tbuckley/cabot-search huggingface dataset:
<i>Plasmodium falciparum</i> erythrocyte membrane protein 1 variants induce cell swelling and disrupt the blood–brain barrier in cerebral malaria
Authors: Yvonne Adams, Rebecca W. Olsen, Anja Bengtsson, Nanna Dalgaard, Mykola Zdioruk, Sanghamitra Satpathi, Prativa K. Behera, Praveen K. Sahu, Sean E. Lawler, Klaus Qvortrup, Samuel C. Wassmer, Anja T.R. Jensen
Journal: The Journal of Experimental Medicine (2021)

Cerebral malaria (CM) is caused by the binding of Plasmodium falciparum–infected erythrocytes (IEs) to the brain microvasculature, leading to inflammation, vessel occlusion, and cerebral swelling. We have previously linked dual intercellular adhesion molecule-1 (ICAM-1)– and endothelial protein C receptor (EPCR)–binding P. falciparum parasites to these symptoms, but the mechanism driving the pathogenesis has not been identified. Here, we used a 3D spheroid model of the blood–brain barrier (BBB) to determine unexpected new features of IEs expressing the dual-receptor binding PfEMP1 parasite proteins. Analysis of multiple parasite lines shows that IEs are taken up by brain endothelial cells in an ICAM-1–dependent manner, resulting in breakdown of the BBB and swelling of the endothelial cells. Via ex vivo analysis of postmortem tissue samples from CM patients, we confirmed the presence of parasites within brain endothelial cells. Importantly, this discovery points to parasite ingress into the brain endothelium as a contributing factor to the pathology of human CM.
The incidence of Epstein-Barr Virus-associated gastric cancer in an Irish population.
Authors: Catherine Weadick, Ronan Andrew McLaughlin, Megan Ramsey, Nabila Al-Julandani, Derek Gerard Power, Michael William Bennett, John Aird, Austin G. Duffy
Journal: Journal of Clinical Oncology (2021)

236 Background: Gastric adenocarcinoma is the fourth most frequent cancer worldwide and the second leading cause of cancer deaths. According to The Cancer Genome Atlas (TCGA) 9% of gastric carcinomas are associated with Epstein-Barr Virus (EBV). EBV- associated gastric carcinoma (EBV-GC) has distinct clinicopathological features, with a marked lymphocytic infiltrate, a generally diffuse histological type and a better prognosis. The immune cell infiltration in EBV-GC suggests a role for immune checkpoint inhibition, which currently has modest activity in unselected gastric cancer. Methods: All cases of gastric or junctional adenocarcinoma diagnosed between Jan 2019 and March 2020 in Mater Misericordiae University Hospital (MMUH) and Jan 2017 and Jan 2019 in Cork University Hospital (CUH) were identified. Electronic medical records were retrospectively reviewed to collect demographic and clinicopathological data such as AJCC TNM stage, tumour subtype and grade, HER-2 status, MMR proficiency and EBV status as determined by EBV-encoded RNA in situ hybridization. Results: N = 103 cases of gastric or junctional adenocarcinoma were identified. 67 male, 36 female, median age 64.5 (range 34 – 95). 40/103 had undergone surgical resection. EBER-ISH was assessed in all patients. 8 of 103 (7.8%) patients showed EBV positivity. These cases were all male patients, median age 62 (range 51-73). The tumours were located as follows; 2 in the cardia, 5 in the body and 1 not documented. The specimens were graded as; 87.5% (7/8) tumours being poorly differentiated and 1/8 moderate to poorly differentiated. The tumour subtypes were specified as; 62.5% (5/8) diffuse, 12.5% (1/8) intestinal and 25% (2/8) mixed intestinal and diffuse. 5/8 patients were locally confined and underwent resection for N0 disease. 3/8 (37.5%) patients had metastatic disease. None of the 8 EBV-GC cases were identified as being HER-2 positive or MMR-deficient. Conclusions: EBV-GC accounted for 7.8% of all gastric cancers in two large tertiary referral centres in Ireland. 37.5% of these patients had metastatic disease. Given this frequency and a possible predictive role in selecting for immunotherapy we conclude that routine assessment of EBV status is feasible in advanced gastric cancer.
Response to: ‘Correspondence on “Glucosamine and O-GlcNAcylation: a novel immunometabolic therapeutic target for OA and chronic, low-grade systemic inflammation?’ by Angelides and Manolios
Authors: Gabriel Herrero-Beaumont, Raquel Largo
Journal: Annals of the Rheumatic Diseases (2021)

