tbuckley/cabot-search huggingface dataset:
Identification of novel cerebrospinal fluid biomarker candidates for dementia with Lewy bodies: a proteomic approach
Authors: Inger van Steenoven, Marleen J. A. Koel-Simmelink, Leonie J. M. Vergouw, Betty M. Tijms, Sander R. Piersma, Thang V. Pham, Claire Bridel, Gian-Luca Ferri, Cristina Cocco, Barbara Noli, Paul F. Worley, Mei-Fang Xiao, Desheng Xu, Patrick Oeckl, Markus Otto, Wiesje M. van der Flier, Frank Jan de Jong, Connie R. Jimenez, Afina W. Lemstra, Charlotte E. Teunissen
Journal: Molecular Neurodegeneration (2020)

Diagnosis of dementia with Lewy bodies (DLB) is challenging, largely due to a lack of diagnostic tools. Cerebrospinal fluid (CSF) biomarkers have been proven useful in Alzheimer's disease (AD) diagnosis. Here, we aimed to identify novel CSF biomarkers for DLB using a high-throughput proteomic approach.We applied liquid chromatography/tandem mass spectrometry with label-free quantification to identify biomarker candidates to individual CSF samples from a well-characterized cohort comprising patients with DLB (n = 20) and controls (n = 20). Validation was performed using (1) the identical proteomic workflow in an independent cohort (n = 30), (2) proteomic data from patients with related neurodegenerative diseases (n = 149) and (3) orthogonal techniques in an extended cohort consisting of DLB patients and controls (n = 76). Additionally, we utilized random forest analysis to identify the subset of candidate markers that best distinguished DLB from all other groups.In total, we identified 1995 proteins. In the discovery cohort, 69 proteins were differentially expressed in DLB compared to controls (p < 0.05). Independent cohort replication confirmed VGF, SCG2, NPTX2, NPTXR, PDYN and PCSK1N as candidate biomarkers for DLB. The downregulation of the candidate biomarkers was somewhat more pronounced in DLB in comparison with related neurodegenerative diseases. Using random forest analysis, we identified a panel of VGF, SCG2 and PDYN to best differentiate between DLB and other clinical groups (accuracy: 0.82 (95%CI: 0.75-0.89)). Moreover, we confirmed the decrease of VGF and NPTX2 in DLB by ELISA and SRM methods. Low CSF levels of all biomarker candidates, except PCSK1N, were associated with more pronounced cognitive decline (0.37 < r < 0.56, all p < 0.01).We identified and validated six novel CSF biomarkers for DLB. These biomarkers, particularly when used as a panel, show promise to improve diagnostic accuracy and strengthen the importance of synaptic dysfunction in the pathophysiology of DLB.
Bosutinib for pretreated patients with chronic phase chronic myeloid leukemia: primary results of the phase 4 BYOND study
Authors: Andreas Hochhaus, Carlo Gambacorti-Passerini, Camille Abboud, Bjørn Tore Gjertsen, Tim H. Brümmendorf, B. Douglas Smith, Thomas Ernst, Pilar Giraldo-Castellano, Ulla Olsson-Strömberg, Susanne Saussele, Nathalie Bardy-Bouxin, Andrea Viqueira, Eric Leip, T. Alexander Russell-Smith, Jocelyn Leone, Gianantonio Rosti, Justin Watts, Francis J. Giles, E. Abruzzese, L. P. Akard, A. Bosi, F. Cervantes, A. Charbonnier, F. Di Raimondo, G. Etienne, V. Garcia Gutierrez, A. P. Guerci-Bresler, H Hjorth-Hansen, J. M. Karsenti, K. R. Kelly, P. Le Coutre, C. Martinez Chamorro, V. G. Oehler, G. Orti Pascual, A. Petzer, E. Pungolino, G. Rege-Cambrin, F. Rigal-Huguet, G. J. Roboz, P. Rousselot, F. M. Sanchez-Guijo, G. Sanz Santillana, P. Schafhausen, C. Scheid, S. Schmidt, G. Specchia, J. L. Steegmann, L. Stenke
Journal: Leukemia (2020)

