tbuckley/cabot-search huggingface dataset:
Abstract 15756: Vascular Guidance of Cardiomyocyte Proliferation During Growth and Regeneration
Authors: Paige DeBeneditts, Anish Karpurapu, Kyla Brezitski, Michael C Thomas, Ravi - Karra
Journal: Circulation (2020)

Introduction: Stimulating cardiomyocyte (CM) proliferation is a major strategy for achieving therapeutic heart regeneration. However, heart regeneration requires coordinated interactions of multiple cell types. Because a hallmark of advanced heart failure is vascular rarefaction, the requirement of cardiac endothelial cells (CECs) for cardiac growth and regeneration is of particular importance. Hypothesis: We hypothesized that CECs are required for CM proliferation during growth and regeneration. Methods and Results: We performed a large-scale histologic assessment of neonatal mouse hearts and found the rate of CEC proliferation to shadow CM proliferation over the first 10 days of life. Using a nearest neighbor analysis, we found the fraction of proliferating CECs to be significantly enriched around cycling CMs compared to non-cycling CMs, suggesting that CEC and CM expansion are coupled within a myovascular niche. Single cell sequencing of neonatal mouse hearts after cryoinjury revealed that a majority of these proliferating CECs also express Vegfr2 . To functionally link CEC and CM proliferation, we generated Cdh5-CreER T2 ; Vefgr2 flox/flox mice to genetically delete Vegfr2 from CECs. Compared to mice with intact Vegfr2 , loss of Vegfr2 from CECs in neonatal mice leads to loss of CECs and severely dampens CM proliferation by 4 days (7.01±0.88% vs 0.39±0.35%, p = 7.4x10-4, n = 9),. Interestingly, CM proliferation is attenuated when Vegfr2 is deleted from CECs despite an increase of hypoxia indicators in CMs, signifying that hypoxia-induced CM proliferation is dependent on CECs. In contrast to CEC depletion, treatment of cryoinjured neonatal hearts with AAV encoding the master angiogenic factor, Vegfa can enhance heart regeneration with increased CM cycling in the borderzone (12.6±2.2% vs 5.4±0.4%, p = 0.02, n = 8), reduced scarring of the left ventricle (3.4±1.4% vs 7.6±1.2%, p = 03, n = 16), and improved fractional shortening (51.7±2.5% vs 36.7±4.3%, p = 0.007, n = 14). Conclusions: CEC and CM expansion are spatiotemporally coupled in a myovascular niche during cardiac growth. CECs play a critical role to support CM proliferation and are likely to provide instructive cues that may be leveraged for therapeutic heart regeneration.
Covid-19 will become endemic but with decreased potency over time, scientists believe
Authors: Ingrid Torjesen
Journal: BMJ (2021)

The SARS-CoV-2 coronavirus will not be eradicated but will become endemic, continuing to circulate in pockets of the global population for years to come and causing outbreaks in regions where it had been eliminated, scientists working in the field believe.

But the impact of the virus on the world in terms of deaths, illness, and the need for social isolation will lessen, they say, as more of the population acquires some immunity to it through exposure to the virus or from vaccination.

The predictions come from a survey carried out in January by the journal Nature of more than 100 immunologists, infectious disease researchers, and virologists working on SARS-CoV-2.1 Almost 90% of respondents said that they expected the coronavirus to become endemic, although more than a third thought that it would be possible to eliminate SARS-CoV-2 from some regions of the world.

While there would be a continual risk of covid-19 outbreaks in areas where …
Multimerin-1 Binds to Specific Motifs in Vessel Wall Collagens and Contributes to Thrombosis: Novel Insights Regarding the Mechanisms That Support Human and Mouse Platelet Adhesion
Authors: Alexander Leatherdale, D'Andra Parker, Subia Tasneem, Yiming Wang, Arkadiusz Bonna, Peter L. Gross, Heyu Ni, Bradley Doble, Richard W. Farndale, Catherine P.M. Hayward
Journal: Blood (2017)
Current Treatment Strategies and Future Directions for Extrapulmonary Neuroendocrine Carcinomas
Authors: Johannes Stelwagen, Elisabeth G. E. de Vries, Annemiek M. E. Walenkamp
Journal: JAMA Oncology (2021)

