tbuckley/cabot-search huggingface dataset:
OP0040 Bucillamine and its metabolites induce synthesis of vegf dose dependently in systemic sclerosis fibroblasts via the nf-kb pathway
Authors: C Hagen, O Distler, U Müller-Ladner, A Carossino, RE Gay, R Nanagara, BA Michel, K Nishioka, M Matucci-Cerinic, S Gay
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Bucillamine (BUC) is an immunomodulatory drug used in the treatment of rheumatoid arthritis with inhibitory effects on B- and T-cell functions. However, the impact of Bucillamine on metabolic pathways of fibroblasts has not been addressed. <h3>Objectives</h3> Since an altered metabolism of fibroblasts is a hallmark of systemic sclerosis (SSc), we investigated whether BUC and its metabolites SA981 and SA679 influence the cytokine pattern of skin fibroblasts and might be of therapeutical use in SSc. <h3>Methods</h3> Cultures of skin fibroblasts from 6 patients with SSc and 5 healthy controls were incubated with BUC, SA981 and SA679 at different concentrations for 6 to 24 h. Quantification for VEGF, IL-6 and TGF-b1 mRNA was performed with real-time PCR (TaqMan). Supernatants were analysed for VEGF by ELISA. In addition, fibroblasts were preincubated with the NF-kB inhibitor pyrrolidine dithiocarbamate (PDTC) and analysed for the expression of VEGF as describe above. The trypan blue dye exclusion test was used to assess the viability of the cells. The effects on the chemotactic activity of fibroblasts were examined in a modified Boyden chamber assay. <h3>Results</h3> VEGF mRNA was increased in all fibroblast cultures after BUC treatment compared to non-treated controls, whereas no effect was observed on the levels of IL-6 and TGF-b1. VEGF mRNA increased dose dependently with both BUC and its metabolites. The most significant induction was observed after treatment with SA981 (1 mg/ml: 7.7 ± 4.3, 0,6 mg/ml: 5.2 ± 2.3; 0,15 mg/ml: 2.9 ± 1.4, 0,05 mg/ml: 2.5 ± 1.9 fold increase, p &lt; 0.05). Fibroblast cultures from patients with SSc showed a consistent higher inducibility of VEGF than cultures from healthy controls (SSc: 9.9 ± 4.3; healthy controls: 5.2 ± 2.8 fold increase, p &lt; 0.05). These results were confirmed on the protein level with a significant rise of VEGF in SSc cultures, but not in healthy controls. The increase of VEGF was not due to unspecific toxicity, since the cell viability was &gt;95% in treated and non-treated fibroblasts. Preincubation with the NF-kB inhibitor PDTC reduced the production of VEGF by 60%. Interestingly, there was a significant increase in the chemotactic activity of supernatants from fibroblasts treated with BUC (133 ± 39 cells/high power field = hpf), SA679 (72 ± 19 cells/hpf) and SA981 (43 ± 5 cells/hpf) compared to non-treated controls (26 ± 7 cells/hpf). <h3>Conclusion</h3> Our results indicate that BUC and its metabolites, in addition to the known immunomodulatory effects, may have favourable influence on neoangiogenesis in SSc through the release of VEGF by skin fibroblasts. Since impaired angiogenesis and inflammatory infiltrates are hallmarks in the pathogenesis of SSc, BUC may be of benefit in the treatment of this disease.
