tbuckley/cabot-search huggingface dataset:
Accepting higher morbidity in exchange for sacrificing fewer animals in studies developing novel infection-control strategies
Authors: Henk J. Busscher, Willem Woudstra, Theo G. van Kooten, Paul Jutte, Linqi Shi, Jianfeng Liu, Wouter L.J. Hinrichs, Hendrik W. Frijlink, Rui Shi, Jian Liu, Javad Parvizi, Stephen Kates, Vincent M. Rotello, Thomas P. Schaer, Dustin Williams, David W. Grainger, Henny C. van der Mei
Journal: Biomaterials (2019)

Preventing bacterial infections from becoming the leading cause of death by the year 2050 requires the development of novel, infection-control strategies, building heavily on biomaterials science, including nanotechnology. Pre-clinical (animal) studies are indispensable for this development. Often, animal infection outcomes bear little relation to human clinical outcome. Here, we review conclusions from pathogen-inoculum dose-finding pilot studies for evaluation of novel infection-control strategies in murine models. Pathogen-inoculum doses are generally preferred that produce the largest differences in quantitative infection outcome parameters between a control and an experimental group, without death or termination of animals due to having reached an inhumane end-point during the study. However, animal death may represent a better end-point for evaluation than large differences in outcome parameters or number of days over which infection persists. The clinical relevance of lower pre-clinical outcomes, such as bioluminescence, colony forming units (CFUs) retrieved or more rapid clearance of infection is unknown, as most animals cure infection without intervention, depending on pathogen-species and pathogen-inoculum dose administered. In human clinical practice, patients suffering from infection present to hospital emergency wards, frequently in life-threatening conditions. Animal infection-models should therefore use prevention of death and recurrence of infection as primary efficacy targets to be addressed by novel strategies. To compensate for increased animal morbidity and mortality, animal experiments should solely be conducted for pre-clinical proof of principle and safety. With the advent of sophisticated in vitro models, we advocate limiting use of animal models when exploring pathogenesis or infection mechanisms.
Exposure to Intravenous Opioids Is Associated With Future Exposure to Opioids in Hospitalized Patients With Inflammatory Bowel Diseases
Authors: Rahul S. Dalal, Sonali Palchaudhuri, Christopher K. Snider, James D. Lewis, Shivan J. Mehta, Gary R. Lichtenstein
Journal: Clinical Gastroenterology and Hepatology (2019)
Integrating high dose inhaled corticosteroids into oral corticosteroids stewardship
Authors: Arnaud Bourdin, Carey Suehs, Jérémy Charriot
Journal: European Respiratory Journal (2020)

Uncertainties still surround high dose inhaled corticosteroids (ICS) use in asthma. In hindsight, certain aspects of the ICS development story can help elucidate why. In 1973, Cameron et al. [1] signed a brilliant paper reporting the results of a double blind, randomised controlled trial demonstrating the oral corticosteroid (OCS)-sparing effect of ICS as the primary outcome. A few years later, the assessment of this benefit was mitigated when a complete weaning of OCS remained unachievable [2]. The benefit of ICS was therefore understood to be mostly based on an improved safety profile purportedly due to reduced systemic diffusion. Thus, the understanding of how ICS was of any benefit to asthma patients when compared to OCS was mostly based on a greater safety profile supposedly due to a reduced systemic diffusion. Similarly, topically administered corticosteroids were also developed in the same time period for diseases affecting the skin, the eyes, the nose or the joints. As for ICS, whether or not these formulations reduce corticosteroid-associated adverse events remains largely debated [3]. If high doses of ICS are equivalent to low dose OCS, they should be considered as such <http://bit.ly/2CYssfB>
Helminth infections drive heterogeneity in human type 2 and regulatory cells
Authors: Karin de Ruiter, Simon P. Jochems, Dicky L. Tahapary, Koen A. Stam, Marion König, Vincent van Unen, Sandra Laban, Thomas Höllt, Moustapha Mbow, Boudewijn P. F. Lelieveldt, Frits Koning, Erliyani Sartono, Johannes W. A. Smit, Taniawati Supali, Maria Yazdanbakhsh
Journal: Science Translational Medicine (2020)

