tbuckley/cabot-search huggingface dataset:
The tumor targeting performance of anti-CD166 Probody drug conjugate CX-2009 and its parental derivatives as monitored by <sup>89</sup>Zr-immuno-PET in xenograft bearing mice
Authors: Marion Chomet, Maxime Schreurs, Margaret Nguyen, Bruce Howng, Ruth Villanueva, Michael Krimm, Olga Vasiljeva, Guus A.M.S van Dongen, Danielle J. Vugts
Journal: Theranostics (2020)

Probody ® therapeutics are recombinant masked monoclonal antibody (mAb) prodrugs that become activated by proteases present in the tumor microenvironment.This makes them attractive for use as Probody drug conjugates (PDCs).CX-2009 is a novel PDC with the toxic drug DM4 coupled to an anti-CD166 Probody therapeutic.CD166 is overexpressed in multiple tumor types and to a lesser extent by healthy tissue.Methods: The tumor targeting potential of CX-2009 was assessed by performing 89 Zr-immuno-PET/biodistribution/therapy studies in a CD166-positive H292 lung cancer mouse model.Head-to-head comparisons of CX-2009 with the Probody therapeutic without DM4 (CX-191), the unmasked antibody drug conjugate (ADC) CX-1031, and the parental mAb CX-090 were performed.All constructs were 89 Zr labeled in a GMP compliant way, administered at 10, 110, or 510 µg, and ex vivo biodistribution was assessed at 24, 72, and 168 hours post-injection.Results: Comparable biodistribution was observed for all constructs, confirmed with PET/CT.Tumors showed the highest uptake: 21.8 ± 2.3 ([ 89 Zr]Zr-CX-2009), 21.8 ± 5.0 ([ 89 Zr]Zr-CX-191), 18.7 ± 2.5 ([ 89 Zr]Zr-CX-1031) and 20.8 ± 0.9 %ID/g ([ 89 Zr]Zr-CX-090) at 110 µg injected.Increasing the dose to 510 µg resulted in lower tumor uptake and higher blood levels for all constructs, suggesting receptor saturation.In addition, CX-2009 and CX-1031 showed similar therapeutic potential.Conclusions: CX-2009 is optimally capable of targeting CD166-expressing tumors when compared with its derivatives, implying that enzymatic activation inside the tumor, required to allow CD166 binding, does not limit tumor targeting.Because CX-2009 does not bind to mouse CD166, however, reduced targeting of healthy organs should be confirmed in ongoing clinical 89 Zr-immuno-PET studies.
The liver in adolescents with ?1-antitrypsin deficiency*1
Authors: T SVEGER
Journal: Hepatology (1995)

Of 200,000 Swedish infants screened for α1-antitrypsin deficiency (α1-ATD), 184 (127 PiZ, 2 PiZ-, 54 PiSZ, and 1 PiS-) children have been followed prospectively, of whom 1 PiSZ and 5 PiZ children died in early childhood. We now report clinical and biochemical signs of liver disease in adolescence and the prognosis of neonatal liver disease up to the age of 18 years. The α1ATD subjects were offered a clinical checkup and liver tests at 16 and 18 years of age, 150 of 178 α1ATD subjects undergoing checkups at age 16 and 166 at age 18. Liver tests were performed in 121 adolescents at both the 16-and 18-year checkups. None of the PiZ and PiSZ subjects checked at the age of 16 and 18 years had any clinical signs of liver disease. Abnormalities of serum alanine aminotransferase (S-ALAT) or γ-glutamyl transferase (SGT) were found at the 16-year checkup (all PiZ and PiSZ subjects tested included) in 17% of PiZ and 8% of PiSZ adolescents, and at the age of 18 years in 12% of PiZ and 15% of PiSZ subjects. In only two cases were both SALAT and S-GT concentrations abnormal at both the 16-year and 18-year follow-ups. Serum procollagen III peptide concentrations were normal in all those with abnormal liver test results. Of 127 PiZ subjects, 22 had manifested clinical signs of liver disease in infancy. Of these 22, two died early in life of cirrhosis. Another two children died of other causes; however, autopsy showed histological signs of cirrhosis in one of them, fibrosis in the other. All of the remaining 18 subjects were clinically healthy at the 16- and 18-year checkups. Marginal liver test abnormalities were found in two of them. To sum up, α1ATD children followed prospectively up to 18 years of age continue to have favorable prognosis.
Autosomal Dominant Polycystic Kidney Disease
Authors: Patricia A. Gabow
Journal: New England Journal of Medicine (1993)