Abstract Bosutinib is approved for newly diagnosed Philadelphia chromosome-positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML) and for Ph+ CP, accelerated (AP), or blast (BP) phase CML after prior treatment with tyrosine kinase inhibitors (TKIs). In the ongoing phase 4 BYOND study (NCT02228382), 163 CML patients resistant/intolerant to prior TKIs ( n = 156 Ph+ CP CML, n = 4 Ph+ AP CML, n = 3 Ph-negative/ BCR-ABL1 + CML) received bosutinib 500 mg once daily (starting dose). As of ≥1 year after last enrolled patient (median treatment duration 23.7 months), 56.4% of Ph+ CP CML patients remained on bosutinib. Primary endpoint of cumulative confirmed major cytogenetic response (MCyR) rate by 1 year was 75.8% in Ph+ CP CML patients after one or two prior TKIs and 62.2% after three prior TKIs. Cumulative complete cytogenetic response (CCyR) and major molecular response (MMR) rates by 1 year were 80.6% and 70.5%, respectively, in Ph+ CP CML patients overall. No patient progressed to AP/BP on treatment. Across all patients, the most common treatment-emergent adverse events were diarrhea (87.7%), nausea (39.9%), and vomiting (32.5%). The majority of patients had confirmed MCyR by 1 year and MMR by 1 year, further supporting bosutinib use for Ph+ CP CML patients resistant/intolerant to prior TKIs.
Bereavement Care in the Wake of COVID-19: Offering Condolences and Referrals
Authors: Wendy G. Lichtenthal, Kailey E. Roberts, Holly G. Prigerson
Journal: Annals of Internal Medicine (2020)

T he coronavirus disease 2019 pandemic has left, and will continue to leave, hundreds of thousands of bereft family members in its wake (1).These deaths are unlike others in recent history.Unprecedented conditions-massive numbers of casualties; forced separations during a patient's final days; and denial of physical touch, final goodbyes, and traditional mourning rituals-pose threats to bereaved family members' mental health, leaving them vulnerable to intense and enduring psychological distress.Front-line physicians are uniquely positioned to provide critically needed psychosocial support to bereaved family members.Regardless of medical specialty, physicians are now caring for more dying patients than ever before and, concomitantly, are tasked with talking to a deceased patient's family members.Many well-intentioned but weary and emotionally depleted physicians search for the words to say and wonder how to know when a bereaved family member is at risk and when they should refer them to a mental health professional.To address this need, we offer words to say and guidance on when to make referrals to offset the risks that the pandemic has posed to family members' mental health.We recognize that communicating condolences in the context of a pandemic is challenging for many reasons, including the sheer volume of deaths, barriers to communication imposed by social distancing, time pressures, compassion fatigue, and mental and physical exhaustion.Our tips aim to make this difficult but potentially impactful interaction both easier for physicians responsible for talking with surviving family members and more comforting and beneficial for the bereaved family members.Specifically, we suggest ways to communicate compassionately, assess risk for acute bereavement challenges, and refer to a mental health professional when indicated (Table andFigure).This guidance is based on decades of research and clinical experience; we acknowledge that studies have not yet confirmed a link between these recommendations and better outcomes, nor their cultural universality.
Ethics Lessons From Seattle’s Early Experience With COVID-19
Authors: Denise M. Dudzinski, Benjamin Y. Hoisington, Crystal E. Brown
Journal: The American Journal of Bioethics (2020)

Ethics consultants and critical care clinicians reflect on Seattle's early experience as the United States' first epicenter of COVID-19. We discuss ethically salient issues confronted at UW Medicine's hospitals and provide lessons for other health care institutions that may soon face what we have faced.
Metabolic Effects of an SGLT2 Inhibitor (Dapagliflozin) During a Period of Acute Insulin Withdrawal and Development of Ketoacidosis in People With Type 1 Diabetes
Authors: Roselle A. Herring, Fariba Shojaee-Moradie, Robert Garesse, Mary Stevenage, Nicola Jackson, Barbara A. Fielding, Agampodi Mendis, Sigurd Johnsen, A. Margot Umpleby, Melanie Davies, David L. Russell-Jones
Journal: Diabetes Care (2020)