We have read with interest the comment from Angelides and Manolios in which they propose an alternative way to account for the potential mechanism of action of glucosamine in osteoarthritis (OA) and other chronic inflammatory diseases.1 Recent and robust epidemiological data suggest that sustained glucosamine intake could partially prevent cardiovascular disease and cancer.2 Our editorial made some hypothetical considerations about the mechanism of action of this compound.3 The editorial also commented on the difficulty of detecting a beneficial effect of glucosamine in OA, due to the modesty of the therapeutic effect, as well as the weakness of the methodological tools employed in OA clinical trials.3

In some way, the relationship between glucosamine and OA takes us fully into the pathophysiology that revolves around immunometabolic regulation, a driver that can account for tissue deterioration in various chronic diseases and still with many aspects to …
Etiology-Dependent Impairment of Diastolic Cardiomyocyte Calcium Homeostasis in Heart Failure With Preserved Ejection Fraction
Authors: Michael Frisk, Christopher Le, Xin Shen, Åsmund T. Røe, Yufeng Hou, Ornella Manfra, Gustavo J.J. Silva, Isabelle van Hout, Einar S. Norden, J. Magnus Aronsen, Martin Laasmaa, Emil K.S. Espe, Fouad A. Zouein, Regis R. Lambert, Christen P. Dahl, Ivar Sjaastad, Ida G. Lunde, Sean Coffey, Alessandro Cataliotti, Lars Gullestad, Theis Tønnessen, Peter P. Jones, Raffaele Altara, William E. Louch
Journal: Journal of the American College of Cardiology (2021)

Whereas heart failure with reduced ejection fraction (HFrEF) is associated with ventricular dilation and markedly reduced systolic function, heart failure with preserved ejection fraction (HFpEF) patients exhibit concentric hypertrophy and diastolic dysfunction. Impaired cardiomyocyte Ca2+ homeostasis in HFrEF has been linked to disruption of membrane invaginations called t-tubules, but it is unknown if such changes occur in HFpEF. This study examined whether distinct cardiomyocyte phenotypes underlie the heart failure entities of HFrEF and HFpEF. T-tubule structure was investigated in left ventricular biopsies obtained from HFrEF and HFpEF patients, whereas cardiomyocyte Ca2+ homeostasis was studied in rat models of these conditions. HFpEF patients exhibited increased t-tubule density in comparison with control subjects. Super-resolution imaging revealed that higher t-tubule density resulted from both tubule dilation and proliferation. In contrast, t-tubule density was reduced in patients with HFrEF. Augmented collagen deposition within t-tubules was observed in HFrEF but not HFpEF hearts. A causative link between mechanical stress and t-tubule disruption was supported by markedly elevated ventricular wall stress in HFrEF patients. In HFrEF rats, t-tubule loss was linked to impaired systolic Ca2+ homeostasis, although diastolic Ca2+ removal was also reduced. In contrast, Ca2+ transient magnitude and release kinetics were largely maintained in HFpEF rats. However, diastolic Ca2+ impairments, including reduced sarco/endoplasmic reticulum Ca2+-ATPase activity, were specifically observed in diabetic HFpEF but not in ischemic or hypertensive models. Although t-tubule disruption and impaired cardiomyocyte Ca2+ release are hallmarks of HFrEF, such changes are not prominent in HFpEF. Impaired diastolic Ca2+ homeostasis occurs in both conditions, but in HFpEF, this mechanism for diastolic dysfunction is etiology-dependent.
Early liver transplantation for corticosteroid non-responders with acute severe autoimmune hepatitis: The SURFASA score
Authors: Eleonora De Martin, Audrey Coilly, Olivier Chazouillères, Olivier Roux, Jean-Marie Peron, Pauline Houssel-Debry, Florent Artru, Christine Silvain, Isabelle Ollivier-Hourmand, Christophe Duvoux, Alexandra Heurgue, Sandrine Barge, Nathalie Ganne-Carrié, Georges-Philippe Pageaux, Camille Besch, Marc Bourlière, Hélène Fontaine, Victor de Ledinghen, Jérôme Dumortier, Filomena Conti, Sylvie Radenne, Marilyne Debette-Gratien, Odile Goria, François Durand, Pascal Potier, Vincent Di Martino, Noemi Reboux, Philippe Ichai, Mylène Sebagh, Philippe Mathurin, Hélène Agostini, Didier Samuel, Jean-Charles Duclos-Vallée
Journal: Journal of Hepatology (2021)
NF106: A Neurofibromatosis Clinical Trials Consortium Phase II Trial of the MEK Inhibitor Mirdametinib (PD-0325901) in Adolescents and Adults With NF1-Related Plexiform Neurofibromas
Authors: Brian D. Weiss, Pamela L. Wolters, Scott R. Plotkin, Brigitte C. Widemann, James H. Tonsgard, Jaishri Blakeley, Jeffrey C. Allen, Elizabeth Schorry, Bruce Korf, Nathan J. Robison, Stewart Goldman, Alexander A. Vinks, Chie Emoto, Tsuyoshi Fukuda, Coretta T. Robinson, Gary Cutter, Lloyd Edwards, Eva Dombi, Nancy Ratner, Roger Packer, Michael J. Fisher
Journal: Journal of Clinical Oncology (2021)