Patients with extrapulmonary neuroendocrine carcinomas (EPNECs) receive essentially the same treatment as those with small cell lung cancer (SCLC) despite differences in origin, clinical course, and survival. This SCLC-based approach is attributable to the rarity of EPNECs, which impedes the use of randomized clinical trials. However, neuroendocrine carcinomas are becoming more common because of the increasing use of systemic cancer therapy for adenocarcinomas. This treatment can transdifferentiate certain adenocarcinomas into neuroendocrine carcinomas. In addition, the treatment landscape for SCLC is slowly changing, potentially impacting the treatment paradigms for EPNECs.New information on tumorigenesis of EPNECs from different origins, either as a primary malignant tumor or after neuroendocrine differentiation from adenocarcinomas, demonstrates their biological similarity. Activated molecular pathways that appear to underlie the development of EPNECs are potentially targetable, and some of these targets, such as poly(adenosine diphosphate-ribose) polymerase, Wee1, and Aurora A kinase, are currently under investigation. Immune checkpoint inhibitors (ICIs) already constituted a new treatment modality for patients with SCLC and produced some promising results in patients with EPNECs.Although only moderately effective, the introduction of ICIs signifies the first new option in systemic treatment of SCLC in decades. To prove the value of ICIs and other new drugs for patients with EPNECs, these patients should be included in clinical trials independent of the primary tumor site. Furthermore, to optimize clinical decision-making for patients with EPNECs, experts from the neuroendocrine tumor board should collaborate with members from tumor site-specific boards, which will require patient referral to a center with EPNEC expertise.
Exploring and exploiting plant cyclic peptides for drug discovery and development
Authors: Jingjing Zhang, Jimin Yuan, Zhijie Li, Chunjin Fu, Menglong Xu, Jing Yang, Xin Jiang, Boping Zhou, Xiufeng Ye, Chengchao Xu
Journal: Medicinal Research Reviews (2021)

Abstract Ever since the discovery of insulin, natural peptides have become an important resource for therapeutic development. Decades of research has led to the discovery of a long list of peptide drugs with broad applications in clinics, from antibiotics to hypertension treatment to pain management. Many of these US FDA‐approved peptide drugs are derived from microorganisms and animals. By contrast, the great potential of plant cyclic peptides as therapeutics remains largely unexplored. These macrocyclic peptides typically have rigid structures, good bioavailability and membrane permeability, making them appealing candidates for drug development and engineering. In this review, we introduce the three major classes of plant cyclic peptides and summarize their potential medical applications. We discuss how we can leverage the genome information of many different plants to quickly search for new cyclic peptides and how we can take advantage of the insights gained from their biosynthetic pathways to transform the process of production and drug development. These recent developments have provided a new angle for exploring and exploiting plant cyclic peptides, and we believe that many more peptide drugs derived from plants are about to come.
Evidence for the involvement of distinct signal transduction pathways in the regulation of constitutive and interferon gamma-dependent gene expression of NADPH oxidase components (gp91-phox, p47-phox, and p22- phox) and high-affinity receptor for IgG (Fc gamma R-I) in human polymorphonuclear leukocytes
Authors: MA Amezaga, F Bazzoni, C Sorio, F Rossi, MA Cassatella
Journal: Blood (1992)
Combinatorial CSF3R and RUNX1 Mutations Involved in the Leukemic Progression of Severe Congenital Neutropenia Confer a G-CSF-Dependent Premalignant State in Mice
Authors: Szabolcs Fatrai, Paulette van Strien, Julia Obenauer, M.M. Van den Heuvel-Eibrink, Ivo Touw
Journal: Blood (2017)
Post-transplantation cyclophosphamide reduces the incidence of acute graft-versus-host disease in patients with acute myeloid leukemia/myelodysplastic syndromes who receive immune checkpoint inhibitors after allogeneic hematopoietic stem cell transplantation
Authors: Chantal Saberian, Noha Abdel-Wahab, Ala Abudayyeh, Hind Rafei, Jacinth Joseph, Gabriela Rondon, Laura Whited, Stephen Gruschkus, Faisal Fa'ak, May Daher, Cristina Knape, Houssein Safa, Mahran Shoukier, Maria E Suarez-Almazor, Megan Marcotulli, Kaysia Ludford, Alison M Gulbis, Marina Konopleva, Maro Ohanian, Farhad Ravandi, Guillermo Garcia-Manero, Betul Oran, Uday R Popat, Rotesh Mehta, Amin M Alousi, Naval Daver, Richard Champlin, Adi Diab, Gheath Al-Atrash
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Immune checkpoint inhibitors (ICIs) are being used after allogeneic hematopoietic stem cell transplantation (alloHCT) to reverse immune dysfunction. However, a major concern for the use of ICIs after alloHCT is the increased risk of graft-versus-host disease (GVHD). We analyzed the association between GVHD prophylaxis and frequency of GVHD in patients who had received ICI therapy after alloHCT. Methods A retrospective study was performed in 21 patients with acute myeloid leukemia (n=16) or myelodysplastic syndromes (n=5) who were treated with antiprogrammed cell death protein 1 (16 patients) or anticytotoxic T lymphocyte-associated antigen 4 (5 patients) therapy for disease relapse after alloHCT. Associations between the type of GVHD prophylaxis and incidence of GVHD were analyzed. Results Four patients (19%) developed acute GVHD. The incidence of acute GVHD was associated only with the type of post-transplantation GVHD prophylaxis; none of the other variables included (stem cell source, donor type, age at alloHCT, conditioning regimen and prior history of GVHD) were associated with the frequency of acute GVHD. Twelve patients received post-transplantation cyclophosphamide (PTCy) for GVHD prophylaxis. Patients who received PTCy had a significantly shorter median time to initiation of ICI therapy after alloHCT compared with patients who did not receive PTCy (median 5.1 months compared with 26.6 months). Despite early ICI therapy initiation, patients who received PTCy had a lower observed cumulative incidence of grades 2–4 acute GVHD compared with patients who did not receive PTCy (16% compared with 22%; p=0.7). After controlling for comorbidities and time from alloHCT to ICI therapy initiation, the analysis showed that PTCy was associated with a 90% reduced risk of acute GVHD (HR 0.1, 95% CI 0.02 to 0.6, p=0.01). Conclusions ICI therapy for relapsed acute myeloid leukemia/myelodysplastic syndromes after alloHCT may be a safe and feasible option. PTCy appears to decrease the incidence of acute GVHD in this cohort of patients.
Cap on public sector exit payments is lifted after BMA’s legal challenge
Authors: Abi Rimmer
Journal: BMJ (2021)