Autosomal dominant polycystic kidney disease is one of the most common hereditary disorders, being 10 times more common than sickle cell disease, 15 times more common than cystic fibrosis, and 20 times more common than Huntington's disease. In addition, the disease accounts for 8 to 10 percent of the cases of end-stage renal disease, for which medical care costs exceed $200 million a year. The name previously given to the disorder, “adult polycystic kidney disease,” belies its true scope by focusing on the kidney and by confining the disorder to adults. In fact, autosomal dominant polycystic kidney disease is a . . .
Abstract 9386: Non-invasive Assessment Of Atherosclerotic Coronary Lesion Length Using Multidetector Computed Tomography Angiography: Comparison To Quantitative Coronary Angiography
Authors: Joella E van Velzen, Michiel A de Graaf, Agnieska Ciarka, Fleur R de Graaf, Martin J Schalij, Lucia J Kroft, Albert de Roos, J. Wouter Jukema, Ernst E van der Wall, Joanne D Schuijf, Jeroen J Bax
Journal: Circulation (2010)

Background: Coronary multidetector computed tomography angiography (CTA) is able to provide valuable information on atherosclerotic plaque extent in the coronary arterial wall, in addition to asses...
Implication of IL-18 in the chronic inflammation of severe refractory asthma
Authors: Nikoletta Rovina, Efrosini Dima, Petros Bakakos, Eleni Tseliou, Konstantina Kontogianni, Spiridon Papiris, Nikolaos Koulouris, Stylianos Loukides
Journal: European Respiratory Journal (2014)

In refractory asthma, where chronic inflammation and airway remodeling are key pathological features, it is suggested that the dysregulation of the Th1/Th2 cytokines production modifies airway inflammation and airway hyperrespnsiveness (AHR).

Interleukin (IL)-18, a pleiotropic proinflammatory cytokine, contributes to the pathophysiology of asthma by modulating airway inflammation. Aim of this study was to investigate IL-18 levels in refractory asthma and its relation to eosinophilic airway inflammation and airway remodelling.

IL-18 levels were measured in sputum supernatants obtained from patients with mild asthma (21 smokers and 24 non smokers), and patients with refractory asthma (n=18). Eosinophilic airway inflammation was assessed by measuring ECP, eosinophil counts in sputum and AHR to methacholine. Airway remodelling was assessed by measuring IL-13, VEGF and transforming growth factor (TGF)-b1 in induced sputum.

Patients with refractory asthma had significantly lower IL-18 levels in sputum compared to smoking and non smoking asthmatics (p<0.001). IL-18 levels were correlated to the macrophages' percentage (r=0.635, p=0.026) and inversely correlated to neutrophils' percentage in sputum (r=-0.715, p=0.009). Furthermore, IL-18 levels in sputum correlated to FEV1 (% pred) (r=0.760, p=0.004), to FVC (% pred) (r=0.620, p=0.032), and to PD20Mch (r=0.733, p=0.007). No correlations were found between IL-18, ECP, TGF-β1, VEGF levels, and eosinophil counts in the sputum of refractory asthma.

These findings suggest that in refractory asthma IL-18 is possibly involved in chronic airway inflammation and airway remodelling through an eosinophil independent pathway.
Radioiodine Therapy for Benign Thyroid Disease
Authors: Markus Dietlein
Journal: Clinical Nuclear Medicine (2020)

