tbuckley/cabot-search huggingface dataset:
Reduced sphingolipid hydrolase activities, substrate accumulation and ganglioside decline in Parkinson’s disease
Authors: Mylene Huebecker, Elizabeth B. Moloney, Aarnoud C. van der Spoel, David A. Priestman, Ole Isacson, Penelope J. Hallett, Frances M. Platt
Journal: Molecular Neurodegeneration (2019)

Haploinsufficiency in the Gaucher disease GBA gene, which encodes the lysosomal glucocerebrosidase GBA, and ageing represent major risk factors for developing Parkinson's disease (PD). Recently, more than fifty other lysosomal storage disorder gene variants have been identified in PD, implicating lysosomal dysfunction more broadly as a key risk factor for PD. Despite the evidence of multiple lysosomal genetic risks, it remains unclear how sphingolipid hydrolase activities, other than GBA, are altered with ageing or in PD. Moreover, it is not fully known if levels of glycosphingolipid substrates for these enzymes change in vulnerable brain regions of PD. Finally, little is known about the levels of complex gangliosides in substantia nigra which may play a significant role in ageing and PD.To study sphingolipid hydrolase activities and glycosphingolipid expression in ageing and in PD, two independent cohorts of human substantia nigra tissues were obtained. Fluorescent 4-methylumbelliferone assays were used to determine multiple enzyme activities. The lysosomal GBA and non-lysosomal GBA2 activities were distinguished using the inhibitor NB-DGJ. Sensitive and quantitative normal-phase HPLC was performed to study glycosphingolipid levels. In addition, glycosphingolipid levels in cerebrospinal fluid and serum were analysed as possible biomarkers for PD.The present study demonstrates, in two independent cohorts of human post-mortem substantia nigra, that sporadic PD is associated with deficiencies in multiple lysosomal hydrolases (e.g. α-galactosidase and β-hexosaminidase), in addition to reduced GBA and GBA2 activities and concomitant glycosphingolipid substrate accumulation. Furthermore, the data show significant reductions in levels of complex gangliosides (e.g. GM1a) in substantia nigra, CSF and serum in ageing, PD, and REM sleep behaviour disorder, which is a strong predictor of PD.These findings conclusively demonstrate reductions in GBA activity in the parkinsonian midbrain, and for the first time, reductions in the activity of several other sphingolipid hydrolases. Furthermore, significant reductions were seen in complex gangliosides in PD and ageing. The diminished activities of these lysosomal hydrolases, the glycosphingolipid substrate accumulation, and the reduced levels of complex gangliosides are likely major contributors to the primary development of the pathology seen in PD and related disorders with age.
Immunosuppression by monocytic myeloid-derived suppressor cells in patients with pancreatic ductal carcinoma is orchestrated by STAT3
Authors: Rosalinda Trovato, Alessandra Fiore, Sara Sartori, Stefania Canè, Rosalba Giugno, Luciano Cascione, Salvatore Paiella, Roberto Salvia, Francesco De Sanctis, Ornella Poffe, Cristina Anselmi, Francesca Hofer, Silvia Sartoris, Geny Piro, Carmine Carbone, Vincenzo Corbo, Rita Lawlor, Samantha Solito, Laura Pinton, Susanna Mandruzzato, Claudio Bassi, Aldo Scarpa, Vincenzo Bronte, Stefano Ugel
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with an overall 5-year survival rate of less than 8%. New evidence indicates that PDAC cells release pro-inflammatory metabolites that induce a marked alteration of normal hematopoiesis, favoring the expansion and accumulation of myeloid-derived suppressor cells (MDSCs). We report here that PDAC patients show increased levels of both circulating and tumor-infiltrating MDSC-like cells. <h3>Methods</h3> The frequency of MDSC subsets in the peripheral blood was determined by flow cytometry in three independent cohorts of PDAC patients (total analyzed patients, <i>n</i> = 117). Frequency of circulating MDSCs was correlated with overall survival of PDAC patients. We also analyzed the frequency of tumor-infiltrating MDSC and the immune landscape in fresh biopsies. Purified myeloid cell subsets were tested in vitro for their T-cell suppressive capacity. <h3>Results</h3> Correlation with clinical data revealed that MDSC frequency was significantly associated with a shorter patients' overall survival and metastatic disease. However, the immunosuppressive activity of purified MDSCs was detectable only in some patients and mainly limited to the monocytic subset. A transcriptome analysis of the immunosuppressive M-MDSCs highlighted a distinct gene signature in which STAT3 was crucial for monocyte re-programming. Suppressive M-MDSCs can be characterized as circulating STAT3/arginase1-expressing CD14<sup>+</sup> cells. <h3>Conclusion</h3> MDSC analysis aids in defining the immune landscape of PDAC patients for a more appropriate diagnosis, stratification and treatment.
cAMP-Binding Protein Epac Induces Cardiomyocyte Hypertrophy
Authors: EricMorel, AndreaMarcantoni, MoniqueGastineau, RikkeBirkedal, FrancescaRochais, AnneGarnier, Anne-MarieLompré, GrégoireVandecasteele, FrankLezoualc’h
Journal: Circulation Research (2005)