To determine the effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on glucose flux, lipolysis, and ketone body concentrations during insulin withdrawal in people with type 1 diabetes.A double-blind, placebo-controlled crossover study with a 4-week washout period was performed in 12 people with type 1 diabetes using insulin pump therapy. Participants received dapagliflozin or placebo in random order for 7 days. Stable isotopes were infused to measure the glucose Ra, Rd, and lipolysis. At isotopic steady state, insulin was withdrawn, and the study was terminated after 600 min or earlier if blood glucose reached 18 mmol/L, bicarbonate <15 mmol/L, venous pH <7.35, or capillary ketones >5.0 mmol/L.At baseline, glucose Ra was significantly higher for the dapagliflozin group than the placebo group. Following insulin withdrawal, plasma glucose concentrations at the end point were significantly lower with dapagliflozin than placebo and glucose Rd area under the curve (AUC)0-180 min and β-hydroxybutyrate (BOHB) AUC0-180 min were significantly higher. There was a small but significantly higher glycerol Ra (measure of lipolysis) AUC0-180 min with dapagliflozin. Nonesterified fatty acid concentrations were not different between treatments. When divided by BMI >27 and <27 kg/m2, basal glucose Ra, BOHB, and glycerol Ra AUC0-180 min were significantly higher in the low-BMI group with dapagliflozin treatment versus the low-BMI group with placebo.During insulin withdrawal, the increase in BOHB with dapagliflozin may be partially due to increased lipolysis. However, reduced renal excretion, reduced BOHB uptake by peripheral tissues, or a metabolic switch to increased ketogenesis within the liver may also play a role.
Invited Commentary to: The diagnostic value of prostate cancer between holmium laser enucleation of the prostate and transurethral resection of the prostate for benign prostatic hyperplasia, comparative study - Retrospective cohort. IJS-D-19-01006R1
Authors: Moisés Rodríguez Socarrás, Julio Fernández Del Álamo
Journal: International Journal of Surgery (2020)
Correspondence to ‘Hypersensitivity reactions with allopurinol and febuxostat: a study using the Medicare claims data’
Authors: Kevin Sheng-Kai Ma, James Cheng-Chung Wei, Wen-Hung Chung
Journal: Annals of the Rheumatic Diseases (2020)

We read with great interest the article by Singh and Cleveland, which the authors reported that the observed hypersensitivity reactions (HSRs) associated with allopurinol and febuxostat were not different.1 This conclusion differs from previous studies on HSRs associated with allopurinol and febuxostat using claimed data2 and intramural databases.3 The discrepancy may arise from different inclusion criteria for the diagnosis of HSRs based on International Classification of Diseases, Ninth Revision (ICD-9) coding system, methods for identifying causative drugs, methods for stratification, as well as ethnicity of the involved population.

The definition of HSR in the study by Singh and Cleveland adopted ICD-9 diagnostic codes specifying eosinophilia (288.3), HSR- associated arthropathy (713.6), anaphylactic reactions (995.0) or unspecified adverse drug effect (995.2) or allergy (995.3), plus the baseline exclusion for E930 to E949.1 On the contrary, in our previous studies, the definition of cutaneous adverse reactions (CARs) using the Taiwanese registry database involved drug-induced dermatitis (693.0), erythema multiforme (695.1) or erythematous conditions (695.89 or 695.9).2–4 Likewise, another study based on intramural database …
Abstract IA21: Exploiting the biology of exosomes for diagnosis and treatment of cancer
Authors: Raghu Kalluri
Journal: Clinical Cancer Research (2020)