The success rate of radioiodine (I-131) therapy for toxic goiter and solitary hyperfunctioning nodules depends on thyroid volume, compensation of hyperthyroidism, timing of the withdrawal of antithyroid drugs, alimentary iodine intake, and the dose concepts in the different thyroid diseases. The aim of treatment with I-131 is to achieve a non-hyperthyroid status, which can be euthyroid or hypothyroid, recompensated by levothyroxine medication. Studies with an intended dose of about 120 Gy to the toxic multinodular goiter reported a success rate of more than 90%. The successful elimination of hyperfunctioning nodules occurred in 90% of patients receiving 300 Gy to the nodule volume and in 94% of patients receiving 400 Gy to the nodule volume. There is an emerging role for I-131 in the treatment for so-called subclinical hyperthyroidism.The success of I-131 treatment in reducing the size of nontoxic goiters depends on the applied I-131 activities per gram thyroid tissue and the distribution of I-131 within the goiter. Disadvantageous are large cystic and fibrotic areas. Most of the shrinkage occurs within the first year, and goiter volumes are decreasing continuously for several years to about 30% of the initial size. With more effective strategies for goiter shrinkage—including the additive use of modified recombinant human thyrotropin in clinical trials—more patients will require levothyroxine medication. Radioiodine therapy for reducing the goiter size can be recommended especially for elderly people, for those with comorbidity and for patients who want to avoid surgery.Radioiodine therapy due to Graves' disease is recommended for patients with persistence of Graves' thyrotoxicosis after 12–24 months of antithyroid drugs or relapse of thyrotoxicosis. In a subgroup of patients with an initially high risk of recurrent thyrotoxicosis (young patients, thyroid volume of >40 mL, TSH-receptor antibodies >10 IU/L after 6 months of antithyroid drugs), radioiodine therapy should be discussed as first-line treatment. For the elimination of Graves' thyrotoxicosis, an ablative concept is preferred (intended dose of 300 Gy) with the aim of replacing thyroid hormone by levothyroxine medication.
Response to ‘To consider or not antimalarials as a prophylactic intervention in the SARS-CoV-2 (Covid-19) pandemic’ by Parperis
Authors: Francesca Romana Spinelli, Fulvia Ceccarelli, Manuela Di Franco, Fabrizio Conti
Journal: Annals of the Rheumatic Diseases (2020)

We thank Konstantinos Parperis for his correspondence to our letter ‘To consider or not antimalarials as a prophylactic intervention in the SARS-CoV-2 (Covid-19) pandemic’ speculating on prophylactic use of antimalarials for subjects at high risk of getting infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1 2 

As the author highlights, at this time, it is preferable to be cautious when addressing this topic. These days, the scientific information is moving faster than usual, and new data are available every day; however, the scientific evidence collected to …
NON-A, NON-B HEPATITIS AND INTRAVENOUS IMMUNOGLOBULIN
Authors: HansD. Ochs, SusannaH. Fischer, FrankS. Virant, MartinL. Lee, HenryS. Kingdon, RalphJ. Wedgwood, RonaldH. Hein, JohnP. Mccue, John Hink
Journal: The Lancet (1985)
Covid-19: Lack of capacity led to halting of community testing in March, admits deputy chief medical officer
Authors: Gareth Iacobucci
Journal: BMJ (2020)

Total free living energy expenditure was compared in lean and obese women by the new doubly labelled water method and partitioned into basal metabolism and thermogenesis plus activity by whole body calorimetry. Average energy expenditure was significantly higher in the obese group (10.22 versus 7.99 MJ/day (2445 versus 1911 kcal/day); p less than 0.001) resulting from an increase in the energy cost of both basal metabolism and physical activity. Self recorded energy intakes were accurate in the lean subjects but underestimated expenditure by 3.5 MJ/day (837 kcal/day) in the obese group. Basal metabolic rate and energy expenditure on thermogenesis plus activity were identical in the two groups when corrected for differences in fat free mass and total body mass. In the obese women in this series there was no evidence that their obesity was caused by a metabolic or behavioural defect resulting in reduced energy expenditure.
Recommendations on pre-hospital &amp; early hospital management of acute heart failure: a consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergenc
Authors: Alexandre Mebazaa, M. Birhan Yilmaz, Phillip Levy, Piotr Ponikowski, W. Frank Peacock, Said Laribi, Arsen D. Ristic, Ekaterini Lambrinou, Josep Masip, Jillian P. Riley, Theresa McDonagh, Christian Mueller, Christopher deFilippi, Veli‐Pekka Harjola, Holger Thiele, Massimo F. Piepoli, Marco Metra, Aldo Maggioni, John McMurray, Kenneth Dickstein, Kevin Damman, Petar M. Seferovic, Frank Ruschitzka, Adelino F. Leite‐Moreira, Abdelouahab Bellou, Stefan D. Anker, Gerasimos Filippatos
Journal: European Journal of Heart Failure (2015)
Total Parenteral Nutrition in the Cancer Patient
Authors: Murray F. Brennan
Journal: New England Journal of Medicine (1981)