cAMP is one of the most important second messenger in the heart. The discovery of Epac as a guanine exchange factor (GEF), which is directly activated by cAMP, raises the question of the role of this protein in cardiac cells. Here we show that Epac activation leads to morphological changes and induces expression of cardiac hypertrophic markers. This process is associated with a Ca2+-dependent activation of the small GTPase, Rac. In addition, we found that Epac activates a prohypertrophic signaling pathway, which involves the Ca2+ sensitive phosphatase, calcineurin, and its primary downstream effector, NFAT. Rac is involved in Epac-induced NFAT dependent cardiomyocyte hypertrophy. Blockade of either calcineurin or Rac activity blunts the hypertrophic response elicited by Epac indicating these signaling molecules coordinately regulate cardiac gene expression and cellular growth. Our results thus open new insights into the signaling pathways by which cAMP may mediate its biological effects and identify Epac ...
Heart-Failure Therapy — New Drugs but Old Habits?
Authors: James C. Fang
Journal: New England Journal of Medicine (2019)

In 2015, empagliflozin, an inhibitor of sodium–glucose cotransporter 2 (SGLT2), lowered the composite cardiovascular end point in the EMPA-REG trial1 involving patients with type 2 diabetes mellitus who were at increased cardiovascular risk. What was remarkable in that finding was that the benefit was driven by reductions in hospitalization for heart failure and cardiovascular mortality but not by a lower frequency of myocardial infarction or stroke. Moreover, empagliflozin appeared to slow deterioration in renal function, and the heart-failure benefits persisted in the presence of renal dysfunction. These early observations regarding heart failure were extended and confirmed in two subsequent trials . . .
Association Between Post–Dural Puncture Headache After Neuraxial Anesthesia in Childbirth and Intracranial Subdural Hematoma
Authors: Albert R. Moore, Paul M. Wieczorek, Jose C. A. Carvalho
Journal: JAMA Neurology (2019)