A cap that limited exit payments made to public sector workers to £95 000 (€109 000; $132 000) has been lifted after a legal challenge from the BMA.

In October last year the UK parliament approved government plans to place a £95 000 cap on exit payments—which include redundancy payments, severance packages, and other payments made as a result of terminating …
Abstract PS6-37: Clinical stage is the only predictor of survival in breast cancer patients with a complete pathological response
Authors: Francisco Acevedo, Benjamin Walbaum, Tomas Merino, Militza Petric, Cesar Sanchez
Journal: Cancer Research (2021)

Abstract INTRODUCTION In breast cancer (BC) patients, achieving a complete pathological response (pCR) after neoadjuvant chemotherapy (NCT) is associated with better prognosis. Despite this, some of these patients will experience recurrences of the disease and will eventually die of BC. We identified clinical factors that can affect recurrence and survival in BC patients who achieve pCR.METHODSRetrospective analysis of a Chilean BC database including patients treated in public and private hospitals in Santiago, Chile from 2010 to 2019. pCR was defined as the absence of residual invasive disease in the breast and in the axillary lymph nodes (ypT0/is N0) at the completion of the NCT. Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS) and BC-specific survival (BCS) was measured from the time of diagnosis to the event or lost to follow-up. We performed Cox regression analysis to identify factors associated with prognosis.RESULTSFrom 855 patients who received NCT, 195 (22.8%) achieved pCR and were included in this study. Clinical characteristics are shown in table 1. 76 (37.9%) patients had hormone receptor positive (HR+) and 113 (57.4%) had Human epidermal growth factor 2 (HER2) positive tumors. 88.7% were treated with a regimen that included anthracyclines and taxanes. With a median follow-up of 36 months, three-year IDFS, DDFS and BCS and their 95% confidence intervals were 90.9% (84.7 - 94.6), 91.8% (86.0 - 95.3) and 93.8% (87.8 - 97.5); respectively. The stage at diagnosis was the only predictor associated with IDFS (Hazard ratio (HR) = 5.6; p = 0.02), DDFS (HR = 4.1, p = 0.07), and BCS (HR = 8.3, p = 0.04). Body mass index (BMI), age, hospital, HR or HER2 status, lymph node involvement, or the presence of an in-situ component, were not associated with prognosis in the multivariate analysis.CONCLUSIONThe clinical stage at diagnosis was the only predictor of survival in patients who achieved pCR after NCT. Short follow-up and few events may have affected these results. This data is consistent with previously published work. Table 1. Tumor and patient characteristicsMedian age49 (24 – 78)HospitalPublic57.4%Private43.6%BMIMedian27.2 (18.5 – 44.7)Overweight38.0%Obese31.9%Receptor StatusRH+/HER2-16.4%RH+/HER2+21.5%RH-/HER2+35.9%RH-/HER2-26.2%Clinical StageI2.1%II47.4%III50.5%Lymph Node +69.7%ypT0/N078.1%ChemotherapyAnthracycline5.1%Taxane6.2%Anthracycline-Taxane88.7% Citation Format: Francisco Acevedo, Benjamin Walbaum, Tomas Merino, Militza Petric, Cesar Sanchez. Clinical stage is the only predictor of survival in breast cancer patients with a complete pathological response [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 PS6-37.
In silico trials predict that combination strategies for enhancing vesicular stomatitis oncolytic virus are determined by tumor aggressivity
Authors: Adrianne L Jenner, Tyler Cassidy, Katia Belaid, Marie-Claude Bourgeois-Daigneault, Morgan Craig