Abstract Humans circulate trillions of exosomes at all times. Exosomes are extracellular vesicles with a size range of 40-150 nm and a lipid bilayer membrane and are released by all cell types. Normal exosomes contain DNA, RNA, and proteins. Some proteins such as CD9, CD63, and flotillin are often detected on the surface of exosomes and serve as markers. Exosomes likely remove excess and/or unnecessary constituents from the cells, functioning like garbage bags. Although their precise physiologic role remains largely unknown, is it suggested that exosomes may mediate specific cell-cell communication and activate signaling pathways in cells they fuse or interact with. Exosomes are detected in the tumor microenvironment, and emerging evidence suggests that they play a role in facilitating tumorigenesis by regulating angiogenesis, immunity, and metastasis. Circulating exosomes could be used as liquid biopsies and noninvasive biomarkers to potentially inform on early detection and diagnosis of cancer patients. Exosomes can be used for the treatment of cancer. This lecture will highlight some of the recent advances in the area of exosomes’ biology and their utility in the diagnosis and treatment of cancer. Additionally, the use of exosomes in personalized therapy for cancer patients will be discussed. Citation Format: Raghu Kalluri. Exploiting the biology of exosomes for diagnosis and treatment of cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr IA21.
Systematic video analysis of ACL injuries in professional male football (soccer): injury mechanisms, situational patterns and biomechanics study on 134 consecutive cases
Authors: Francesco Della Villa, Matthew Buckthorpe, Alberto Grassi, Alberto Nabiuzzi, Filippo Tosarelli, Stefano Zaffagnini, Stefano Della Villa
Journal: British Journal of Sports Medicine (2020)

Background A few small studies have reported on the mechanisms of ACL injury in professional male football. Aim To describe the mechanisms, situational patterns and biomechanics (kinematics) of ACL injuries in professional male football matches. Methods We identified 148 consecutive ACL injuries across 10 seasons of professional Italian football. 134 (90%) injury videos were analysed for mechanism and situational pattern, while biomechanical analysis was possible in 107 cases. Three independent reviewers evaluated each video. ACL injury epidemiology (month), timing within the match and pitch location at the time of injury were also reported. Results 59 (44%) injuries were non-contact, 59 (44%) were indirect contact and 16 (12%) were direct contact. Players were frequently perturbed immediately prior to injury. We identified four main situational patterns for players who suffered a non-contact or an indirect contact injury: (1) pressing and tackling (n=55); (2) tackled (n=24); (3) regaining balance after kicking (n=19); and (4) landing from a jump (n=8). Knee valgus loading (n=83, 81%) was the dominant injury pattern across all four of these situational patterns (86%, 86%, 67% and 50%, respectively). 62% of the injuries occurred in the first half of the matches (p&lt;0.01). Injuries peaked at the beginning of the season (September–October) and were also higher at the end of the season (March–May). Conclusions 88% of ACL injuries occurred without direct knee contact, but indirect contact injuries were as frequent as non-contact injuries, underlying the importance of mechanical perturbation. The most common situational patterns were pressing, being tackled and kicking.
Changes in respiratory symptoms during 48-week treatment with ARD-3150 (inhaled liposomal ciprofloxacin) in bronchiectasis: results from the ORBIT-3 and -4 studies
Authors: James D. Chalmers, David Cipolla, Bruce Thompson, Angela M. Davis, Anne O'Donnell, Gregory Tino, Igor Gonda, Charles Haworth, Juergen Froehlich
Journal: European Respiratory Journal (2020)