PURPOSE Patients with neurofibromatosis type 1 (NF1) frequently develop plexiform neurofibromas (PNs), which can cause significant morbidity. We performed a phase II trial of the MAPK/ERK kinase inhibitor, mirdametinib (PD-0325901), in patients with NF1 and inoperable PNs. The primary objective was response rate based on volumetric magnetic resonance imaging analysis. METHODS Inclusion criteria included age ≥ 16 years and a PN that was either progressive or causing significant morbidity. First-dose pharmacokinetics were performed. Patients completed patient-reported outcome measures. Patients received mirdametinib by mouth twice a day at 2 mg/m 2 /dose (maximum dose = 4 mg twice a day) in a 3-week on/1-week off sequence. Each course was 4 weeks in duration. Evaluations were performed after four courses for the first year and then after every six courses. Patients could receive a maximum of 24 total courses. RESULTS Nineteen patients were enrolled, and all 19 received mirdametinib. The median age was 24 years (range, 16-39 years); the median baseline tumor volume was 363.8 mL (range, 3.9-5,161 mL). Eight of the 19 patients (42%) achieved a partial response of the target PN by course 12, and 10 (53%) had stable disease. One patient (5%) developed progressive disease at course 8. Significant and durable decreases were observed in pain ratings. CONCLUSION To our knowledge, this analysis represents the first characterization of the activity and pharmacokinetics of mirdametinib in patients with NF1 and PNs and is the first published response study for MAPK/ERK kinase inhibitors in adults with NF1 and PNs. Mirdametinib given at 2 mg/m 2 /dose (maximum dose, 4 mg) twice daily in a 3-week on/1-week off sequence resulted in a 42% partial response rate with preliminary evidence of reduction in pain.
Factors Associated With US Public Motivation to Use and Distribute COVID-19 Self-tests
Authors: Cedric Bien-Gund, Karen Dugosh, Trisha Acri, Kathleen Brady, Harsha Thirumurthy, Jessica Fishman, Robert Gross
Journal: JAMA Network Open (2021)

This survey study examines factors associated with motivation to use and distribute self-tests for COVID-19 infection among US adults.
3D Registration of pre-surgical prostate MRI and histopathology images via super-resolution volume reconstruction
Authors: Rewa R. Sood, Wei Shao, Christian Kunder, Nikola C. Teslovich, Jeffrey B. Wang, Simon J.C. Soerensen, Nikhil Madhuripan, Anugayathri Jawahar, James D. Brooks, Pejman Ghanouni, Richard E. Fan, Geoffrey A. Sonn, Mirabela Rusu
Journal: Medical Image Analysis (2021)