Women giving birth have high rates of dural puncture secondary to neuraxial anesthesia and are at high risk for a resulting headache. It appears to be unknown whether there is a significant association between post-dural puncture headache and subsequent intracranial subdural hematoma.To determine the association of post-dural puncture headache with postpartum intracranial subdural hematoma.This cohort study of patients used hospital discharges recorded in the US Agency for Healthcare Research and Quality National Readmission Database for women who experienced childbirth from January 2010 to December 2016. Patients were included if they had been admitted for childbirth, had 2 months of follow-up data, and did not receive a diagnostic lumbar puncture. Only the first delivery for a calendar year was studied. Data were analyzed from January 2018 to June 2019.Women with post-dural puncture headache associated with neuraxial anesthesia in the 2-month postpartum period were identified using International Classification of Disease (Ninth Edition and Tenth Edition) codes and were compared with those without post-dural puncture headaches.The primary outcome was intracranial subdural hematoma in the 2-month postpartum period. Secondary outcomes included in-hospital mortality and occurrence of neurosurgery.A total of 26 469 771 patients with 26 498 194 deliveries were included. Exclusion of repeated deliveries (n = 28 423), deliveries without 2 months of follow-up data (n = 4 329 621), and deliveries with diagnostic lumbar puncture (n = 9334) resulted in a final cohort of 22 130 815 patients and deliveries. For the cohort, the mean (SD) age was 28.1 (6.0) years, and there were 68 374 post-dural puncture headaches, for an overall rate of 309 (95% CI, 302-316) per 100 000. There were 342 cases of subdural hematoma identified, indicating a rate of 1.5 (95% CI, 1.3-1.8) per 100 000 women. Of these, 100 cases were in women with post-dural puncture headache, indicating a rate of 147 (95% CI, 111-194) hematoma cases per 100 000 deliveries in this subgroup. Post-dural puncture headache had an unadjusted absolute risk increase of 145 (95% CI, 117-174) subdural hematoma cases per 100 000 deliveries. After adjusting for confounders, post-dural puncture headache had an odds ratio for subdural hematoma of 199 (95% CI, 126-317; P < .001) and an adjusted absolute risk increase of 130 (95% CI, 90-169; P < .001) per 100 000 deliveries.The presence of presumed post-dural puncture headache after neuraxial anesthesia in childbirth, compared with no headache, was associated with a small but statistically significant absolute increase in the risk of being diagnosed with intracranial subdural hematoma. Further research is needed to establish if this association is causal for this rare outcome.
The association of smoking and socioeconomic status on cutaneous melanoma: a population‐based, data‐linkage, case–control study
Authors: J.A.G. Gibson, T.D. Dobbs, R. Griffiths, J. Song, A. Akbari, S. Whitaker, A. Watkins, S.M. Langan, H.A. Hutchings, R.A. Lyons, I.S. Whitaker
Journal: British Journal of Dermatology (2019)

Background Previous studies have identified an inverse association between melanoma and smoking; however, data from population-based studies are scarce. Objectives To determine the association between smoking and socioeconomic (SES) on the risk of development of melanoma. Furthermore, we sought to determine the implications of smoking and SES on survival. Methods We conducted a population-based case–control study. Cases were identified from the Welsh Cancer Intelligence and Surveillance Unit (WCISU) during 2000–2015 and controls from the general population. Smoking and SES were obtained from data linkage with other national databases. The association of smoking status and SES on the incidence of melanoma were assessed using binary logistic regression. Multivariate survival analysis was performed on a melanoma cohort using a Cox proportional hazard model using survival as the outcome. Results During 2000–2015, 9636 patients developed melanoma. Smoking data were obtained for 7124 (73·9%) of these patients. There were 26 408 controls identified from the general population. Smoking was inversely associated with melanoma incidence [odds ratio (OR) 0·70, 95% confidence interval (CI) 0·65–0·76]. Smoking was associated with an increased overall mortality [hazard ratio (HR) 1·30, 95% CI 1·09–1·55], but not associated with melanoma-specific mortality. Patients with higher SES had an increased association with melanoma incidence (OR 1·58, 95% CI 1·44–1·73). Higher SES was associated with an increased chance of both overall (HR 0·67, 95% CI 0·56–0·81) and disease-specific survival (HR 0·69, 95% CI 0·53–0·90). Conclusions Our study has demonstrated that smoking appeared to be associated with reduced incidence of melanoma. Although smoking increases overall mortality, no association was observed with melanoma-specific mortality. Further work is required to determine if there is a biological mechanism underlying this relationship or an alternative explanation, such as survival bias. What's already known about this topic? Previous studies have been contradictory with both negative and positive associations between smoking and the incidence of melanoma reported. Previous studies have either been limited by publication bias because of selective reporting or underpowered. What does this study add? Our large study identified an inverse association between smoking status and melanoma incidence. Although smoking status was negatively associated with overall disease survival, no significant association was noted in melanoma-specific survival. Socioeconomic status remains closely associated with melanoma. Although higher socioeconomic populations are more likely to develop the disease, patients with lower socioeconomic status continue to have a worse prognosis.
Abstract 14239: Trends and Outcomes in Hospitalizations With Acute Diastolic Heart Failure, 2003 to 2012
Authors: Parag Goyal, Zaid I Almarzooq, Irina Sobol, Maria Karas, Harsimran S Singh, Rajesh V Swaminathan, Dmitriy N Feldman, Robert M Minutello, Geoffrey Bergman, S. Chiu Wong, Evelyn M Horn, Luke K Kim
Journal: Circulation (2015)