It is not known if inhaled antibiotics improve respiratory symptoms in patients with bronchiectasis. In the recent phase-3 ORBIT trials, 48 weeks' treatment with ARD-3150 (inhaled liposomal ciprofloxacin) did not significantly improve symptoms using the prespecified method of analysis comparing baseline symptoms to those after 48 weeks, when patients had been off treatment for 28 days. This method of analysis does not take account of possible improvements in symptoms while on active treatment. A post hoc analysis of two identical randomised trials of ARD-3150 (ORBIT-3 and -4) administered 28 days on and 28 days off in patients with bronchiectasis and chronic Pseudomonas aeruginosa infection. The quality-of-life bronchiectasis respiratory symptom scale (QOL-B-RSS), which has a one-week recall period, was administered every 28 days. We examined whether respiratory symptoms improved during on-treatment periods and the relationship of changes in QOL-B-RSS to changes in bacterial load using a mixed-model repeated measures approach. ARD-3150 treatment resulted in a significant improvement in respiratory symptoms during the on-treatment periods with concordant results between ORBIT-3 (estimate 1.4 points, se 0.49; p=0.004) and ORBIT-4 (estimate 1.1 point, se 0.41; p=0.006). The proportion of patients achieving a symptom improvement above the minimum clinically important difference was higher with ARD-3150 compared with placebo during on-treatment cycles (p=0.024). Changes in respiratory symptoms were correlated with changes in bacterial load in the treatment group (r=−0.89, p&lt;0.0001). Individual estimates for decrements in the QOL-B RSS during exacerbation were −9.4 points ( se 0.91) in ORBIT-3 and −10.8 points (0.74) in ORBIT-4 (both p&lt;0.0001). Inhaled ARD-3150 resulted in significant improvements in respiratory symptoms during the on-treatment periods which were lost during off-treatment periods. These results supports the concept that reducing bacterial load can improve respiratory symptoms in patients with bronchiectasis.
DEF6 deficiency, a mendelian susceptibility to EBV infection, lymphoma, and autoimmunity
Authors: Benjamin Fournier, Maud Tusseau, Marine Villard, Christophe Malcus, Emilie Chopin, Emmanuel Martin, Debora Jorge Cordeiro, Nicole Fabien, Mathieu Fusaro, Alexandra Gauthier, Nathalie Garnier, David Goncalves, Sonia Lounis, Christelle Lenoir, Anne-Laure Mathieu, Marion Moreews, Magali Perret, Capucine Picard, Cécile Picard, Françoise Poitevin, Sébastien Viel, Yves Bertrand, Thierry Walzer, Alexandre Belot, Sylvain Latour
Journal: Journal of Allergy and Clinical Immunology (2020)
Publisher Correction: Single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis
Authors: Priscilla K. Brastianos, Eudocia Quant Lee, Justine V. Cohen, Sara M. Tolaney, Nancy U. Lin, Nancy Wang, Ugonma Chukwueke, Michael D. White, Naema Nayyar, Albert Kim, Christopher Alvarez-Breckenridge, Ian Krop, Maura Keeley Mahar, Mia S. Bertalan, Brian Shaw, Joana L. Mora, Nathaniel Goss, Megha Subramanian, Lakshmi Nayak, Jorg Dietrich, Deborah A. Forst, Brian V. Nahed, Tracy T. Batchelor, Helen A. Shih, Elizabeth R. Gerstner, Beverly Moy, Donald Lawrence, Anita Giobbie-Hurder, Scott L. Carter, Kevin Oh, Daniel P. Cahill, Ryan J. Sullivan
Journal: Nature Medicine (2020)
Macrophage hypophagia as a mechanism of innate immune exhaustion in mAb-induced cell clearance
Authors: Jonathan J. Pinney, Fátima Rivera-Escalera, Charles C. Chu, Hannah E. Whitehead, Karl R. VanDerMeid, Ashley M. Nelson, Michelle C. Barbeau, Clive S. Zent, Michael R. Elliott
Journal: Blood (2020)
Abstract NT-104: SYNERGISTIC COMBINATION OF MORTALIN-TARGETING AND P53 REACTIVATOR DRUGS FOR OVARIAN CANCER
Authors: Satish Kumar Ramraj, Doris M. Benbrook
Journal: Clinical Cancer Research (2019)