Mass cytometry identifies clusters of type 2 and regulatory immune responses in pre– and post–anthelmintic treatment human blood samples.
Intrahepatic bacterial metataxonomic signature in non-alcoholic fatty liver disease
Authors: Silvia Sookoian, Adrian Salatino, Gustavo Osvaldo Castaño, Maria Silvia Landa, Cinthia Fijalkowky, Martin Garaycoechea, Carlos Jose Pirola
Journal: Gut (2020)

Objective We aimed to characterise the liver tissue bacterial metataxonomic signature in two independent cohorts of patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD) diagnosis, as differences in the host phenotypic features—from moderate to severe obesity—may be associated with significant changes in the microbial DNA profile. Design and methods Liver tissue samples from 116 individuals, comprising of 47 NAFLD overweight or moderately obese patients, 50 NAFLD morbidly obese patients elected for bariatric surgery and 19 controls, were analysed using high-throughput 16S rRNA gene sequencing. Results Liver bacterial DNA profile significantly differs between morbidly obese and non-morbidly obese patients with NAFLD. Bacteroidetes (p=1.8e-18) and Firmicutes (p=0.0044) were over-represented in morbidly obese patients and Proteobacteria (p=5.2e-10)—specifically Gammaproteobacteria and Alphaproteobacteria, and Deinococcus-Thermus (p=0.00012)—were over-represented in the non-morbidly obese cohort. Cohort-specific analysis of liver microbial DNA signatures shows patterns linked to obesity. The imbalance in Proteobacteria (Alpha or Gamma) among non-morbidly obese patients, and Peptostreptococcaceae, Verrucomicrobia, Actinobacteria and Gamma Proteobacteria DNA among morbidly obese patients was associated with histological severity. Decreased amounts of bacterial DNA from the Lachnospiraceae family were associated with more severe histological features. Proteobacteria DNA was consistently associated with lobular and portal inflammation scores. Microbial DNA composition corresponded to predicted functional differences. Conclusion This is the first comprehensive study showing that the liver tissue of NAFLD patients contains a diverse repertoire of bacterial DNA (up to 2.5×10 4 read counts). The liver metataxonomic signature may explain differences in the NAFLD pathogenic mechanisms as well as physiological functions of the host.
Up-Regulation of Mir-21 and Mir-130a and Serum Leptin Levels on Leg Ulcers Development in Sickle Cell Anemia
Authors: Thais Helena Chaves Batista, Rodrigo Marcionilo Santana, Marcondes José de Vasconcelos Costa Sobreira, Gabriela da Silva Arcanjo, Diego Arruda Falcao, Diego A Pereira-Martins, Aderson da Silva Araujo, Fernando Ferreira Costa, Mario José Abdalla Saad, Bruno de Melo Carvalho, Luydson Richardson Silva Vasconcelos, Antonio R. Lucena-Araujo, Marcos Andre Cavalcanti Bezerra
Journal: Blood (2019)
In vitro activity profile of the novel hypoxia-activated cytotoxic prodrug TH-302
Authors: Charles Hart, Fanying Meng, Monica Banica, James Evans, Leslie Lan, Gustavo Lorente, Jian Duan, Mark Matteucci
Journal: Cancer Research (2008)