MATRix–RICE therapy and autologous haematopoietic stem-cell transplantation in diffuse large B-cell lymphoma with secondary CNS involvement (MARIETTA): an international, single-arm, phase 2 trial
Authors: Andrés J M Ferreri, Jeanette K Doorduijn, Alessandro Re, Maria Giuseppina Cabras, Jeffery Smith, Fiorella Ilariucci, Mario Luppi, Teresa Calimeri, Chiara Cattaneo, Jahanzaib Khwaja, Barbara Botto, Claudia Cellini, Luca Nassi, Kim Linton, Pam McKay, Jacopo Olivieri, Caterina Patti, Francesca Re, Alessandro Fanni, Vikram Singh, Jacoline E C Bromberg, Kelly Cozens, Elisabetta Gastaldi, Massimo Bernardi, Nicola Cascavilla, Andrew Davies, Christopher P Fox, Maurizio Frezzato, Wendy Osborne, Anna Marina Liberati, Urban Novak, Renato Zambello, Emanuele Zucca, Kate Cwynarski
Journal: The Lancet Haematology (2021)

Secondary CNS lymphoma is a rare but potentially lethal event in patients with diffuse large B-cell lymphoma. We aimed to assess the activity and safety of an intensive, CNS-directed chemoimmunotherapy consolidated by autologous haematopoietic stem-cell transplantation (HSCT) in patients with secondary CNS lymphoma.
The political and security dimensions of the humanitarian health response to violent conflict
Authors: Paul H Wise, Annie Shiel, Nicole Southard, Eran Bendavid, Jennifer Welsh, Stephen Stedman, Tanisha Fazal, Vanda Felbab-Brown, David Polatty, Ronald J Waldman, Paul B Spiegel, Karl Blanchet, Rita Dayoub, Aliyu Zakayo, Michele Barry, Daniel Martinez Garcia, Heather Pagano, Robert Black, Michelle F Gaffey, Zulfiqar A Bhutta
Journal: The Lancet (2021)
Association of Psychiatric Disorders With Mortality Among Patients With COVID-19
Authors: Katlyn Nemani, Chenxiang Li, Mark Olfson, Esther M. Blessing, Narges Razavian, Ji Chen, Eva Petkova, Donald C. Goff
Journal: JAMA Psychiatry (2021)

To date, the association of psychiatric diagnoses with mortality in patients infected with coronavirus disease 2019 (COVID-19) has not been evaluated.To assess whether a diagnosis of a schizophrenia spectrum disorder, mood disorder, or anxiety disorder is associated with mortality in patients with COVID-19.This retrospective cohort study assessed 7348 consecutive adult patients for 45 days following laboratory-confirmed COVID-19 between March 3 and May 31, 2020, in a large academic medical system in New York. The final date of follow-up was July 15, 2020. Patients without available medical records before testing were excluded.Patients were categorized based on the following International Statistical Classification of Diseases, Tenth Revision, Clinical Modification diagnoses before their testing date: (1) schizophrenia spectrum disorders, (2) mood disorders, and (3) anxiety disorders. Patients with these diagnoses were compared with a reference group without psychiatric disorders.Mortality, defined as death or discharge to hospice within 45 days following a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test result.Of the 26 540 patients tested, 7348 tested positive for SARS-CoV-2 (mean [SD] age, 54 [18.6] years; 3891 [53.0%] women). Of eligible patients with positive test results, 75 patients (1.0%) had a history of a schizophrenia spectrum illness, 564 (7.7%) had a history of a mood disorder, and 360 (4.9%) had a history of an anxiety disorder. After adjusting for demographic and medical risk factors, a premorbid diagnosis of a schizophrenia spectrum disorder was significantly associated with mortality (odds ratio [OR], 2.67; 95% CI, 1.48-4.80). Diagnoses of mood disorders (OR, 1.14; 95% CI, 0.87-1.49) and anxiety disorders (OR, 0.96; 95% CI, 0.65-1.41) were not associated with mortality after adjustment. In comparison with other risk factors, a diagnosis of schizophrenia ranked behind only age in strength of an association with mortality.In this cohort study of adults with SARS-CoV-2-positive test results in a large New York medical system, adults with a schizophrenia spectrum disorder diagnosis were associated with an increased risk for mortality, but those with mood and anxiety disorders were not associated with a risk of mortality. These results suggest that schizophrenia spectrum disorders may be a risk factor for mortality in patients with COVID-19.
