tbuckley/cabot-search huggingface dataset:
P08.02 Harnessing T cells to target brain metastasis
Authors: S R Gregory, C Fife, J Williams, H Carrasco Hope, T Andreou, F James, R Brownlie, J Newton-Bishop, R Salmond, M Lorger
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Up to 60% of melanoma patients develop brain metastases (BrM). These patients have a poor prognosis and limited treatment options. Immune checkpoint inhibitors (ICI) targeting Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and Programmed cell death protein-1 (PD-1) have revolutionized the treatment of melanoma and their efficacy has been also demonstrated in melanoma BrM. Our group previously demonstrated that ICI (combined α-PD-1 and α-CTLA-4) enhances chemokine-dependent infiltration of cytotoxic T lymphocytes (CTLs) into melanoma BrMs in preclinical models, accompanied by upregulated expression of T cell attracting chemokines in tumours. Notably, CTLs infiltrating BrM expressed only some of the chemokine receptors (CRs) interacting with ICI-induced chemokines in BrM, providing a rationale to over-express the “missing” CRs in T cells to enhance their homing to tumours in the context of adoptive T cell therapy (ACT). MATERIALS AND METHODS OT-I cells were isolated from OT-I mice and differentiated ex vivo into effector (TEF) and memory (TCM) CD8+ T cells. Tumour infiltrating lymphocytes (TILs) from B16 tumour-bearing mice treated with ICI were isolated using magnetic beads, activated and expanded ex vivo. Expression of CRs and activation markers in ex vivo cultured T cells were quantified by qPCR and/or flow cytometry. The migration of human blood CD8+ T cells towards chemokines of interest were measured in ex vivo migration assays. RESULTS The same CRs that were missing on BrM-infiltrating CTLs in vivo models were also absent from OT-I TEF (CCR7low/CD44high/CD62Llow) and TCM (CCR7high/CD44low/CD62Lhigh) cells, as well as from TILs expanded ex vivo for use in ACT. Furthermore, we observed no increase in migration of human T cells towards chemokines interacting with the “missing” CRs in comparison to the baseline migration, suggesting that these CRs are also absent from human T cells. CONCLUSION Ex vivo expanded T cells that are used in ACT are missing several CRs that are interacting with chemokines upregulated in BrM. We hypothesise that the use of genetically engineered T cells expressing the “missing” CRs in ACT has the potential to enhance ACT efficacy in combination with ICI.
Gut Microbiome Alterations in COVID-19
Authors: Tao Zuo, Xiaojian Wu, Weiping Wen, Ping Lan
Journal: Genomics Proteomics & Bioinformatics (2021)