1441  TH-302 is a hypoxia-activated cytotoxic prodrug comprised of a 2-nitroimidazole hypoxia trigger linked to a dibromo isophosphoramide mustard toxin. TH-302 exhibits potent in vitro cytotoxicity under hypoxia, is efficacious in both ectopic and orthotopic xenograft cancer models, and demonstrates a favorable PK and tox profile. TH-302 is currently in a Phase 1 clinical trial for the treatment of cancer. Here we present details of TH-302’s in vitro activity profile.  Examination of TH-302’s cytotoxic potency and hypoxia selectivity in different cancer cell lines (PC-3, MIA PaCa-2, ACHN, HCT 116) yielded results comparable to those observed in H460 cells (in a 2h exposure 3d proliferation assay  300). The cytoxicity of TH-302 under normoxia across the entire panel of 60 human cancer cell lines comprising the NCI-60 showed none to be more sensitive than H460 under normoxia (2d proliferation assay). This latter result indicates that, at least within this panel of cell lines, none are able to significantly activate TH-302 in a hypoxia-independent manner. When TH-302 was tested in pairs of cell lines that allow the profiling of susceptibility to efflux by the major drug resistance pumps (i.e. MDR1, MRP1, and BCRP), TH-302 showed no difference in potency or selectivity in lines over-expressing the specific pump, versus matched control lines (MESSA vs. MESSA-DX5; H69 vs. H69AR; HEK293-PCDNA vs. HEK293-BCRP, respectively). This result indicates that TH-302 is not a substrate for these clinically relevant drug resistance pumps.  The oxygen concentration dependence of TH-302 activation cytotoxicity was examined employing a set of defined gas mixtures (0%, 0.1%, 0.3%, 0.6%, 1%, 10%, 21% O2) in the 2h exposure 3d proliferation assay with H460 cells. Results demonstrated an O2 concentration dependence of prodrug activation (IC 50’s were 0.1, 1, 3, 5, 7, 30, and 30µM, respectively).  Examining downstream effects of TH-302 activity, we demonstrate both γH2AX phosphorylation and G2/M phase cell cycle arrest in a TH-302 concentration- and time-dependent manner in H460 cells. These activities mirrored the cytotoxicity profile in terms of potency and hypoxia-selectivity. Utilization of CHO cell-based DNA repair mutant cell lines showed that lines deficient in homologous recombination (irs1SF and UV41) exhibited greater sensitivity to TH-302 under hypoxia than the parental control line (AA8) or in lines deficient in base or nucleotide excision repair (EM9, UV35). These findings are consistent with a DNA cross-linking mechanism of action underlying TH-302’s cytotoxicity in vitro.  Taken together, these results demonstrate that TH-302 exhibits a favorable in vitro activity profile for a hypoxia-activated prodrug in clinical development.
Public Health and Online Misinformation: Challenges and Recommendations
Authors: Briony Swire-Thompson, David Lazer
Journal: Annual Review of Public Health (2019)

The internet has become a popular resource to learn about health and to investigate one's own health condition. However, given the large amount of inaccurate information online, people can easily become misinformed. Individuals have always obtained information from outside the formal health care system, so how has the internet changed people's engagement with health information? This review explores how individuals interact with health misinformation online, whether it be through search, user-generated content, or mobile apps. We discuss whether personal access to information is helping or hindering health outcomes and how the perceived trustworthiness of the institutions communicating health has changed over time. To conclude, we propose several constructive strategies for improving the online information ecosystem. Misinformation concerning health has particularly severe consequences with regard to people's quality of life and even their risk of mortality; therefore, understanding it within today's modern context is an extremely important task.
Effectiveness of using cardiac biomarkers to detect late anthracycline cardiotoxicity in childhood leukemia survivors.
Authors: Beata Mladosievicova, Dagmar Urbanova, Eva Radvanska, Eva Mikuskova, Iveta Simkova
Journal: Journal of Clinical Oncology (2012)

9592 Background: Cardiotoxicity is usually detected only when clinical symptoms or progressive cardiac dysfunction has already occurred. Cardiac biomarkers (troponin T and N-terminal fragment brain natriuretic peptide precursor) have been hypothesized to reflect subclinical anthracycline cardiotoxicity earlier than echocardiography. This study aims to assess the effectiveness of using cTNT and NTproBNP in asymptomatic long-term survivors of childhood leukemia treated with and without antracyclines (ANT). Methods: Sixty-nine childhood leukemia survivors 5 - 25 years after completion of therapy were evaluated with immunochemical analysis of cTnT and NT-proBNP and echocardiography. Patients from group I (n = 36) received combined therapy with anthracyclines (ANT) with total cumulative dose 95-600 (median 221) mg/m 2 , patients from group II (n = 33) received therapy without anthracyclines (nonANT). Control group consisted from 44 age- and gender-matched apparently healthy subjects. Results: Levels of NTproBNP were significantly higher in ANT group than in controls (median 51,52 vs 17,37 pg/ml; p=0.0026). Patients treated with ANT had significantly increased median values of NTproBNP compared with patients in non ANT group (51,52 vs 12,24 pg/ml; p=0.0002). CTnT levels remained below the diagnostic cut-off levels in all groups. No patient had echocardiographic abnormalities, but significant differences were found in mean values of left ventricular ejection fraction and deceleration time between patients treated with and without ANT. Conclusions: Assessment of plasma NTproBNP concentrations may be an effective tool for detection of late subclinical cardiac damage in survivors of childhood leukemia previously treated with low ANT doses. Higher NTproBNP levels in patients after ANT therapy might reflect an initial stage of cardiotoxicity before the development of echocardiographic abnormalities. This study was supported by a grant from Ministry of Health 2007/42-UK-18, Slovakia.
Entities also require relational coding and binding
Authors: Timothy F Brady, Igor S Utochkin
Journal: Behavioral and Brain Sciences (2019)

