tbuckley/cabot-search huggingface dataset:
The Glia-Neuron Lactate Shuttle and Elevated ROS Promote Lipid Synthesis in Neurons and Lipid Droplet Accumulation in Glia via APOE/D
Authors: Lucy Liu, Kevin R. MacKenzie, Nagireddy Putluri, Mirjana Maletić-Savatić, Hugo J. Bellen
Journal: Cell Metabolism (2017)

Elevated reactive oxygen species (ROS) induce the formation of lipids in neurons that are transferred to glia, where they form lipid droplets (LDs). We show that glial and neuronal monocarboxylate transporters (MCTs), fatty acid transport proteins (FATPs), and apolipoproteins are critical for glial LD formation. MCTs enable glia to secrete and neurons to absorb lactate, which is converted to pyruvate and acetyl-CoA in neurons. Lactate metabolites provide a substrate for synthesis of fatty acids, which are processed and transferred to glia by FATP and apolipoproteins. In the presence of high ROS, inhibiting lactate transfer or lowering FATP or apolipoprotein levels decreases glial LD accumulation in flies and in primary mouse glial-neuronal cultures. We show that human APOE can substitute for a fly glial apolipoprotein and that APOE4, an Alzheimer's disease susceptibility allele, is impaired in lipid transport and promotes neurodegeneration, providing insights into disease mechanisms.
Human antibodies to the dengue virus E-dimer epitope have therapeutic activity against Zika virus infection
Authors: Estefania Fernandez, Wanwisa Dejnirattisai, Bin Cao, Suzanne M Scheaffer, Piyada Supasa, Wiyada Wongwiwat, Prabagaran Esakky, Andrea Drury, Juthathip Mongkolsapaya, Kelle H Moley, Indira U Mysorekar, Gavin R Screaton, Michael S Diamond
Journal: Nature Immunology (2017)
Clinicopathologic Correlation of Anti–Vascular Endothelial Growth Factor–Treated Type 3 Neovascularization in Age-Related Macular Degeneration
Authors: Miaoling Li, Rosa Dolz-Marco, Jeffrey D. Messinger, Lan Wang, Richard M. Feist, Christopher A. Girkin, Sarra Gattoussi, Daniela Ferrara, Christine A. Curcio, K. Bailey Freund
Journal: Ophthalmology (2017)
A First-in-Human Phase I Study of the Anticancer Stem Cell Agent Ipafricept (OMP-54F28), a Decoy Receptor for Wnt Ligands, in Patients with Advanced Solid Tumors
Authors: Antonio Jimeno, Michael Gordon, Rashmi Chugh, Wells Messersmith, David Mendelson, Jakob Dupont, Robert Stagg, Ann M. Kapoun, Lu Xu, Shailaja Uttamsingh, Rainer K. Brachmann, David C. Smith
Journal: Clinical Cancer Research (2017)

Purpose: Wnt signaling is implicated in tumor cell dedifferentiation and cancer stem cell function. Ipafricept (OMP-54F28) is a first-in-class recombinant fusion protein with the extracellular part of human frizzled 8 receptor fused to a human IgG1 Fc fragment that binds Wnt ligands. This trial evaluated ipafricept in patients with solid tumors.Experimental design: A 3+3 design was used; ipafricept was given intravenously every 3 weeks. The objectives were determination of dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and preliminary efficacy.Results: 26 patients were treated in seven dose-escalation cohorts (0.5, 1, 2.5, 5, 10, 15, and 20 mg/kg). No further dose escalation was pursued as PK modeling indicated that the target efficacious dose was reached at 10 mg/kg, and fragility fractures occurred at 20 mg/kg. Most common related grade 1 and 2 adverse events (AEs; ≥20% of patients) were dysgeusia, decreased appetite, fatigue, and muscle spasms. Ipafricept-related grade 3 TEAEs included hypophosphatemia and weight decrease (1 subject each, 3.8%). Ipafricept half-life was ∼4 days and had low incidence of antidrug antibody formation (7.69%) with no impact on drug exposure. Six patients had β-C-terminal telopeptide (β-CTX) doubling from baseline, which was reversible. PD modulation of Wnt pathway genes in hair follicles occurred ≥2.5 mg/kg. Two desmoid tumor and a germ cell cancer patient experienced stable disease for >6 months.Conclusions: Ipafricept was well tolerated, with RP2D of 15 mg/kg Q3W. Prolonged SD was noted in desmoid tumor and germ cell cancer patients. Clin Cancer Res; 23(24); 7490-7. ©2017 AACR.
Reply to: “Diagnostic and prognostic role of circulating microparticles in hepatocellular carcinoma”
Authors: Sabine K. Urban, Marcin Krawczyk, Arnulf Willms, Hanna Sänger, Frank Lammert, Jesus M. Banales, Piotr Milkiewicz, Veronika Lukacs-Kornek, Miroslaw Kornek
Journal: Journal of Hepatology (2017)
£10m scheme will cover GPs’ indemnity fees over winter
Authors: Zosia Kmietowicz
Journal: BMJ (2017)