Three-dimensional cell-culture platform based on hydrogel with tunable microenvironmental properties to improve insulin-secreting function of MIN6 cells
Authors: Miao Zhang, Sen Yan, Xueqin Xu, Tingting Yu, Zhaobin Guo, Ming Ma, Yi Zhang, Zhuxiao Gu, Yiwei Feng, Chunyue Du, Mengqi Wan, Ke Hu, Xiao Han, Ning Gu
Journal: Biomaterials (2021)
AncPhore: A versatile tool for anchor pharmacophore steered drug discovery with applications in discovery of new inhibitors targeting metallo-β-lactamases and indoleamine/tryptophan 2,3-dioxygenases
Authors: Qingqing Dai, Yuhang Yan, Xiangli Ning, Gen Li, Junlin Yu, Ji Deng, Lingling Yang, Guo-Bo Li
Journal: Acta Pharmaceutica Sinica B (2021)

We herein describe AncPhore, a versatile tool for drug discovery, which is characterized by pharmacophore feature analysis and anchor pharmacophore (i.e., most important pharmacophore features) steered molecular fitting and virtual screening. Comparative analyses of numerous protein–ligand complexes using AncPhore revealed that anchor pharmacophore features are biologically important, commonly associated with protein conservative characteristics, and have significant contributions to the binding affinity. Performance evaluation of AncPhore showed that it had substantially improved prediction ability on different types of target proteins including metalloenzymes by considering the specific contributions and diversity of anchor pharmacophore features. To demonstrate the practicability of AncPhore, we screened commercially available chemical compounds and discovered a set of structurally diverse inhibitors for clinically relevant metallo-β-lactamases (MBLs); of them, 4 and 6 manifested potent inhibitory activity to VIM-2, NDM-1 and IMP-1 MBLs. Crystallographic analyses of VIM-2:4 complex revealed the precise inhibition mode of 4 with VIM-2, highly consistent with the defined anchor pharmacophore features. Besides, we also identified new hit compounds by using AncPhore for indoleamine/tryptophan 2,3-dioxygenases (IDO/TDO), another class of clinically relevant metalloenzymes. This work reveals anchor pharmacophore as a valuable concept for target-centered drug discovery and illustrates the potential of AncPhore to efficiently identify new inhibitors for different types of protein targets.
Seasonal malaria chemoprevention in the Sahel subregion of Africa: a cost-effectiveness and cost-savings analysis
Authors: Colin Gilmartin, Justice Nonvignon, Matthew Cairns, Paul Milligan, Fadima Bocoum, Peter Winskill, Diego Moroso, David Collins
Journal: The Lancet Global Health (2021)

The intermittent administration of seasonal malaria chemoprevention (SMC) is recommended to prevent malaria among children aged 3-59 months in areas of the Sahel subregion in Africa. However, the cost-effectiveness and cost savings of SMC have not previously been evaluated in large-scale studies.We did a cost-effectiveness and cost-savings analysis of a large-scale, multi-country SMC campaign with sulfadoxine-pyrimethamine plus amodiaquine for children younger than 5 years in seven countries in the Sahel subregion (Burkina Faso, Chad, Guinea, Mali, Niger, Nigeria, and The Gambia) in 2016. The financial and economic costs were analysed from the programmatic perspective and are reported in 2016 US$ for each country. The estimated numbers of averted malaria cases, deaths, and disability-adjusted life-years (DALYs) were based on numbers of SMC treatments administered and modelled malaria transmission. Cost savings were calculated from a programmatic perspective corresponding to the diagnostic and treatment costs for malaria cases averted.The total cost of SMC for all seven countries was $22·8 million, and the weighted average economic cost of administering four monthly SMC cycles was $3·63 per child (ranging from $2·71 in Niger to $8·20 in The Gambia). Based on 80% modelled effectiveness of SMC, the incremental economic cost per malaria case averted ranged from $2·91 in Niger to $30·73 in The Gambia; the cost per severe case averted ranged from $119·63 in Niger to $506·00 in The Gambia; the cost per death averted ranged from $533·56 in Niger to $2256·92 in The Gambia; and the cost per DALY averted (discounted by 3%) ranged from $18·66 in Niger to $78·91 in The Gambia. The estimated total economic cost savings to the health systems in all seven countries were US$66·0 million and the total net economic cost savings were US$43·2 million.SMC is a low-cost and highly cost-effective intervention that contributes to substantial cost savings by reducing malaria diagnostic and treatment costs among children.Unitaid.