Abstract Since the outset of the coronavirus disease 2019 (COVID-19) pandemic, the gut microbiome in COVID-19 has garnered substantial interest, given its significant roles in human health and pathophysiology. Accumulating evidence is unveiling that the gut microbiome is broadly altered in COVID-19, including the bacterial microbiome, mycobiome, and virome. Overall, the gut microbial ecological network is significantly weakened and becomes sparse in patients with COVID-19, together with a decrease in gut microbiome diversity. Beyond the existence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the gut microbiome of patients with COVID-19 is also characterized by enrichment of opportunistic bacteria, fungi, and eukaryotic viruses, which are also associated with disease severity and presentation. Meanwhile, a multitude of symbiotic bacteria and bacteriophages are decreased in abundance in patients with COVID-19. Such gut microbiome features persist in a significant subset of patients with COVID-19 even after disease resolution, coinciding with ‘long COVID’ (also known as post-acute sequelae of COVID-19). The broadly-altered gut microbiome is largely a consequence of SARS-CoV-2infection and its downstream detrimental effects on the systemic host immunity and the gut milieu. The impaired host immunity and distorted gut microbial ecology, particularly loss of low-abundance beneficial bacteria and blooms of opportunistic fungi including Candida, may hinder the reassembly of the gut microbiome post COVID-19. Future investigation is necessary to fully understand the role of the gut microbiome in host immunity against SARS-CoV-2 infection, as well as the long-term effect of COVID-19 on the gut microbiome in relation to the host health after the pandemic.
Demographic and Clinical Characteristics Associated With Severity, Clinical Outcomes, and Mortality of COVID-19 Infection in Gabon
Authors: Berthe Amélie Iroungou, Laurette Guignali Mangouka, Berthold Bivigou-Mboumba, Pamela Moussavou-Boundzanga, Judicaël Obame-Nkoghe, Farrel Nzigou Boucka, Augustin Mouinga-Ondeme, Avelin Fobang Aghokeng, Romain Tchoua, Pascal Pineau, Jean Raymond Nzenze
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Since the emergence of COVID-19 in central China, sub-Saharan African countries, with the exception of South Africa, have been relatively spared during the COVID-19 pandemic. Consequently, few descriptive studies from this region are available. <h3>Objective</h3> To describe the clinical characteristics and outcomes of patients with COVID-19 infection in Gabon, from March to June 2020. <h3>Design, Setting, and Participants</h3> A single-center, cross-sectional study of 837 patients with COVID-19 was conducted from March to June 2020 in the Armed Forces Hospital in Libreville, Gabon. <h3>Main Outcomes and Measures</h3> Demographic and clinical characteristics and imaging findings of hospitalized patients with COVID-19. <h3>Results</h3> Of the 837 patients enrolled, 572 (68.3%) were men, and 264 (31.5%) were women (male to female ratio, 2:1); the median (interquartile range [IQR]) age was 35 (30-45) years (mean [SD] age, 38.0 [12.2] years. The mortality rate associated with COVID-19 was low (1.4%). Of these 837 patients, 524 (62.6%) were categorized as having no symptoms, 282 (33.7%) as having mild symptoms, and 31 (3.7%) as having severe symptoms. Patients with severe symptoms were older (mean [SD] age, 46.1 [14.7] years) than patients with mild symptoms (mean [SD] age, 41.3 [12.5] years) and those with no symptoms (mean [SD] age, 35.7 [11.3] years) (Kruskal-Wallis χ<sup>2</sup><sub>2</sub> = 53.5;<i>P</i> &lt; .001). History of diabetes was the principal risk factor associated with both severe symptoms in 5 of 31 patients (16.1%) and mild symptoms in 11 of 282 (3.9%) compared with no symptoms in 5 of 524 (0.9%) (Pearson χ<sup>2</sup><sub>2</sub> = 30.9;<i>P</i> &lt; .001). Patients with severe symptoms and a fatal outcome were older (mean [SD] age, 53.4 [15.1] years) than survivors (mean [SD] age, 41.5 [12.9] years) (<i>t</i><sub>20.83</sub> = 2.2;<i>P</i> = .03). <h3>Conclusions and Relevance</h3> In this single-center, cross-sectional study in Libreville, Gabon, the mortality rate associated with COVID-19 infection from March to June 2020 was low, and patients who died of COVID-19 infection were younger on average than reported elsewhere, possibly reflecting a smaller elderly population in Gabon.
Carrier-free prodrug nanoparticles based on dasatinib and cisplatin for efficient antitumor in vivo
Authors: Lu Yang, Jiaxi Xu, Zheng Xie, Faquan Song, Xin Wang, Rupei Tang
Journal: Asian Journal of Pharmaceutical Sciences (2021)

Carrier-free drug self-delivery systems consisting of amphiphilic drug-drug conjugate (ADDC) with well-defined structure and nanoscale features have drawn much attention in tumor drug delivery. Herein, we report a simple and effective strategy to prepare ADDC using derivatives of cisplatin (CP) and dasatinib (DAS), which further self-assembled to form reduction-responsive nanoparticles (CP-DDA NPs). DAS was modified with succinic anhydride and then connected with CP derivative by ester bonds. The size, micromorphology and in vitro drug release of CP-DDA NPs were characterized. The biocompatibility and bioactivity of these carrier-free nanoparticles were then investigated by HepG2 cells and H22-tumor bearing mice. In vitro and in vivo experiments proved that CP-DDA NPs had excellent anti-tumor activity and significantly reduced toxicities. This study provides a new strategy to design the carrier-free nanomedicine composed of CP and DAS for synergistic tumor treatment.
Compulsory covid vaccination: Loss of care home workers puts beds and care at risk, warn unions and providers
Authors: Matthew Limb
Journal: BMJ (2021)