NHS England has made £10m (€11.4m; $13.4m) available for indemnity costs to help GPs working out-of-hours shifts over the winter.

The scheme will run from 1 October 2017 until after the Easter weekend, 2 April 2018. NHS England said that it would allow doctors to commit to more out-of-hours sessions without needing to negotiate changes to their indemnity cover.

GPs who want to work additional sessions will agree a likely number of sessions they will work over the period with their out-of-hours …
Mechanisms for induction of hyaluronan synthesis and CD44 expression in human skin fibroblasts by PDGF-BB
Authors: Lingli Li, Yuejuan Li, Trias Asteriou, Carl Henrik Heldin, Paraskevi Heldin
Journal: Cancer Research (2005)

4502  The molecular mechanisms through which platelet-derived growth factor-BB (PDGF-BB) affects the synthesis of hyaluronan in human skin fibroblast cultures were investigated. Using specific inhibitors of intracellular signaling pathways, we conclude that MEK1/2, PI3K and NFkB are crucial for the stimulation of hyaluronan synthesis by PDGF-BB. This stimulatory effect was mediated by an up-regulation of HAS2 and, to a lesser extent, HAS1 genes which encode hyaluronan synthesizing enzymes; the expression of the HAS3 gene, as well as the HYAL1 and HYAL2 genes which encode hyaluronan degradative enzymes, were not affected by PDGF-BB. In a separate series of experiments, the role of hyaluronan in PDGF-BB-stimulated migration of human skin fibroblasts was investigated. After wounding of a confluent cell culture, PDGF-BB enhanced the cell migration in a hyaluronan-independent, but CD44-dependent manner. Furthermore, PDGF-BB stimulated fibroblasts exhibited an up-regulated CD44 expression in lamellipodial membrane protrusions. Our data suggest that PI3K or MEK1/2 pathways are involved in PDGF-BB-induced increase of hyaluronan synthesis, and that PDGF-BB most likely exerts control over CD44 localization.
Adapive radiotherapy in head and neck cancer.
Authors: Deepak Gupta, Tejinder Kataria, Trinanjan Basu, Shikha Goyal, Shyam S Bisht, Ashu Abhishke, Anurita Srivastava, Rahul Patil, Kushal Narang, Vikash Kumar
Journal: Journal of Clinical Oncology (2015)