TOTAL parenteral nutrition (TPN) is a life-saving method of nutritional support for patients who are unable to ingest, digest, or absorb sufficient nutrients to prevent death from starvation. The dramatic demonstration by Dudrick et al.1 that intravenous feeding could provide the sole means of nutritional support, promote growth in a child, and restore weight loss in an adult has received appropriate acclaim. Widespread application of their technique of TPN or "hyperalimentation" has occurred. In 1970 there were 114 referenced articles on intravenous hyperalimentation; in 1979, this figure had increased 600 per cent, and over 3700 articles on intravenous hyperalimentation appeared . . .
Plasma cfDNA in Glioblastoma—Letter
Authors: Takeshi Takayasu, Yoshua Esquenazi, Leomar Y. Ballester
Journal: Clinical Cancer Research (2020)

We read enthusiastically the recent article by Bagley and colleagues ([1][1]). The authors prospectively investigated plasma cell-free DNA (cfDNA) concentration and mutations in patients with glioblastoma. This is an interesting topic and we commend the authors for their efforts. However, there are
Rivaroxaban for Thromboprophylaxis in Acutely Ill Medical Patients
Authors: Alexander T Cohen, Theodore E Spiro, Alex C Spyropoulos
Journal: New England Journal of Medicine (2013)

Cohen AT, 2013, NEW ENGL J MED, V368, P513, DOI 10.1056-NEJMoa1111096; Eriksson BI, 2008, NEW ENGL J MED, V358, P2765, DOI 10.1056-NEJMoa0800374; Lassen MR, 2008, NEW ENGL J MED, V358, P2776, DOI 10.1056-NEJMoa076016
Robust production of IL-33 and TSLP by lung endothelial cells in response to low-dose dsRNA stimulation
Authors: Maiko Emi-Sugie, Tetsuo Shoda, Kyoko Futamura, Tomohiro Takeda, Akira Ainai, Hideki Hasegawa, Hirohisa Saito, Kenji Matsumoto, Akio Matsuda
Journal: Journal of Allergy and Clinical Immunology (2020)
Abstract 272: Dose Optimization of Early High-Dose Valproic Acid for Neuroprotection After Cardiac Arrest
Authors: Cindy H Hsu, Mohamad H Tiba, Brendan M McCracken, Carmen I Colmenero, Zachary Pickell, Danielle C Leander, Anne M Weitzel, Tulasi Jinka, Brandon C Cummings, Manjunath P Pai, Kevin R Ward, Robert W Neumar
Journal: Circulation (2019)