Introduction: Hospitalizations for heart failure with preserved ejection fraction (HFpEF) are increasing. There is limited data examining contemporary trends and outcomes in patients hospitalized with HFpEF. Hypothesis: Outcomes in patients hospitalized with HFpEF are improving over time. Methods: We examined all hospitalizations with acute heart failure (n=5,829,546) in 2003-2012 using the Nationwide Inpatient Database. Based on ICD-9 codes, we identified 2,329,391 (~40%) as acute diastolic heart failure without concurrent systolic heart failure, or HFpEF. Patient characteristics, in-hospital mortality rates, and length of stay (LOS) were examined. Results: Compared to those with heart failure with reduced ejection fraction (HFrEF), those with HFpEF were older (mean 76±13 vs 72±14 years), more likely female (64% vs 42%), and more likely to have hypertension (67% vs 64%), atrial fibrillation (43% vs 39%), chronic pulmonary disease (38% vs 32%), renal failure (36% vs 35%), and anemia (34% vs. 26%) (all p&lt;0.001). Over time, HFpEF comprised increasing proportions of men and patients aged ≥75. Compared to HFrEF, in-hospital mortality rate was lower (4.3% vs 5.1%), and mean LOS was higher in HFpEF (7.0 vs 6.8 days) (both p&lt;0.001). The in-hospital mortality rate for HFpEF declined by 13% from 2003 to 2012 (4.8% to 4.2%, p-for-trend &lt;0.001), reflecting improved survival in females and those aged ≥65 years (both p-for-trend&lt;0.01). Mean LOS declined by 8% (7.4 to 6.8 days, p-for-trend&lt;0.001). Adjusting for potential confounders using multivariate regression analysis, pulmonary circulation disease (OR 1.90, 95%CI [1.86 to 1.94]), liver disease (OR 1.57, CI [1.52-1.63]), and renal failure (OR 1.35, CI [1.33-1.37]) were independent predictors of in-hospital mortality. Whereas atrial fibrillation (OR 1.07 [CI 1.06-1.08]) was mildly associated with in-hospital mortality, traditional factors of hypertension (OR 0.64 [CI 0.63-0.65]), diabetes (OR 0.77 [CI 0.76-0.78]), and CAD (OR 0.79 [CI 0.78-0.80]) were inversely related (all p&lt;0.001). Conclusions: Hospitalizations for HFpEF place a significant burden on the U.S. health care system. Our study, which represents the largest cohort of HFpEF to date, shows that outcomes have improved between 2003 and 2012.
Structural and Functional Remodeling of Amygdala GABAergic Synapses in Associative Fear Learning
Authors: Yu Kasugai, Elisabeth Vogel, Heide Hörtnagl, Sabine Schönherr, Enrica Paradiso, Markus Hauschild, Georg Göbel, Ivan Milenkovic, Yvan Peterschmitt, Ramon Tasan, Günther Sperk, Ryuichi Shigemoto, Werner Sieghart, Nicolas Singewald, Andreas Lüthi, Francesco Ferraguti
Journal: Neuron (2019)
NHS long term plan is a “fantastic opportunity” to reduce variation in cancer care
Authors: Elisabeth Mahase
Journal: BMJ (2019)

The NHS long term plan is a unique opportunity to reduce variation in cancer care across the country and hold NHS and political leaders to account on their promises, experts have said.

At the Westminster Health Forum on cancer care on 17 September, speakers highlighted the vast variation in cancer mortality, as well as waiting and treatment times across England, and outlined the ways to improve patient outcomes.