Compulsory covid vaccination: Loss of care home workers puts beds and care at risk, warn unions and providers Matthew LimbSocial care of elderly and vulnerable people, a sector that currently has an estimated 120 000 vacancies, could be severely hit as thousands of care home workers face losing their jobs for failing a legal requirement to have covid vaccinations, trade unions and care home providers have warned.1
ASXL1 mutations are associated with distinct epigenomic alterations that lead to sensitivity to venetoclax and azacytidine
Authors: Nora E. Rahmani, Nandini Ramachandra, Srabani Sahu, Nadege Gitego, Andrea Lopez, Kith Pradhan, Tushar D. Bhagat, Shanisha Gordon-Mitchell, Bianca Rivera Pena, Mohammad Kazemi, Keshav Rao, Orsi Giricz, Shahina Bano Maqbool, Raul Olea, Yongmei Zhao, Jinghang Zhang, Hamid Dolatshad, Vickram Tittrea, Dharamveer Tatwavedi, Shalini Singh, Juseong Lee, Tianyu Sun, Ulrich Steidl, Aditi Shastri, Daichi Inoue, Omar Abdel-Wahab, Andrea Pellagatti, Evripidis Gavathiotis, Jacqueline Boultwood, Amit Verma
Journal: Blood Cancer Journal (2021)

Abstract The BCL2-inhibitor, Venetoclax (VEN), has shown significant anti-leukemic efficacy in combination with the DNMT-inhibitor, Azacytidine (AZA). To explore the mechanisms underlying the selective sensitivity of mutant leukemia cells to VEN and AZA, we used cell-based isogenic models containing a common leukemia-associated mutation in the epigenetic regulator ASXL1 . KBM5 cells with CRISPR/Cas9-mediated correction of the ASXL1 G710X mutation showed reduced leukemic growth, increased myeloid differentiation, and decreased HOXA and BCL2 gene expression in vitro compared to uncorrected KBM5 cells. Increased expression of the anti-apoptotic gene, BCL2 , was also observed in bone marrow CD34+ cells from ASXL1 mutant MDS patients compared to CD34+ cells from wild-type MDS cases. ATAC-sequencing demonstrated open chromatin at the BCL2 promoter in the ASXL1 mutant KBM5 cells. BH3 profiling demonstrated increased dependence of mutant cells on BCL2 . Upon treatment with VEN, mutant cells demonstrated increased growth inhibition. In addition, genome-wide methylome analysis of primary MDS samples and isogenic cell lines demonstrated increased gene-body methylation in ASXL1 mutant cells, with consequently increased sensitivity to AZA. These data mechanistically link the common leukemia-associated mutation ASXL1 to enhanced sensitivity to VEN and AZA via epigenetic upregulation of BCL2 expression and widespread alterations in DNA methylation.
Perceived provider barriers to collecting and documenting a complete family history in a statewide oncology consortium.
Authors: Shayna Weiner, Erika Amini, Erika Koeppe, Ken Resnicow, Elena Martinez Stoffel, Jennifer J. Griggs
Journal: Journal of Clinical Oncology (2021)

221 Background: A complete family history is essential in identifying patients who may benefit from genetic evaluation for hereditary cancer syndromes. Fewer than 40% of patients with cancer have a complete family history documented in their medical record. As part of a larger study of patient- and provider-focused interventions for increasing genetic testing, we conducted a survey of provider barriers to collecting and documenting a complete family history in a statewide, physician-led quality consortium of nearly all medical and gynecologic oncologists in Michigan. Methods: A novel survey instrument was created by adapting existing literature and clinician input. Surveys were mailed to medical and gynecologic oncologists with follow up electronic surveys sent to non-respondents. Questions addressed patient-specific barriers as well as known constraints faced by oncologists. Each barrier was rated from low to high using a 10-point Likert scale. Descriptive statistics, including mean scores and standard deviations (SD), were calculated. Results: Of 317 surveys sent, 194 (61.2%) were returned. Oncologists rated constraints on their time lower than lack of patient knowledge and understanding of their family history and its importance as a barrier. Open-ended responses indicated that the processes of collecting a family history (e.g. templates for collecting family history that omit age at diagnosis) and patients being overwhelmed at the time of consultation also interfered with collecting a complete family history. Conclusions: Oncologists perceive patient knowledge of their family history, including the ages of affected family members, and understanding of its importance as barriers to completion and documentation of a family history. Explaining the importance of the family history to patients, prompting new patients to provide their family history, and improving the process, including the timing of collection, may increase the proportion of oncology patients who have a complete family history collected and documented.[Table: see text]
Socioeconomic inequalities in prevalence and development of multimorbidity across adulthood: A longitudinal analysis of the MRC 1946 National Survey of Health and Development in the UK
Authors: Amal R. Khanolkar, Nishi Chaturvedi, Valerie Kuan, Daniel Davis, Alun Hughes, Marcus Richards, David Bann, Praveetha Patalay
Journal: PLoS Medicine (2021)