e17002 Background: We have earlier published a study which showed the feasibility of a single mid therapy rescan to adapt anatomic and tumour volume changes to help reduce the treated volumes and doses received by normal structures especially in locally advanced head and neck cancer(HNC). We designed the present study to evaluate efficacy and toxicityof adaptive radiotherapy among HNC patients. Methods: 36 patients were included & 32 were stage III and IV. 34 received concurrent chemotherapy. All Patients underwent radiotherapy(RT) planning CT scans (contrast) at baseline and after 46 Gy of RT. Target volumes (gross tumor volume GTV, high risk and low risk clinical target volume CTV and respective planning target volume PTV) were delineated on both scans. A total dose of 70 gray (Gy) was planned to high risk PTV. Phase I delivered 54 Gy to all PTVs. Phase II plans for 16 Gy to high risk PTV were developed on mid-treatment scans. Changes in target volumes, demographics and clinical details were noted along with the response toxicity during treatment and on followup. Results: All the patients completed planned RT dose. 29(80.5%) had at least 5 cycles of concurrent chemotherapy. Median reduction in gross tumor volume and gross nodal volume on mid treatment scan were 34% and 43.2% respectively. Twenty (45.2%) patients experienced grade 3 acute mucositis. No patients developed grade 3 or above hematological toxicity. In four patients were feeding tube was placed before or during the treatment. None of patients had grade 3 or more xerostomia or dysphagia. Twenty nine (80.5%) patients achieved complete response at first follow up . Five had residual locoregional disease and two of these underwent salvage neck dissection. Four patients had local recurrences and all four had infield recurrences. Four patients had distant metastases, of which two had local recurrence as well. Median disease free survival(DFS) and overall survival(OS) of 17.5 months and 25.5 months,the 2 years DFS and OS were 72% and 75% , respectively. Conclusions: Treatment planning with adaptation to anatomic and tumor volume or shape changes may help tilt the balance towards better dose delivery as well as better normal tissue sparing. Large prospective studies may help define which patient would benefit from such approaches.
Junior doctor is cleared of wrongdoing after patient “misremembered” events
Authors: Clare Dyer
Journal: BMJ (2017)

A junior doctor who was accused of wrongly telling a patient that he had cancer has been exonerated after a medical practitioners tribunal found that the patient had become flustered at the mention of the word “cancer” and misunderstood the doctor’s comments.

Richard Schofield, who qualified in 2011, waited nearly three years for his hearing, only for the General Medical Council’s case against him to swiftly unravel.

The two expert witnesses, one for the GMC and one for Schofield, wrote in a joint statement, “The experts agree that in their experience it is common for patients of all ages, when faced with ‘bad’ news (including, for example, the possibility that they may have cancer), to become less receptive to receiving information. Both experts have witnessed this phenomenon in their working lives.”

Schofield, …
Clinical and radiological outcomes of 5-year drug-free remission-steered treatment in patients with early arthritis: IMPROVED study
Authors: Gülşah Akdemir, Lotte Heimans, Sytske Anne Bergstra, Robbert J Goekoop, Maikel van Oosterhout, Johannes H L M van Groenendael, André J Peeters, Gerda M Steup-Beekman, Leroy R Lard, Peter B J de Sonnaville, Bernard A M Grillet, Tom W J Huizinga, Cornelia F Allaart
Journal: Annals of the Rheumatic Diseases (2017)

To determine the 5-year outcomes of early remission induction therapy followed by targeted treatment aimed at drug-free remission (DFR) in patients with early arthritis.In 12 hospitals, 610 patients with early (<2 years) rheumatoid arthritis (RA) or undifferentiated arthritis (UA) started on methotrexate (MTX) 25 mg/week and prednisone (60 mg/day tapered to 7.5 mg/day). Patients not in early remission (Disease Activity Score <1.6 after 4 months) were randomised (single blind) to arm 1, adding hydroxychloroquine 400 mg/day and sulfasalazine 2000 mg/day, or arm 2, switching to MTX plus adalimumab 40 mg/2 weeks. Treatment adjustments over time aimed at DFR. Outcomes were remission percentages, functional ability, toxicity and radiological damage progression after 5 years.After 4 months, 387 patients were in early remission, 83 were randomised to arm 1 and 78 to arm 2. After 5 years, 295/610 (48%) patients were in remission, 26% in sustained DFR (SDFR) (≥1 year) (220/387 (57%) remission and 135/387 (35%) SDFR in the early remission group, 50% remission, 11% SDFR in the randomisation arms without differences between the arms). More patients with UA (37% vs 23% RA, p=0.001) and more anticitrullinated protein antibody (ACPA)-negative patients (37% vs 18% ACPA-positive, p<0.001) achieved SDFR.Overall, mean Health Assessment Questionnaire was 0.6 (0.5), and median (IQR) damage progression was 0.5 (0-2.7) Sharp/van der Heijde points, with only five patients showing progression >25 points in 5 years.Five years of DFR-steered treatment in patients with early RA resulted in almost normal functional ability without clinically relevant joint damage across treatment groups. Patients who achieved early remission had the best clinical outcomes. There were no differences between the randomisation arms. SDFR is a realistic treatment goal.
Patterns of chemotherapy (CT) use in a U.S.-wide population-based cohort of patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Thomas Adam Abrams, Gary Meyer, Julie Moloney, Jeffrey A. Meyerhardt, Deborah Schrag, Charles S. Fuchs
Journal: Journal of Clinical Oncology (2012)