Minimal residual disease (MRD) detection with circulating tumor DNA (ctDNA) from personalized assays in stage II-III colorectal cancer patients in a U.K. multicenter prospective study (TRACC).
Authors: Gayathri Anandappa, Naureen Starling, Ruwaida Begum, Annette Bryant, Shruti Sharma, Derrick Renner, Maria Aresu, Clare Peckitt, Himanshu Sethi, Andrew Feber, Vanessa Alice Potter, Marius Paraoan, Muti Abulafi, Nicol George, Graham Branagan, Sarah Duff, Nicholas West, Alexey Aleshin, Ian Chau, David Cunningham
Journal: Journal of Clinical Oncology (2021)

102 Background: Numerous studies have shown the clinical utility of ctDNA, a non-invasive biomarker to detect MRD and stratify CRC patients who are more likely to relapse. We present an analysis of MRD detection in CRC patients from a prospective multicentre UK study, who were monitored pre- and post-surgery before adjuvant chemotherapy (ACT). Methods: The study recruited patients diagnosed with stage II-III CRC (n=122), including a subset of rectal patients who underwent tri-modality treatment (TMT). All patients had their primary tumor resected and 56% (68/122) received ACT. Paired plasma samples (n=244) were collected before surgery/neaodjuvant chemoradiotherapy and after surgery; median follow-up for survival was 15.48 months (0.16 - 42.1 months). Individual tumors and matched germline DNA were whole-exome sequenced and somatic single nucleotide variants (SNVs) identified. Multiplex PCR assays were designed to track tumor-specific SNVs (Signatera, bespoke mPCR NGS assay) in plasma samples. The study evaluated ctDNA status and clinical outcomes including radiologic imaging. Cox regression was used to calculate recurrence-free survival (RFS) in patients stratified by post-op ctDNA status. Patients were also stratified into low and high-risk groups based on the clinicopathological features. Multivariate analysis was performed with covariates: ctDNA, age, gender, laterality, stage, number of lymph node resected, MSI &amp; TMB. Results: Pre-treatment ctDNA was detected in 93.4% (100/107) of patients. Post-operative ctDNA status prior to ACT was assessed in 107 patients, of whom, 13% (14/107) were MRD-positive (MRDpos). Of the MRDpos patients 42.9% (6/14) eventually relapsed. In contrast, only 8.6% (8/93) of MRD-negative (MRDneg) cases relapsed (HR: 10; 95% CI: 3.3-30; p&lt;0.001). MRD rates stratified by risk features in each of the stages with respective recurrence rates are shown in Table. In stage III patients (n=64), 45.4% (5/11) of the MRDpos patients relapsed, whilst only 17% (9/53) of the MRDneg cases relapsed (HR: 9; 95% CI:2.6-32; p&lt;0.0001). In the multivariate analysis, ctDNA status was the most significant prognostic factor associated with RFS (HR: 28.8, 95% CI: 3.5-234.1; p&lt;0.001). Conclusions: Postoperative ctDNA analysis with tumor informed assay enables detection of CRC patients at high-risk of recurrence. Early detection of MRD could guide ACT decisions in intervention trials and is currently underway in TRACC. Clinical trial information: NCT04050345. [Table: see text]
Cardiac mechanostructure: Using mechanics and anisotropy as inspiration for developing epicardial therapies in treating myocardial infarction
Authors: Kiera D. Dwyer, Kareen L.K. Coulombe
Journal: Bioactive Materials (2021)

The mechanical environment and anisotropic structure of the heart modulate cardiac function at the cellular, tissue and organ levels. During myocardial infarction (MI) and subsequent healing, however, this landscape changes significantly. In order to engineer cardiac biomaterials with the appropriate properties to enhance function after MI, the changes in the myocardium induced by MI must be clearly identified. In this review, we focus on the mechanical and structural properties of the healthy and infarcted myocardium in order to gain insight about the environment in which biomaterial-based cardiac therapies are expected to perform and the functional deficiencies caused by MI that the therapy must address. From this understanding, we discuss epicardial therapies for MI inspired by the mechanics and anisotropy of the heart focusing on passive devices, which feature a biomaterials approach, and active devices, which feature robotic and cellular components. Through this review, a detailed analysis is provided in order to inspire further development and translation of epicardial therapies for MI.