Introduction: High-dose valproic acid (VPA) has been shown to improve the survival and neurologic outcomes in preclinical brain injury models including asphyxial cardiac arrest (CA) in rats. However, its pharmacokinetics, pharmacodynamics, and safety profiles in large animal CA models are unknown. Hypothesis: High-dose VPA can be safely administered after return of spontaneous circulation (ROSC) and cross the blood-brain barrier dose-dependently in a swine CA model. Methods: After 8 minutes of untreated ventricular fibrillation CA, male Yorkshire swine [43.3 (3.0) kg] were resuscitated for up to 16 minutes until ROSC. They were randomized to receive placebo, 75 mg/kg, 150 mg/kg, or 300 mg/kg VPA as 90-minute intravenous infusion (n=5 per group) beginning 20 minutes after sustained ROSC. Animals were monitored for 2 additional hours after infusion ended and then euthanized. Experimental operators were blinded to the treatments. Results: The mean total cardiac arrest duration was 15.0 (1.6) minutes, with no significant differences between groups. At end of infusion, the serum free VPA concentration increased dose dependently, from 139.2 (10.1) mcg/mL [75 mg/kg VPA] to 287.2 (24.6) mcg/mL [150 mg/kg VPA] to 565.6 (36.5) mcg/mL [300 mg/kg VPA] (p&lt;0.05). This corresponded to a dose-dependent decrease in the fraction of serum protein-bound VPA, from 41.8% (1.8) [75 mg/kg VPA] to 23.4% (3.8) [150 mg/kg VPA] to 14.4% (3.8) [300 mg/kg VPA] (p&lt;0.05). Brain total VPA concentrations at end of experiment were 26.1 (3.1) mcg/g [75 mg/kg VPA], 72.5 (18.9) mcg/g [150 mg/kg VPA], and 212.3 (33.4) mcg/g [300 mg/kg VPA] (p&lt;0.05). There was a strong linear correlation between serum free VPA and brain total VPA concentrations (R 2 =0.98). All animals survived until euthanasia, although the 300 mg/kg group required more epinephrine to maintain mean arterial pressure greater than or equal to 80 mmHg and had higher lactic acidosis. Conclusion: Brain VPA concentrations correlate strongly with serum free VPA when high-dose intravenous VPA is given after ROSC in a swine CA model. These results provide the foundation for dose-optimization studies of high-dose VPA as a neuroprotective therapy following resuscitation from CA.
High‐Throughput Screening and Hierarchical Topography‐Mediated Neural Differentiation of Mesenchymal Stem Cells
Authors: Liangliang Yang, Klaudia Malgorzata Jurczak, Lu Ge, Patrick van Rijn
Journal: Advanced Healthcare Materials (2020)

Abstract Biophysical factors such as anisotropic topography composed of micro/nanosized structures are important for directing the fate of human bone marrow‐derived mesenchymal stem cells (hBM‐MSCs) and have been applied to neuronal differentiation. Via high‐throughput screening (HTS) methods based on topography gradients, the optimum topography is determined and translated toward a hierarchical architecture designed to mimic the nerve nano/microstructure. The polydimethylsiloxane (PDMS)‐based topography gradient with amplitudes ( A ) from 541 to 3073 nm and wavelengths ( W ) between 4 and 30 µm is developed and the fate commitment of MSC toward neuron lineage is investigated. The hierarchical structures, combining nano‐ and microtopography (W0.3/W26 parallel/perpendicular) are fabricated to explore the combined topography effects on neuron differentiation. From the immunofluorescent staining results (Tuj1 and MAP2), the substrate characterized by W : 26 µm; A : 2.9 µm shows highest potential for promoting neurogenesis. Furthermore, the hierarchical features (W0.3/W26 parallel) significantly enhance neural differentiation. The hBM‐MSCs on the hierarchical substrates exhibit a significantly lower percentage of nuclear Yes‐associated protein (YAP)/TAZ and weaker cell contractility indicating that the promoted neurogenesis is mediated by the cell tension and YAP/TAZ pathway. This research provides new insight into designing biomaterials for applications in neural tissue engineering and contributes to the understanding of topography‐mediated neuronal differentiation.
Targeting Hippo-Dependent and Hippo-Independent YAP1 Signaling for the Treatment of Childhood Rhabdomyosarcoma
Authors: Katherine K. Slemmons, Choh Yeung, Joshua T. Baumgart, Jhazeel O. Martinez Juarez, Amy McCalla, Lee J. Helman
Journal: Cancer Research (2020)