3537 Background: Few population studies have examined treatment regimens and duration in mCRC since the introduction of biologic therapies in 2004. Methods: We assessed 4,877 consecutive mCRC pts who received CT between Jan 2004 and Mar 2011 at academic, private, and community hospital-based practices participating in a US-wide CT order entry (COE) system that captures patient demographics, stage and treatment data. Multivariate analyses of prospectively recorded patient and provider characteristics identified significant predictors of specific therapeutic approaches. Results: Among all pts, median age was 64; 55% male; (ECOG PS 0/1/2+) (56%/33%/11%). In first-line CT, 17% of pts received fluoropyrimidine (FU) only, while 16% received FU and irinotecan and 65% received FU and oxaliplatin. Older pts, those with poorer ECOG PS, and those treated in private practices were significantly more likely to receive FU only (all p ≤0.05). 53% of all pts received treatment in line 2, 28% in line 3, and 13% in line 4. Mean duration of treatment was 170 days (line 1), 139 (line 2), 135 (line 3) and 126 (line 4). Bevacizumab (bev) was administered to 65% of pts at some point in their treatment. Among the 51% who received bev in line 1, 33% continued bev beyond progression (BBP) in line 2. Pts treated at academic centers, pts who received longer duration of line 1 therapy, and pts whose providers had greater CRC pt volume were significantly more likely to continue BBP. Overall, 23% of pts received cetuximab (cet) (4% of all line 1 pts, 17% of line 2, 31% of line 3, and 29% of line 4). Mean duration of cet use was 168 days (line 1), 125 (line 2), 133 (line 3) and 129 (line 4). Pts treated at academic centers, pts who received longer duration of line 1 therapy, and pts treated in the West US were significantly more likely to ever receive cet. Cet use decreased by 18% following FDA label change restricting use to KRAS wt pts in Jun 2009 (p &lt;0.001). Of all pts, 6% received panitumumab at some point. Of those, 39% had previously received cet. Conclusions: This population-based study provides insight into treatment patterns of mCRC in the US. Usage of biologic agents varies significantly according to patient, practice, and provider characteristics.
Prognostic significance of a diagnosis of multiple lung cancers.
Authors: Jarushka Naidoo, Kaitlin Woo, Camelia S. Sima, David J Finley, William D. Travis, Valerie W. Rusch, Mark G. Kris, Marjorie Glass Zauderer
Journal: Journal of Clinical Oncology (2015)