The use of MRI for prostate cancer diagnosis and treatment is increasing rapidly. However, identifying the presence and extent of cancer on MRI remains challenging, leading to high variability in detection even among expert radiologists. Improvement in cancer detection on MRI is essential to reducing this variability and maximizing the clinical utility of MRI. To date, such improvement has been limited by the lack of accurately labeled MRI datasets. Data from patients who underwent radical prostatectomy enables the spatial alignment of digitized histopathology images of the resected prostate with corresponding pre-surgical MRI. This alignment facilitates the delineation of detailed cancer labels on MRI via the projection of cancer from histopathology images onto MRI. We introduce a framework that performs 3D registration of whole-mount histopathology images to pre-surgical MRI in three steps. First, we developed a novel multi-image super-resolution generative adversarial network (miSRGAN), which learns information useful for 3D registration by producing a reconstructed 3D MRI. Second, we trained the network to learn information between histopathology slices to facilitate the application of 3D registration methods. Third, we registered the reconstructed 3D histopathology volumes to the reconstructed 3D MRI, mapping the extent of cancer from histopathology images onto MRI without the need for slice-to-slice correspondence. When compared to interpolation methods, our super-resolution reconstruction resulted in the highest PSNR relative to clinical 3D MRI (32.15 dB vs 30.16 dB for BSpline interpolation). Moreover, the registration of 3D volumes reconstructed via super-resolution for both MRI and histopathology images showed the best alignment of cancer regions when compared to (1) the state-of-the-art RAPSODI approach, (2) volumes that were not reconstructed, or (3) volumes that were reconstructed using nearest neighbor, linear, or BSpline interpolations. The improved 3D alignment of histopathology images and MRI facilitates the projection of accurate cancer labels on MRI, allowing for the development of improved MRI interpretation schemes and machine learning models to automatically detect cancer on MRI.
Ranitidine’s <i>N</i>-nitrosodimethylamine Problem May be Tip of the Iceberg
Authors: C. Michael White
Journal: JAMA Network Open (2021)

Lior Z. Braunstein, MD; Elizabeth D. Kantor, PhD; Kelli O’Connell, MSPHc; Amber Jessop Hudspeth, MSc; Qian Wu, PhD; Nicola Zenzola, MSc; David Y. Light, BSc
Tumor burden in serotonin secreting pancreatic neuroendocrine tumors after initiating telotristat ethyl.
Authors: Susan Giacalone, Valentina Di Gialleonardo, Kris Murali, Vijay N. Joish
Journal: Journal of Clinical Oncology (2021)

367 Background: Pancreatic neuroendocrine tumors (pNETs) characterized by high serotonin levels and carcinoid syndrome (CS) are rare. We evaluated tumor burden in a subgroup of patients with pNETS from the real-world TELEACE study before and after initiating telotristat ethyl (TE) in US clinical practice. Methods: Detailed methods of the TELEACE study have been reported previously. This was a retrospective, single arm, pre-post physician panel-based chart review of patients who received TE for at least 6 months. Descriptive statistics analyzed demographic, clinical, laboratory and radiological data extracted from medical charts of TELEACE patients with pNETS. Results: Fifty-two patients with pNETS initiating TE were eligible for this analysis. The average age at the time of TE initiation was 60+10.4 years; 64% were males. The majority of patients had well-differentiated (60%) tumors and low-grade (54%) tumor status. Patients received TE for an average of 11.5+7.84 months, and 21% were still receiving TE at the time of data extraction. Diarrhea and flushing were the most common CS symptoms recorded at the time of TE initiation. Urinary 5-HIAA levels were reported for 9 patients before and for 2 patients after TE initiation. Mean (median) 5-HIAA levels before and after TE initiation were 693 (211) and 22 (22) µmol/24h, respectively. Significant mean reduction in tumor size of 0.67 cm after TE initiation (P = 0.017) was observed. Conclusions: This subgroup analysis of the TELEACE study population showed that the addition of TE to somatostatin analog treatment may positively impact tumor burden for patients with functional pNETs.
Metabolic profiling of bile acids in urine of patients with acute alcohol associated hepatitis
Authors: L. He, V. Vatsalya, X. Ma, J. Zhang, X. Yin, S. Kim, W. Feng, C. J. McClain, X. Zhang
Journal: Hepatology (2020)