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Immunotherapies, driven by immune-mediated antitumorigenicity, offer the potential for significant improvements to the treatment of multiple cancer types. Identifying therapeutic strategies that bolster antitumor immunity while limiting immune suppression is critical to selecting treatment combinations and schedules that offer durable therapeutic benefits. Combination oncolytic virus (OV) therapy, wherein complementary OVs are administered in succession, offer such promise, yet their translation from preclinical studies to clinical implementation is a major challenge. Overcoming this obstacle requires answering fundamental questions about how to effectively design and tailor schedules to provide the most benefit to patients. Methods We developed a computational biology model of combined oncolytic vaccinia (an enhancer virus) and vesicular stomatitis virus (VSV) calibrated to and validated against multiple data sources. We then optimized protocols in a cohort of heterogeneous virtual individuals by leveraging this model and our previously established in silico clinical trial platform. Results Enhancer multiplicity was shown to have little to no impact on the average response to therapy. However, the duration of the VSV injection lag was found to be determinant for survival outcomes. Importantly, through treatment individualization, we found that optimal combination schedules are closely linked to tumor aggressivity. We predicted that patients with aggressively growing tumors required a single enhancer followed by a VSV injection 1 day later, whereas a small subset of patients with the slowest growing tumors needed multiple enhancers followed by a longer VSV delay of 15 days, suggesting that intrinsic tumor growth rates could inform the segregation of patients into clinical trials and ultimately determine patient survival. These results were validated in entirely new cohorts of virtual individuals with aggressive or non-aggressive subtypes. Conclusions Based on our results, improved therapeutic schedules for combinations with enhancer OVs can be studied and implemented. Our results further underline the impact of interdisciplinary approaches to preclinical planning and the importance of computational approaches to drug discovery and development.
Recent Advances in Cell Membrane‐Derived Biomimetic Nanotechnology for Cancer Immunotherapy
Authors: Faisal Raza, Hajra Zafar, Shulei Zhang, Zul Kamal, Jing Su, Wei‐En Yuan, Qiu Mingfeng
Journal: Advanced Healthcare Materials (2021)

Abstract Immunotherapy will significantly impact the standard of care in cancer treatment. Recent advances in nanotechnology can improve the efficacy of cancer immunotherapy. However, concerns regarding efficiency of cancer nanomedicine, complex tumor microenvironment, patient heterogeneity, and systemic immunotoxicity drive interest in more novel approaches to be developed. For this purpose, biomimetic nanoparticles are developed to make innovative changes in the delivery and biodistribution of immunotherapeutics. Biomimetic nanoparticles have several advantages that can advance the clinical efficacy of cancer immunotherapy. Thus there is a greater push toward the utilization of biomimetic nanotechnology for developing effective cancer immunotherapeutics that demonstrate increased specificity and potency. The recent works and state‐of‐the‐art strategies for anti‐tumor immunotherapeutics are highlighted here, and particular emphasis has been given to the applications of cell‐derived biomimetic nanotechnology for cancer immunotherapy.
Comparison of 68Ga-FAPI and 18F-FDG PET/CT in the Imaging of Pancreatic Cancer With Liver Metastases
Authors: Maoxue Deng, Yue Chen, Liang Cai
Journal: Clinical Nuclear Medicine (2021)