Recreated Ancestral Opsin Associated with Marine to Freshwater Croaker Invasion Reveals Kinetic and Spectral Adaptation
Authors: Alexander Van Nynatten, Gianni M Castiglione, Eduardo de A. Gutierrez, Nathan R Lovejoy, Belinda S W Chang
Journal: Molecular Biology and Evolution (2021)

Abstract Rhodopsin, the light-sensitive visual pigment expressed in rod photoreceptors, is specialized for vision in dim-light environments. Aquatic environments are particularly challenging for vision due to the spectrally dependent attenuation of light, which can differ greatly in marine and freshwater systems. Among fish lineages that have successfully colonized freshwater habitats from ancestrally marine environments, croakers are known as highly visual benthic predators. In this study, we isolate rhodopsins from a diversity of freshwater and marine croakers and find that strong positive selection in rhodopsin is associated with a marine to freshwater transition in South American croakers. In order to determine if this is accompanied by significant shifts in visual abilities, we resurrected ancestral rhodopsin sequences and tested the experimental properties of ancestral pigments bracketing this transition using in vitro spectroscopic assays. We found the ancestral freshwater croaker rhodopsin is redshifted relative to its marine ancestor, with mutations that recapitulate ancestral amino acid changes along this transitional branch resulting in faster kinetics that are likely to be associated with more rapid dark adaptation. This could be advantageous in freshwater due to the redshifted spectrum and relatively narrow interface and frequent transitions between bright and dim-light environments. This study is the first to experimentally demonstrate that positively selected substitutions in ancestral visual pigments alter protein function to freshwater visual environments following a transition from an ancestrally marine state and provides insight into the molecular mechanisms underlying some of the physiological changes associated with this major habitat transition.
HP0034 Responsiveness of selected disease-specific patient-assessed instruments in ankylosing spondylitis (as)
Authors: KL Haywood, AM Garratt, K Dziedzic, PT Dawes
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Introduction</h3> Five instruments, including an individualised measure of AS-related quality of life, the Patient-Generated Index (PGI-AS), have been assessed for measurement properties of reliability, validity and responsiveness in a large group of AS patients. Responsiveness refers to the ability to detect clinically important change and is an essential requirement for evaluative instruments. <h3>Objective</h3> To establish comparative evidence in support of instrument longitudinal validity and responsiveness. <h3>Methodology</h3> A questionnaire containing all instruments was mailed to over 450 patients randomly selected from six AS databases. Patients completed the questionnaire at baseline (response rate 76.9%; males 74.2%; mean age 46.0 yrs (SD 12.6), range 18–75 yrs; mean symptom duration 19.8 yrs) and 6 months. Self-reported AS and general health transition at 6 months were the criteria used to assess validity and responsiveness. The relationship between changes in instrument scores and responses to transition items was assessed for a linear trend. <h3>Results</h3> Significant correlations between mean change in instrument scores and both forms of transition question supports the longitudinal validity of all instruments (p &lt; 0.001): the largest levels of change were found for the PGI-AS and the Bath AS Disease Activity Index (BASDAI), both demonstrating a stronger relationship with general transition. The modified standardised response mean (MSRM) was used to assess responsiveness (Table 1). The Body Chart, a measure of AS specific pain, had a moderate relationship with AS transition only (better –0.44, worse 0.51), which may support the importance of specific pain evaluation. <h3>Conclusion</h3> Although certain domains may not be expected to change over 6-months, this period reflects normal practice in AS evaluation in many rheumatology centres. The responsiveness of the PGI-AS and BASDAI may make them suitable for routine monitoring where management may result in small but important changes in health related quality of life.