Rhabdomyosarcoma is the most common childhood soft-tissue sarcoma, yet patients with metastatic or recurrent disease continue to do poorly, indicating a need for new treatments. The SRC family tyrosine kinase YES1 is upregulated in rhabdomyosarcoma and is necessary for growth, but clinical trials using single agent dasatinib, a SRC family kinase inhibitor, have failed in sarcomas. YAP1 (YES-associated protein) is highly expressed in rhabdomyosarcoma, driving growth and survival when the upstream Hippo tumor suppressor pathway is silenced, but efforts to pharmacologically inhibit YAP1 have been unsuccessful. Here we demonstrate that treatment of rhabdomyosarcoma with DNA methyltransferase inhibitor (DNMTi) upregulates Hippo activators RASSF1 and RASSF5 by promoter demethylation, activating canonical Hippo signaling and increasing inactivation of YAP1 by phosphorylation. Treatment with DNMTi decreased rhabdomyosarcoma cell growth and increased apoptosis and differentiation, an effect partially rescued by expression of constitutively active YAP (S127A), suggesting the effects of DNMTi treatment are, in part, due to Hippo-dependent inhibition of YAP1. In addition, YES1 and YAP1 interacted in the nucleus of rhabdomyosarcoma cells, and genetic or pharmacologic suppression of YES1 resulted in cytoplasmic retention of YAP1 and decreased YAP1 target gene expression, suggesting YES1 regulates YAP1 in a Hippo-independent manner. Combined treatment with DNMTi and dasatinib targeted both Hippo-dependent and Hippo-independent regulation of YAP1, ablating rhabdomyosarcoma cell growth in vitro and trending toward decreased tumor growth in vivo. These results show that the mechanisms regulating YAP1 in rhabdomyosarcoma can be inhibited by combinatorial therapy of DNMTi and dasatinib, laying the groundwork for future clinical investigations. SIGNIFICANCE: This study elucidates the signaling pathways that regulate the oncogenic protein YAP1 and identifies a combination therapy to target these pathways in the childhood tumor rhabdomyosarcoma.
Efficacy and Safety of Ramucirumab in Asian and Non-Asian Patients with Advanced Hepatocellular Carcinoma and Elevated Alpha-Fetoprotein: Pooled Individual Data Analysis of Two Randomized Studies
Authors: Chia-Jui Yen, Masatoshi Kudo, Ho-Yeong Lim, Chih-Hung Hsu, Arndt Vogel, Giovanni Brandi, Rebecca Cheng, Ioana Simona Nitu, Paolo Abada, Yanzhi Hsu, Andrew X. Zhu, Yoon-Koo Kang
Journal: Liver Cancer (2020)

REACH-2 and REACH were randomized, placebo-controlled, double-blind, multicenter phase 3 trials which showed survival benefits of ramucirumab treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP). We evaluated the efficacy and safety of ramucirumab in Asian and non-Asian patients with AFP ≥400 ng/mL from REACH-2 and REACH.We pooled Asian and non-Asian patients from the REACH-2 and REACH trials and performed an individual patient data meta-analysis. Overall survival (OS) and progression-free survival were evaluated using the Kaplan-Meier method. Hazard ratios (HRs) were estimated with a stratified Cox regression model.In the pooled REACH-2 and REACH patient population, 291 Asian patients were randomly assigned to receive ramucirumab (n = 168) or placebo (n = 123), and 251 non-Asian patients received ramucirumab (n = 148) or placebo (n = 103). The median OS was significantly longer in the ramucirumab arm in comparison to the placebo arm for Asian patients (8.08 vs. 4.76 months, stratified HR 0.73 [95% CI 0.56-0.95], p = 0.0189) and non-Asian patients (7.98 vs. 5.22 months, stratified HR 0.65 [95% CI 0.49-0.86], p = 0.0028). The overall response rate (ORR) and disease control rate (DCR) were significantly higher in the ramucirumab arm compared to the placebo arm for Asian patients (ORR: 4.2 vs. 0.8%; DCR: 53.6 vs. 33.3%) and non-Asian patients (ORR: 6.8 vs. 1.0%; DCR: 59.5 vs. 41.7%). The most common grade ≥3 treatment-emergent adverse events reported in the ramucirumab arm were hypertension (7.7%), decreased appetite (1.2%), and ascites (1.2%) for Asian patients and hypertension (16.9%), ascites (8.8%), asthenia (4.7%), and fatigue (5.4%) for non-Asian patients.This pooled analysis of the REACH-2/REACH trials demonstrates significant benefits, with a manageable safety profile, of ramucirumab treatment in Asian and non-Asian patients with advanced HCC and baseline AFP ≥400 ng/mL.