Background We aimed to estimate multimorbidity trajectories and quantify socioeconomic inequalities based on childhood and adulthood socioeconomic position (SEP) in the risks and rates of multimorbidity accumulation across adulthood. Methods and findings Participants from the UK 1946 National Survey of Health and Development (NSHD) birth cohort study who attended the age 36 years assessment in 1982 and any one of the follow-up assessments at ages 43, 53, 63, and 69 years ( N = 3,723, 51% males). Information on 18 health conditions was based on a combination of self-report, biomarkers, health records, and prescribed medications. We estimated multimorbidity trajectories and delineated socioeconomic inequalities (based on childhood and adulthood social class and highest education) in multimorbidity at each age and in longitudinal trajectories. Multimorbidity increased with age (0.7 conditions at 36 years to 3.7 at 69 years). Multimorbidity accumulation was nonlinear, accelerating with age at the rate of 0.08 conditions/year (95% CI 0.07 to 0.09, p &lt; 0.001) at 36 to 43 years to 0.19 conditions/year (95% CI 0.18 to 0.20, p &lt; 0.001) at 63 to 69 years. At all ages, the most socioeconomically disadvantaged had 1.2 to 1.4 times greater number of conditions on average compared to the most advantaged. The most disadvantaged by each socioeconomic indicator experienced an additional 0.39 conditions (childhood social class), 0.83 (adult social class), and 1.08 conditions (adult education) at age 69 years, independent of all other socioeconomic indicators. Adverse adulthood SEP was associated with more rapid accumulation of multimorbidity, resulting in 0.49 excess conditions in partly/unskilled compared to professional/intermediate individuals between 63 and 69 years. Disadvantaged childhood social class, independently of adulthood SEP, was associated with accelerated multimorbidity trajectories from age 53 years onwards. Study limitations include that the NSHD cohort is composed of individuals of white European heritage only, and findings may not be generalizable to the non-white British population of the same generation and did not account for other important dimensions of SEP such as income and wealth. Conclusions In this study, we found that socioeconomically disadvantaged individuals have earlier onset and more rapid accumulation of multimorbidity resulting in widening inequalities into old age, with independent contributions from both childhood and adulthood SEP.
PRESIDENT ROOSEVELT ON THE REWARDS OF SCHOLARSHIP.
Journal: JAMA (1905)

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Bionanoscale Recognition Underlies Cell Fate and Therapy
Authors: Shan Sun, Peng Deng, Li Mu, Xiangang Hu, Shuqing Guo
Journal: Advanced Healthcare Materials (2021)

Abstract Understanding the bionanoscale recognition of nanostructured architectures is critical to the design and application of nanomaterials, but the related information is not well understood. In this study, it is found that bionanoscale recognition underlies cell fate and therapy. For example, 1T phase (octahedral coordination) monolayer MoS 2 exhibits a markedly stronger affinity for fibronectin than the 2H structure (triangular prism coordination) and promotes cell spreading and differentiation. The van der Waals energy and increased turn components contribute to the high adhesion of fibronectin onto the 1T‐MoS 2 structure. 1T‐MoS 2 exhibits a significantly stronger affinity ( K D , 6.59 × 10 −7 m ) for liposomes than 2H‐MoS 2 (1.21 × 10 −6 m ) due to strong hydrophobic interactions. The existence of octahedrally coordinated atomic structures that improve cell viability by enhancing the neurite length is first proven by random forest and structural equation models. Consequently, octahedral coordination disaggregates α ‐synuclein (e.g., by decreasing β ‐sheets and increasing coil structures) and protects cells and hosts against Parkinson's disease. As a proof‐of‐principle demonstration, these findings indicate that bionanoscale recognition underlies the design of biomaterials and cell therapeutics.
3D‐Printed Regenerative Magnesium Phosphate Implant Ensures Stability and Restoration of Hip Dysplasia
Authors: Nasim Golafshan, Koen Willemsen, Firoz Babu Kadumudi, Elke Vorndran, Alireza Dolatshahi‐Pirouz, Harrie Weinans, Bart C. H. van der Wal, Jos Malda, Miguel Castilho
Journal: Advanced Healthcare Materials (2021)