Northern California hepatitis C elimination project: Tele-mentoring led to quick adoption of hepatitis C treatment
Authors: S. Sarkar, J. B. Zepeda, P. Morris, R. Kanner, J. Slepin, A. Gonzalez-Flores, R. Hluhanich, N. Terrault
Journal: Hepatology (2020)

Background: Hepatitis C virus (HCV) remains a major public health crisis in rural communities across Northern California Successful detection and linkage-to-care continues to face significant challenges especially with the lack of 'treaters' in these communities A targeted approach to primary care provider (PCP) education in rural communities utilizing telementoring was developed as part of a multifaceted initiative to increase provider capacity within Northern California (called ECHO-PLUS) The primary intent was to cultivate local HCV treatment champions, providing patients access to timely care Methods: Tele-mentoring using a telemedicine-based approach with provider and patient both in the exam room at the PCP 'mentee' site, and an HCV specialist and specialty pharmacist at the mentor site  Prior to the first patient encounter, mentees received 1-hour CME-certified HCVfocused education Subsequently, patients were scheduled for clinic times with new visits lasting 30 minutes and follow-ups lasting 15 minutes There was additional 5-10 minutes pre/ post visit discussion between mentor and mentee related to management of the patient's hepatitis C A provider readiness survey was done independently by the specialist and pharmacist on a Likert-type scale with three questions (scored 1-5, total score 15) following each patient visit Results: A total of 19 providers from 14 discrete clinics located in 14 counties spread over Northern California and Central Valley participated 11 of the 19 providers saw at least one HCV patient with a mentor;the other 8 providers only attended the CME-based HCV education Of the 11 participating providers, 5 classified themselves as 'experienced' having treated previously with PEG-interferon and 6 as 'inexperienced' or never-treated HCV A total of 60 hours of tele-mentoring sessions were completed with 31 patients treated jointly, all of whom successfully underwent HCV treatment Inexperienced treaters saw at least 3 patients and a maximum of 6 patients, while experienced treaters saw 1-2 patients Experienced treaters had 1 5-3 hours of tele-mentoring compared to 3-7 hours for inexperienced treaters Provider readiness surveys showed a median improvement by 7-points with a final score of 13 5 versus starting score of 6 5, with inexperienced treaters showing the greatest change Within a month of tele-mentoring completion defined by their readiness survey, the prior inexperienced treaters noted treating 2-5 patients independently Conclusion: Individualized tele-mentoring led to early adoption of HCV therapy ECHO programs combining various modalities of telemedicine can help successfully create 'champion' providers in rural and underserved communities providing essential care that becomes especially relevant with the surge of SARS-CoV-2
Melanoma surveillance for high-risk patients via telemedicine: Examination of real-world data from an integrated store-and-forward total body photography and dermoscopy service
Authors: Andrea Tan, Elizabeth Greenwald, Shirin Bajaj, Debbie Belen, Taylor Sheridan, Jennifer A. Stein, Tracey N. Liebman, Adrian Bowling, David Polsky
Journal: Journal of the American Academy of Dermatology (2021)