A 65-year-old man with suspected pancreatic cancer underwent 18F-FDG PET/CT for initial staging. Mild FDG uptake was observed in the pancreatic mass and bone destruction in the 10th rib on the right. No significant FDG uptake was seen with the multiple hypodense or isodense nodules in the liver. However, 68Ga-FAPI PET/CT revealed intense FAPI uptake in the pancreas and the 10th rib and multiple lesions in the liver. Finally, a biopsy confirmed carcinoma in the head of the pancreas with liver metastasis. This case highlighted that 68Ga-FAPI may outperform 18F-FDG PET/CT in identifying micrometastases of bones and hidden liver metastases.
Sex-Related Differences in Cardiac Channelopathies
Authors: Babken Asatryan, Lauren Yee, Yael Ben-Haim, Stephan Dobner, Helge Servatius, Laurent Roten, Hildegard Tanner, Lia Crotti, Jonathan R. Skinner, Carol Ann Remme, Philippe Chevalier, Argelia Medeiros-Domingo, Elijah R. Behr, Tobias Reichlin, Katja E. Odening, Andrew D. Krahn
Journal: Circulation (2021)

Sex-related differences in prevalence, clinical presentation, and outcome of cardiac channelopathies are increasingly recognized, despite their autosomal transmission and hence equal genetic predisposition among sexes. In congenital long-QT syndrome, adult women carry a greater risk for Torsades de pointes and sudden cardiac death than do men. In contrast, Brugada syndrome is observed predominantly in adult men, with a considerably higher risk of arrhythmic sudden cardiac death in adult men than in women. In both conditions, the risk for arrhythmias varies with age. Sex-associated differences appear less evident in other cardiac channelopathies, likely a reflection of their rare(r) occurrence and our limited knowledge. In several cardiac channelopathies, sex-specific predictors of outcome have been identified. Together with genetic and environmental factors, sex hormones contribute to the sex-related disparities in cardiac channelopathies through modulation of the expression and function of cardiac ion channels. Despite these insights, essential knowledge gaps exist in the mechanistic understanding of these differences, warranting further investigation. Precise application of the available knowledge may improve the individualized care of patients with cardiac channelopathies. Promoting the reporting of sex-related phenotype and outcome parameters in clinical and experimental studies and advancing research on cardiac channelopathy animal models should translate into improved patient outcomes. This review provides a critical digest of the current evidence for sex-related differences in cardiac channelopathies and emphasizes their clinical implications and remaining gaps requiring further research.
Nanoencapsulated rituximab mediates superior cellular immunity against metastatic B-cell lymphoma in a complement competent humanized mouse model
Authors: Jing Wen, Lan Wang, Jie Ren, Emiko Kranz, Shilin Chen, Di Wu, Toshio Kanazawa, Irvin Chen, Yunfeng Lu, Masakazu Kamata
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Despite the numerous applications of monoclonal antibodies (mAbs) in cancer therapeutics, animal models available to test the therapeutic efficacy of new mAbs are limited. NOD.Cg- Prkdc scid Il2rg tm1Wjl /SzJ (NSG) mice are one of the most highly immunodeficient strains and are universally used as a model for testing cancer-targeting mAbs. However, this strain lacks several factors necessary to fully support antibody-mediated effector functions—including antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity (CDC)—due to the absence of immune cells as well as a mutation in the Hc gene, which is needed for a functional complement system. Methods We have developed a humanized mouse model using a novel NSG strain, NOD.Cg −Hc1 Prkdc scid Il2rgtm1Wjl/SzJ (NSG −Hc1 ), which contains the corrected mutation in the Hc gene to support CDC in addition to other mechanisms endowed by humanization. With this model, we reevaluated the anticancer efficacies of nanoencapsulated rituximab after xenograft of the human Burkitt lymphoma cell line 2F7-BR44. Results As expected, xenografted humanized NSG −Hc1 mice supported superior lymphoma clearance of native rituximab compared with the parental NSG strain. Nanoencapsulated rituximab with CXCL13 conjugation as a targeting ligand for lymphomas further enhanced antilymphoma activity in NSG −Hc1 mice and, more importantly, mediated antilymphoma cellular responses. Conclusions These results indicate that NSG −Hc1 mice can serve as a feasible model for both studying antitumor treatment using cancer targeting as well as understanding induction mechanisms of antitumor cellular immune response.