Abstract Osteoarthritis of the hip is a painful and debilitating condition commonly occurring in humans and dogs. One of the main causes that leads to hip osteoarthritis is hip dysplasia. Although the current surgical methods to correct dysplasia work satisfactorily in many circumstances, these are associated with serious complications, tissue resorption, and degeneration. In this study, a one‐step fabrication of a regenerative hip implant with a patient‐specific design and load‐bearing properties is reported. The regenerative hip implant is fabricated based on patient imaging files and by an extrusion assisted 3D printing process using a flexible, bone‐inducing biomaterial. The novel implant can be fixed with metallic screws to host bone and can be loaded up to physiological loads without signs of critical permanent deformation or failure. Moreover, after exposing the hip implant to accelerated in vitro degradation, it is confirmed that it is still able to support physiological loads even after losing ≈40% of its initial mass. In addition, the osteopromotive properties of the novel hip implant is demonstrated as shown by an increased expression of osteonectin and osteocalcin by cultured human mesenchymal stem cells after 21 days. Overall, the proposed hip implant provides an innovative regenerative and mechanically stable solution for hip dysplasia treatment.
OS08.4.A Retrospective analysis of <i>in vivo</i> 1H-magnetic resonance spectroscopy based on a machine learning approach enables reliable prediction of <i>IDH</i> mutation in patients with glioma
Authors: E Bumes, C Fellner, S Lenz, R Linker, S Weis, C Wendl, S Wimmer, P Hau, W Gronwald, M Hutterer
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Mutation of isocitrate dehydrogenase (IDH) is not only an important landmark in the development of low-grade gliomas, but also has prognostic significance and is a potential therapeutic target. There is a high need to determinate IDH mutation status at diagnosis and during the course of therapy in a non-invasive and reliable manner. We established a machine learning approach based on a support vector machine to detect IDH mutation status in in vivo standard 1H-magnetic resonance spectroscopy (1H-MRS) at 3T with an accuracy of 88.2%, a sensitivity of 95.5% (95% CI, 77.2–99.9%), and a specificity of 75% (95% CI, 42.85–94.5%) in a prospective monocentric clinical trial. Here, the same method is applied in a retrospective cohort at 1.5T and tested for transferability. MATERIAL AND METHODS Validation cohort. The validation cohort comprised 100 patients with glioma for which standard in vivo 1H-MRS spectra had been acquired between 2002 and 2007. Standard single voxel spectroscopy had been measured at 1.5T using a PRESS sequence with a TR of 1500ms and a TE of 30ms. One sample had to be excluded due to non-malignant histology and for 15 samples the IDH mutation status was not available. Therefore, the validation cohort comprised 84 samples, of which 35 were bearing an IDH mutation in immunohistochemistry (sequencing for confirmation is outstanding). Machine learning. To transfer our method to an independent validation cohort our previously established machine learning approach was first trained on all samples of the 3T group. The trained algorithm was then applied to the data of the validation cohort. Here, among other factors the different field strengths, with which the spectra were acquired (3T vs. 1.5T) had to be considered. RESULTS 27 samples of the validation cohort had to be excluded due to poor spectra quality. Our approach correctly detected IDH mutation status in 47 of 62 patients (75.8%), although the technical conditions were significantly different from our published prospective cohort. 17 of 30 patients bearing an IDH mutation were correctly identified, while 30 of 32 wild type patients were determined successfully. CONCLUSION Our approach to detect IDH mutation status has promising application in an unselected retrospective cohort, demonstrating transferability across different technical conditions. Further investigations to improve our technique and an advanced neuropathological processing of the samples are planned.