Abstract Although Bastin et al. propose a useful model for thinking about the structure of memory and memory deficits, their distinction between entities and relational encoding is incompatible with data showing that even individual objects – prototypical “entities” – are made up of distinct features which require binding. Thus, “entity” and “relational” brain regions may need to solve fundamentally the same problems.
Response to: ‘response to: irritable bowel syndrome symptoms in axial spondyloarthritis more common than among healthy controls: is it an overlooked comorbidity?’ by Proft et al.
Authors: Johan Karlsson Wallman, Elisabeth Mogard, Jan Marsal, Kristofer Andréasson, Anna Jöud, Mats Geijer, Lars Erik Kristensen, Elisabet Lindqvist, Tor Olofsson
Journal: Annals of the Rheumatic Diseases (2019)

We appreciate the correspondence by Proft et al regarding our study entitled ‘Irritable bowel syndrome symptoms in axial spondyloarthritis more common than among healthy controls: is it an overlooked comorbidity?’,1 2 and thank Annals of the Rheumatic Diseases for the opportunity to respond. We also acknowledge the major contributions of Proft et al to the field of spondyloarthritis (SpA) research.

Regarding our main result, that irritable bowel syndrome (IBS) symptoms are significantly more common among patients with axial SpA without known inflammatory bowel disease (IBD) (n=182) than in healthy controls (n=50), Proft et al point out that the increased prevalence is likely due to other causes than actual clinical IBS (in particular gut inflammation and side effects of non-steroidal anti-inflammatory drug (NSAID) use).

In response to this, we would first like to draw attention to the rule-out character of the ROME III criteria used to diagnose IBS, as also brought up by Proft et al . According to these, a clinical IBS diagnosis requires both a typical constellation of gastrointestinal symptoms, as defined by the criteria, and the exclusion of organic causes such as IBD or malignancies. The main finding of our study, that 30% of the axial SpA patients in the well-characterised SPARTAKUS cohort reported IBS symptoms, as opposed to 16% of healthy controls (sex/age-adjusted OR 2.5; p=0.036), refers to self-reported symptoms, as defined by the ROME III criteria, but irrespective of their underlying cause (and hence not per se meeting the exclusion condition). This important distinction—between IBS symptoms and a clinical IBS diagnosis—is made throughout our report.

In the second part of our study, we then performed a hypothesis-generating analysis of potential drivers behind the observed IBS symptoms. Similar to Proft et al , …
A phase II study of clofarabine and daunorubicin in patients age 60 or older with newly diagnosed adult acute myeloid leukemia.
Authors: Carlos Enrique Vigil, Elizabeth A. Griffiths, James E Thompson, Wei Tan, Jessica Greene, Laurie Ann Ford, Eunice S. Wang, Meir Wetzler
Journal: Journal of Clinical Oncology (2012)

