-immunoprecipitation (Co-IP), GST-pull down and ubiquitination analysis et al. Finally, whether metformin affects the pathogenesis of gastric cancer by regulating CCDC65 and its-mediated signaling was investigated. Results: Here, we found that downregulated CCDC65 level was showed as an unfavourable factor in gastric cancer patients. Subsequently, CCDC65 or its domain (a.a. 130-484) was identified as a significant suppressor in GC growth and metastasis in vitro and in vivo. Molecular basis showed that CCDC65 bound to ENO1, an oncogenic factor has been widely reported to promote the tumor pathogenesis, by its domain (a.a. 130-484) and further promoted ubiquitylation and degradation of ENO1 by recruiting E3 ubiquitin ligase FBXW7. The downregulated ENO1 decreased the binding with AKT1 and further inactivated AKT1, which led to the loss of cell proliferation and EMT signal. Finally, we observed that metformin, a new anti-cancer drug, can significantly induce CCDC65 to suppress ENO1-AKT1 complex-mediated cell proliferation and EMT signals and finally suppresses the malignant phenotypes of gastric cancer cells. Conclusion: These results firstly highlight a critical role of CCDC65 in suppressing ENO1-AKT1 pathway to reduce the progression of gastric cancer and reveals a new molecular mechanism for metformin in suppressing gastric cancer. Our present study provides a new insight into the mechanism and therapy for gastric cancer.
P-292 Tumor downstaging as an associated factor with recurrence of disease in patients with operated rectal cancer after neoadjuvant chemoradiotherapy: Real-world data from Peru
Authors: R. Motta, O. Cordova, S. Quiroz, P. Ybazeta, V. Failoc Rojas, C. Aliaga, A. Figueroa
Journal: Annals of Oncology (2021)
Mast cell surfaceome characterization reveals CD98 heavy chain is critical for optimal cell function
Authors: Siddhartha S Saha, Nyssa B Samanas, Irina Miralda, Nicholas J Shubin, Kerri Niino, Gauri Bhise, Manasa Acharya, Albert J Seo, Nathan Camp, Gail H Deutsch, Richard G James, Adrian M Piliponsky
Journal: Journal of Allergy and Clinical Immunology (2021)
GD2-directed bispecific trifunctional antibody outperforms dinutuximab beta in a murine model for aggressive metastasized neuroblastoma
Authors: Felix Zirngibl, Sara M Ivasko, Laura Grunewald, Anika Klaus, Silke Schwiebert, Peter Ruf, Horst Lindhofer, Kathy Astrahantseff, Lena Andersch, Johannes H Schulte, Holger N Lode, Angelika Eggert, Kathleen Anders, Patrick Hundsdoerfer, Annette Künkele
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Neuroblastoma is the most common extracranial solid tumor of childhood. Patients with high-risk disease undergo extremely aggressive therapy and nonetheless have cure rates below 50%. Treatment with the ch14.18 monoclonal antibody (dinutuximab beta), directed against the GD2 disialoganglioside, improved 5-year event-free survival in high-risk patients when administered in postconsolidation therapy and was recently implemented in standard therapy. Relapse still occurred in 57% of these patients, necessitating new therapeutic options. Bispecific trifunctional antibodies (trAbs) are IgG-like molecules directed against T cells and cancer surface antigens, redirecting T cells (via their CD3 specificity) and accessory immune cells (via their functioning Fc-fragment) toward tumor cells. We sought proof-of-concept for GD2/CD3-directed trAb efficacy against neuroblastoma. Methods We used two GD2-specific trAbs differing only in their CD3-binding specificity: EKTOMUN (GD2/human CD3) and SUREK (GD2/mouse Cd3). This allowed trAb evaluation in human and murine experimental settings. Tumor-blind trAb and the ch14.18 antibody were used as controls. A coculture model of human peripheral blood mononuclear cells (PBMCs) and neuroblastoma cell lines was established to evaluate trAb antitumor efficacy by assessing expression of T-cell surface markers for activation, proinflammatory cytokine release and cytotoxicity assays. Characteristics of tumor-infiltrating T cells and response of neuroblastoma metastases to SUREK treatment were investigated in a syngeneic immunocompetent neuroblastoma mouse model mimicking minimal residual disease. Results We show that EKTOMUN treatment caused effector cell activation and release of proinflammatory cytokines in coculture with neuroblastoma cell lines. Furthermore, EKTOMUN mediated GD2-dependent cytotoxic effects in human neuroblastoma cell lines in coculture with PBMCs, irrespective of the level of target antigen expression. This effect was dependent on the presence of accessory immune cells. Treatment with SUREK reduced the intratumor Cd4/Cd8 ratio and activated tumor infiltrating T cells in vivo. In a minimal residual disease model for neuroblastoma, we demonstrated that single-agent treatment with SUREK strongly reduced or eliminated neuroblastoma metastases in vivo. SUREK as well as EKTOMUN demonstrated superior tumor control compared with the anti-GD2 antibody, ch14.18. Conclusions Here we provide proof-of-concept for EKTOMUN preclinical efficacy against neuroblastoma, presenting this bispecific trAb as a promising new agent to fight neuroblastoma.
Use of Bone Resorption Inhibitors in Metastatic Castration-Resistant Prostate Cancer—20 Years Later, and the Answer Is Still Yes
Authors: Samuel U. Takvorian, Naomi B. Haas
Journal: JAMA Network Open (2021)

Edoardo Francini, MD, PhD; Francesco Montagnani, MD, MS; Pier Vitale Nuzzo, MD, PhD; Miguel Gonzalez-Velez, MD; Nimira S. Alimohamed, MD; Pietro Rosellini, MD; Irene Moreno-Candilejo, MD; Antonio Cigliola, MD; Jaime Rubio-Perez, MD; Francesca Crivelli, MD; Grace K. Shaw, BHS; Li Zhang, MD; Roberto Petrioli, MD; Carmelo Bengala, MD; Guido Francini, MD; Jesus Garcia-Foncillas, MD, PhD; Christopher J. Sweeney, MBBS; Celestia S. Higano, MD; Alan H. Bryce, MD; Lauren C. Harshman, MD; Richard Lee-Ying, MD; Daniel Y. C. Heng, MD, MPH