Abstract PURPOSE: TP53 gene missense mutations represent the most common genetic defect in fallopian tube (FT) lesions and high grade serous ovarian cancer (HGSOC) and cause of drug resistance. We hypothesized that drugs with complementary p53 protein-targeted mechanisms (SHetA2 drug release of p53 from mortalin binding, PRIMA-1MET drug reactivation of p53 transcription activity) synergistically kill ovarian cancer cells without harming normal cells. EXPERIMENTAL DESIGN: SHetA2-mediated cytoplasmic to nuclear/mitochondrial p53 translocation was studied in wildtype and mutant p53 ovarian cancer cell lines using Western blot analysis of subcellular-enriched fractions and fluorescent microscopic imaging of immunocytochemistry. Human FT epithelial cells (hFTSECs) were used as healthy controls. The p53 reactivator drugs PRIMA-1 and PRIMA-1MET were combined with SHetA2 to study drug interactions and mechanisms using Western blot, rtPCR, cytotoxicity, reactive oxygen species (ROS) and ATP assays. RESULTS: SHetA2 induced p53 nuclear and mitochondrial accumulation in ovarian cancer cell lines, but not in hFTSECs. Both mortalin and p53 expression altered SHetA2 cytotoxicity in ovarian cancer cells. Modest effects of PRIMA-1MET on cell lines inversely correlated with SLC7A11 expression, a known biomarker of PRIMA-1MET sensitivity. SHetA2 induced SLC7A11 in the presence of wildtype or missense mutant p53, but inhibited SLC7A11 in the absence of p53. SHetA2 and PRIMA-1MET were synergistic-to-strongly synergistic in ovarian cancer cells with mutant p53, synergistic with wildtype p53, additive with null p53 and antagonistic in hFTSECs. Elevated apoptosis, p53 transcription activity and ROS in combination with reduced ATP were associated with this mutant p53-dependent synergy. CONCLUSION: Altogether, our findings identified the SHetA2 and PRIMA-1MET combination as a promising new therapeutic strategy for the treatment of HGSOCs with missense mutant p53. GRANT SUPPORT: Supported by the US National Cancer Institute grant R01 CA196200 and Foundation for Women's Cancer- Ovarinnovate: Ovarcome Research Excellence Award. Citation Format: Satish Kumar Ramraj, Doris M. Benbrook. SYNERGISTIC COMBINATION OF MORTALIN-TARGETING AND P53 REACTIVATOR DRUGS FOR OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-104.
UK’s response to covid-19: crude, unadjusted mortality figures are not the whole story
Authors: Aryeh L Greenberg, Harry Greenberg
Journal: BMJ (2020)

We were surprised to read the editorial by Scally and colleagues, which criticises the UK government’s handling of the covid-19 pandemic.1 We agree that the UK response has been comparatively slow on testing, community contact tracing, and the eventual move to lockdown. But the authors play a simple game of mortal calculus, using the total …
Targeted nanoparticles towards increased L cell stimulation as a strategy to improve oral peptide delivery in incretin-based diabetes treatment
Authors: Yining Xu, Herlinde De Keersmaecker, Kevin Braeckmans, Stefaan De Smedt, Patrice D. Cani, Véronique Préat, Ana Beloqui
Journal: Biomaterials (2020)

The delivery of therapeutic peptides via the oral route remains one of biggest challenges in the pharmaceutical industry. Recently, we have described an alternative improved drug delivery system for peptide delivery via the oral route, consisting of a lipidic nanocapsule. Despite the striking effects observed, it is still essential to develop strategies to strengthen the nanocarriers' glucagon-like peptide-1 (GLP-1) secretory effect of the nanocarrier and/or prolong its antidiabetic effect in vivo to facilitate its translation into the clinic. For this purpose, we developed and compared different fatty acid-targeted lipid and polymeric nanoparticles and evaluated the L cell stimulation induced by the nanocarriers in murine L cells in vitro and in normal healthy mice in vivo. We further examined the antidiabetic effect in vivo in an obese/diabetic mouse model induced by high-fat diet feeding and examined the effect of the oral administration frequency. Among the tested nanocarriers, only lipid-based nanocarriers that were surface-modified with DSPE-PEG