They said that a combination of better diagnostics, staffing, and patient pathways, in addition to support for outlier providers, would enable the NHS to achieve the aims laid out in the long term plan.1

The plan, which was announced by health secretary Matt Hancock in January 2019, set two key goals in terms of cancer. The first was that by 2028 the proportion of cancers diagnosed at stages one and two would rise from around half to three quarters of cancer patients. The second was that from 2028 55 000 more people each year would survive their cancer for at least five years following diagnosis.2

However, in 2018-19, …
Phase Ia Study of Anti-NaPi2b Antibody–Drug Conjugate Lifastuzumab Vedotin DNIB0600A in Patients with Non–Small Cell Lung Cancer and Platinum-Resistant Ovarian Cancer
Authors: David E. Gerber, Jeffrey R. Infante, Michael S. Gordon, Sarah B. Goldberg, Miguel Martín, Enriqueta Felip, Maria Martinez Garcia, Joan H. Schiller, David R. Spigel, Julie Cordova, Valerie Westcott, Yulei Wang, David S. Shames, YounJeong Choi, Robert Kahn, Randall C. Dere, Divya Samineni, Jian Xu, Kedan Lin, Katie Wood, Stephanie Royer-Joo, Vanessa Lemahieu, Eva Schuth, Anjali Vaze, Daniel Maslyar, Eric W. Humke, Howard A. Burris
Journal: Clinical Cancer Research (2019)

This phase I trial assessed the safety, tolerability, and preliminary antitumor activity of lifastuzumab vedotin (LIFA), an antibody-drug conjugate of anti-NaPi2b mAb (MNIB2126A) and a potent antimitotic agent (monomethyl auristatin E).LIFA was administered to patients with non-small cell lung cancer (NSCLC) and platinum-resistant ovarian cancer (PROC), once every 3 weeks, by intravenous infusion. The starting dose was 0.2 mg/kg in this 3+3 dose-escalation design, followed by cohort expansion at the recommended phase II dose (RP2D).Overall, 87 patients were treated at doses between 0.2 and 2.8 mg/kg. The MTD was not reached; 2.4 mg/kg once every 3 weeks was selected as the RP2D based on overall tolerability profile. The most common adverse events of any grade and regardless of relationship to study drug were fatigue (59%), nausea (49%), decreased appetite (37%), vomiting (32%), and peripheral sensory neuropathy (29%). Most common treatment-related grade ≥3 toxicities among patients treated at the RP2D (n = 63) were neutropenia (10%), anemia (3%), and pneumonia (3%). The pharmacokinetic profile was dose proportional. At active doses ≥1.8 mg/kg, partial responses were observed in four of 51 (8%) patients with NSCLC and 11 of 24 (46%) patients with PROC per RECIST. All RECIST responses occurred in patients with NaPi2b-high by IHC. The CA-125 biomarker assessed for patients with PROC dosed at ≥1.8 mg/kg showed 13 of 24 (54%) had responses (≥50% decline from baseline).LIFA exhibited dose-proportional pharmacokinetics and an acceptable safety profile, with encouraging activity in patients with PROC at the single-agent RP2D of 2.4 mg/kg.
Macrophage Exclusion after Radiation Therapy (MERT): A First in Human Phase I/II Trial using a CXCR4 Inhibitor in Glioblastoma
Authors: Reena P. Thomas, Seema Nagpal, Michael Iv, Scott G. Soltys, Sophie Bertrand, Judith S. Pelpola, Robyn Ball, Jaden Yang, Vandana Sundaram, Sophia B. Chernikova, Jonathan Lavezo, Donald Born, Hannes Vogel, J. Martin Brown, Lawrence D. Recht
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Preclinical studies have demonstrated that postirradiation tumor revascularization is dependent on a stromal cell–derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)-driven process in which myeloid cells are recruited from bone marrow. Blocking this axis results in survival improvement in preclinical models of solid tumors, including glioblastoma (GBM). We conducted a phase I/II study to determine the safety and efficacy of Macrophage Exclusion after Radiation Therapy (MERT) using the reversible CXCR4 inhibitor plerixafor in patients with newly diagnosed glioblastoma. Patients and Methods: We enrolled nine patients in the phase I study and an additional 20 patients in phase II using a modified toxicity probability interval (mTPI) design. Plerixafor was continuously infused intravenously via a peripherally inserted central catheter (PICC) line for 4 consecutive weeks beginning at day 35 of conventional treatment with concurrent chemoradiation. Blood serum samples were obtained for pharmacokinetic analysis. Additional studies included relative cerebral blood volume (rCBV) analysis using MRI and histopathology analysis of recurrent tumors. Results: Plerixafor was well tolerated with no drug-attributable grade 3 toxicities observed. At the maximum dose of 400 μg/kg/day, biomarker analysis found suprathreshold plerixafor serum levels and an increase in plasma SDF-1 levels. Median overall survival was 21.3 months [95% confidence interval (CI), 15.9–NA] with a progression-free survival of 14.5 months (95% CI, 11.9–NA). MRI and histopathology support the mechanism of action to inhibit postirradiation tumor revascularization. Conclusions: Infusion of the CXCR4 inhibitor plerixafor was well tolerated as an adjunct to standard chemoirradiation in patients with newly diagnosed GBM and improves local control of tumor recurrences.
NCDs and the WHO Essential Medicines Lists: children need universal health coverage too
Authors: Nicola J Gray, Jean-Pierre Chanoine, Mychelle Y Farmer, Jordan D Jarvis, Kate Armstrong, Ronald D Barr, Thomas A Faunce, P Michele Lashley, François Ndikumwenayo, Marie Hauerslev, Catherine W Karekezi, Jonathan D Klein, Rosalind E Ambrose, Kate Armstrong, Ronald D Barr, Jean-Pierre Chanoine, Mychelle Y Farmer, Thomas A Faunce (posthumous), Nicola J Gray, Marie Hauerslev, Jordan D Jarvis, Catherine W Karekezi, Jonathan D Klein, P Michele Lashley, François Ndikumwenayo, Kiran A Patel, Syed Jamal Raza, VTSK Siriwardana, Sherri L Smith, Rosemary Wyber
Journal: The Lancet Child & Adolescent Health (2019)
Correction to: Trifluridine/Tipiracil: A Review in Metastatic Gastric Cancer
Authors: Connie Kang, Sohita Dhillon, Emma D. Deeks
Journal: Drugs (2019)