Background: Bile acids (BAs) play an important role in the development of alcohol associated liver disease (ALD) In the current study, the urine BA concentrations in patients with acute alcohol associated hepatitis (AAH) were analyzed by solid-phase extract (SPE) liquid chromatographymass spectrometry (LC-MS), and the urine BA levels were compared between healthy controls and AAH patients with different severity were compared Methods: Baseline urine samples were collected from 28 well-characterized AAH patients (Model for End-Stage Liver Disease [MELD] score: non-severe [MELD20]), 3 alcohol use disorder (AUD) patients, and 9 healthy controls (HC) SPE-LCMS analysis identified a total of 29 BAs from urine samples  Urine was used because it is non-invasive and represents an easily accessible biological fluid in this time of COVID-19 restrictions Results: Seventeen BAs of 29 BAs analyzed had significant changes in their abundance levels within the AAH patient cohort Associations of demographic, drinking, and clinical data were analyzed with candidate BAs MELD scores showed positive correlations with certain conjugated BAs and negative correlations with the few unconjugated BAs;taurineconjugated CDCA and MELD showed highest association 6,7-diketolithocholic acid and apocholic acid had nonsignificant abundance changes in the non-severe AAH patients compared to HC but were significantly increased in severe AAH AUROC analysis showed that the differences of these two compounds was sufficiently large to distinguish severe AAH from non-severe AAH (Fig 1) Notably, the abundance levels of glycine-conjugated DCA and glycohyocholic acid were significantly increased, while those of deoxycholic acid and 23-nordeoxycholic acid were markedly decreased, in AAH patients compared to AUD subjects Importantly, we observed that the abundance levels of most conjugated BAs increased by disease stage in a stepwise manner, and some unconjugated BAs decreased in AAH patients who did not survive Conclusion: The abundance changes of specific BAs are closely correlated with the severity of AAH Urine primary BAs were increased in AAH and secondary BAs were decreased in diseases, demonstrating that BAs (individually or as a group) could be potential laboratory biomarkers for detecting early stage of AAH, and may have prognostic values in AAH morbidity
Using breath analysis as a screening tool to detect gastric cancer: A systematic review.
Authors: Ghazal Haddad, Stef Schouwenburg, Ashraf Altesha, Wei Xu, Geoffrey Liu
Journal: Journal of Clinical Oncology (2021)

175 Background: In its early stages, gastric cancer symptoms are frequently lacking, resulting in an often late and incurable diagnosis. A non-invasive, cheap, and reliable screening method for gastric cancer could improve outcomes and increase the number of surgically resectable gastric cancers. Breath analysis has emerged as an experimental method of non-invasive screening of gastric cancer and identification of individuals suitable for confirmatory, diagnostic upper gastrointestinal endoscopy. We aimed to evaluate the accuracy and applicability of breath analysis for gastric cancer detection in adults. Methods: This systematic review searched MEDLINE, EMBASE, BIOSIS, CENTRAL, and Compendex until 11 July 2019 for original studies analyzing exhaled breath to detect gastric cancer in patients. Two authors then independently screened the abstracts, titles, and full texts. Summary sensitivity and specificity analyses were obtained using a hierarchical bivariate method. Positive predictive value and number needed to screen (NNS) of breath analysis methods for gastric cancer detection were calculated for each country using gastric cancer prevalence by country obtained from the Global Cancer Observatory. Non-quantitative results were descriptively summarized. Risk of bias was assessed using the QUADAS-2 tool. This study protocol was pre-registered in PROSPERO (CRD42020139422). Results: Twenty studies were included. Together, the studies included 2,976 subjects. The pooled mean age of the subjects in the gastric cancer groups was 60.5 ± 11 years while the pooled mean age for control groups was 55.4 ± 12 years. Within these twenty studies, breath analysis technologies most commonly used were mass spectrometry (MS)-based methods; other methods included volatile organic compound sensors, thermal desorption tubes, and silicon nanowire field effect transistors. Across all included studies, we found and summarized the characteristics of 131 chemical compounds found in the exhaled breath of study subjects. Eleven studies (total n = 1905) involving all technologies reported quantitative results, with sensitivities ranging from 67-100% and specificities from 71-98%. The summary sensitivity across six studies utilizing MS-based breath analysis methods was 85.3% (95% CI: 82-96%); summary specificity was 81.7%. (95% CI: 78-85%). Based on the MS-based values, we estimated that screening with MS-based breath tests could lower the NNS by more than four-fold in the 15 countries with the highest prevalence of gastric cancer. Conclusions: Breath analysis is a promising method for gastric cancer detection with good diagnostic performance and potential to decrease the NNS for endoscopy-based gastric cancer detection. However, due to the heterogeneity of breath analysis technologies, rigorous studies with standardized, reproducible methods are needed to evaluate the clinical applicability of these technologies.