6602 Background: The outcome of acute myeloid leukemia (AML) patients (pts) ≥60 years (yrs) old remains poor, with a median overall survival of a few months. Neither the addition of other drugs during induction of the traditional 7+3 regimen nor an increase of cytarabine or daunorubicin doses has improved their overall survival. We have therefore designed a combination of clofarabine and daunorubicin. Aims: Determine the safety and efficacy of clofarabine and daunorubicin in pts ≥ 60 yrs of age. Methods: Induction-clofarabine 20 mg/m 2 /d in a 1-hour IV for 5 days followed 3 hrs later by daunorubicin 50 mg/m 2 IV over 5 minutes on days 1, 3, and 5. Pts who did not achieve complete remission (CR) or CR without platelet recovery (CRp) were eligible for a second round of induction as above. Consolidation - 2 cycles of clofarabine 20mg/m 2 /d for 3 days and daunorubicin 50 mg/m 2 /day on days 1 and 3. Results: Twenty-one pts were enrolled. The median age was 69 (range 60-85) yrs. Seven pts (34%) had secondary AML and 52% had complex karyotype. Twenty-one pts completed one induction cycle, one pt received a second induction due to residual disease and 6 pts underwent consolidation therapy. The principal toxicity was grade ≥3 infections and prolonged thrombocytopenia and neutropenia, which occurred in 18% and 21% of pts, respectively. Three deaths were documented from treatment complications (sepsis and fungal infections). Eight (38.1%) pts achieved either a CR or CRp. Responses were observed in 5/11 (45.5%) pts with high risk features (complex karyotype and/or presence of FLT3). The median disease free-survival was 1.9 (range, 0.9-8) months and the median overall survival was 6.5 (range, 4.2-14.2) months. The 1-yr overall survival was 35%. Conclusions: These preliminary results suggest that clofarabine in combination with daunorubicin is safe, well-tolerated with minimal toxicity, and active for the upfront treatment of ≥60 yrs old AML pts, including those with adverse features. Future trials will explore additional modifications to this regimen in order to optimize therapy for this group of pts with high risk features and frequent treatment failure.
Developing and Sustaining an Effective and Resilient Oncology Careforce: Opportunities for Action
Authors: Samuel U Takvorian, Erin Balogh, Sharyl Nass, Virginia L Valentin, Lori Hoffman-Hogg, Randall A Oyer, Robert W Carlson, Neal J Meropol, Lisa Kennedy Sheldon, Lawrence N Shulman
Journal: JNCI Journal of the National Cancer Institute (2019)

Abstract Advances in cancer care have led to improved survival, which, coupled with demographic trends, have contributed to rapid growth in the number of patients needing cancer care services. However, with increasing caseload, care complexity, and administrative burden, the current workforce is ill equipped to meet these burgeoning new demands. These trends have contributed to clinician burnout, compounding a widening workforce shortage. Moreover, family caregivers, who have unique knowledge of patient preferences, symptoms, and goals of care, are infrequently appreciated and supported as integral members of the oncology “careforce.” A crisis is looming, which will hinder access to timely, high-quality cancer care if left unchecked. Stemming from the proceedings of a 2019 workshop convened by the National Cancer Policy Forum of the National Academies of Sciences, Engineering, and Medicine, this commentary characterizes the factors contributing to an increasingly strained oncology careforce and presents multilevel strategies to improve its efficiency, effectiveness, and resilience. Together, these will enable today’s oncology careforce to provide high-quality care to more patients while improving the patient, caregiver, and clinician experience.
Enzyme Evolution: An Epistatic Ratchet versus a Smooth Reversible Transition
Authors: Moshe Ben-David, Misha Soskine, Artem Dubovetskyi, Kesava-Phaneendra Cherukuri, Orly Dym, Joel L Sussman, Qinghua Liao, Klaudia Szeler, Shina Caroline Lynn Kamerlin, Dan S Tawfik
Journal: Molecular Biology and Evolution (2019)

Abstract Evolutionary trajectories are deemed largely irreversible. In a newly diverged protein, reversion of mutations that led to the functional switch typically results in loss of both the new and the ancestral functions. Nonetheless, evolutionary transitions where reversions are viable have also been described. The structural and mechanistic causes of reversion compatibility versus incompatibility therefore remain unclear. We examined two laboratory evolution trajectories of mammalian paraoxonase-1, a lactonase with promiscuous organophosphate hydrolase (OPH) activity. Both trajectories began with the same active-site mutant, His115Trp, which lost the native lactonase activity and acquired higher OPH activity. A neo-functionalization trajectory amplified the promiscuous OPH activity, whereas the re-functionalization trajectory restored the native activity, thus generating a new lactonase that lacks His115. The His115 revertants of these trajectories indicated opposite trends. Revertants of the neo-functionalization trajectory lost both the evolved OPH and the original lactonase activity. Revertants of the trajectory that restored the original lactonase function were, however, fully active. Crystal structures and molecular simulations show that in the newly diverged OPH, the reverted His115 and other catalytic residues are displaced, thus causing loss of both the original and the new activity. In contrast, in the re-functionalization trajectory, reversion compatibility of the original lactonase activity derives from mechanistic versatility whereby multiple residues can fulfill the same task. This versatility enables unique sequence-reversible compositions that are inaccessible when the active site was repurposed toward a new function.