The article Trifluridine/Tipiracil: A Review in Metastatic Gastric Cancer, written by Connie Kang, Sohita Dhillon and Emma D. Deeks, was originally published Online First without open access
Vascular Effects of Acute Hyperglycemia in Humans Are Reversed by l-Arginine
Authors: DarioGiugliano, RaffaeleMarfella, LudovicoCoppola, GiovanniVerrazzo, RitaAcampora, RiccardoGiunta, FrancescoNappo, CarmelaLucarelli, FeliceD’Onofrio
Journal: Circulation (1997)

Background Acute hyperglycemia may increase vascular tone in normal humans via a glutathione-sensitive, presumably free radical–mediated pathway. The objective of this study was to investigate whether or not the vascular effects of hyperglycemia are related to reduced availability of nitric oxide. Methods and Results Acute hyperglycemia (15 mmol/L, 270 mg/dL) was induced in 12 healthy subjects with an artificial pancreas. Systolic and diastolic blood pressures, heart rate, and plasma catecholamines showed significant increases (P<.05) starting after 30 minutes of hyperglycemia; leg blood flow decreased significantly (15%; P<.05) at 60 and 90 minutes. Platelet aggregation to ADP and blood viscosity also showed significant increments (P<.05). The infusion of l-arginine (n=7, 1 g/min) but not d-arginine (n=5, 1 g/min) or l-lysine (n=5, 1 g/min) in the last 30 minutes of the hyperglycemic clamp completely reversed all hemodynamic and rheological changes brought about by hyperglycemia. Infusion of NG-monomethy...