7545 Background: The Martini-Melamed criteria (J Thor Card Surg, 1975) have been used since 1975 to clinically differentiate MLCs from lung metastases, which impacts upon treatment choices. The survival of patients (pts) with MLCs compared to those with one lung cancer (LC), and either local or distant recurrent LC, is unclear. Herein, we evaluated the Martini-Melamed criteria for its ability to appropriately identify patients with MLCs. Methods: After IRB approval, we conducted a retrospective review of all pts who underwent an R0 resection for stage IA-IIIA LC from 2008-2013 in our institution. Clinicopathologic data for all pts was collected. MLCs were defined using the Martini-Melamed criteria. We used the Kaplan-Meier method to assess overall survival (OS) of pts with one LC, recurrent LC, or an MLC, from the time of surgery/pathologic confirmation of their one LC, recurrent disease or MLC respectively. Results: 2,858 pts were identified: one LC (n=2403), recurrent LC (n=347), MLCs (n=108). Median OS for pts in these subgroups was: one LC (32.3mos, 95% CI: 30.8-34.6mos), MLC (not reached=NR), recurrent LC (10.5mos, 95% CI: 9.5-13.7mos). The 2-year OS for pts in these subgroups stratified by stage is depicted in the table. Conclusions: Pts with MLCs had a 2-yr OS that stage for stage, was similar to pts with one resected LC. Pts with recurrent LC had a poor 2-yr OS by original stage. Clearly, the Martini-Melamed criteria identify a clinically significant patient population with a different disease natural history. However, translational studies in MLCs are needed to investigate the tumor biology and patient features that underpin this distinct clinical entity. Lung Cancers by Original Stage (n) Two-year Overall Survival Log-rank p value One Lung Cancer (2403) IA IB IIA IIB IIIA 0.77 0.71 0.63 0.68 0.57 <0.01 Multiple Lung Cancers (108) IA IB II/III 0.83 0.75 0.88 0.44 Recurrent Lung Cancer (341) IA IB IIA IIB IIIA 0.31 0.18 0.29 0.33 0.08 0.046
Abstract 17531: Importance of Programmed Stimulation Under Conscious Sedation for Patients Referred for Epicardial Ventricular Tachycardia Ablation
Authors: Babak Nazer, Nitish Badhwar, Christopher Woods, Thomas Dewland, Brian Moyers, Edward P Gerstenfeld
Journal: Circulation (2014)

Background: Many non-ischemic cardiomyopathy (NICMP) patients referred for catheter ablation undergo an up-front epicardial approach under general anesthesia (GA). However, GA may suppress inducibi...
Patch testing with the European baseline series fragrance markers: a 2016 update
Authors: C.Y. Ung, J.M.L. White, I.R. White, P. Banerjee, J.P. McFadden
Journal: British Journal of Dermatology (2017)

Fragrance contact allergy is common and is currently screened for using the following European baseline series fragrance markers: fragrance mix (FM)I, FMII, Myroxylon pereirae and hydroxyisohexyl 3-cyclohexene carboxaldehyde.To investigate the validity of patch testing using these fragrance markers in detecting fragrance allergy to 26 individual fragrance substances for which cosmetic ingredient labelling is mandatory within the European Union.We conducted a retrospective review of the patch test records of all patients with eczema who underwent testing using the European baseline series, extended with the individual fragrance substances during the period from 2015 to 2016.Overall, 359 patients (17·2%) reacted to one or more allergens from the labelled fragrance substance series and/or a fragrance marker from the European baseline series. The allergens that were positive with the greatest frequencies were oxidized linalool [n = 154; 7·4%, 95% confidence interval (CI) 6·3-8·6], oxidized limonene (n = 89; 4·3%, 95% CI 3·4-5·2) and Evernia furfuracea (n = 44; 2·1%, 95% CI 1·5-2·8). Of the 319 patients who reacted to any of the labelled fragrance substances, only 130 (40·8%) also reacted to a baseline series fragrance marker. The sensitivity of our history-taking for detecting fragrance allergy was 25·7%.Given the evolving trends in fragrance allergy, patch testing with FMI, FMII, M. pereirae and hydroxyisohexyl 3-cyclohexene carboxaldehyde is no longer sufficient for screening for fragrance allergy.
Outcomes for Elderly Patients (pts) with Follicular Lymphoma (FL) Using Individual Patient Data (IPD) from 5922 Pts in 18 Randomized Controlled Trials (RCTs): a Follicular Lymphoma Analysis of Surrogate Hypothesis (FLASH) Group Study
Authors: Christopher Flowers, Fang-Shu Ou, Qian Shi, Eva Hoster, Bruce A. Peterson, Howard S. Hochster, Pauline Brice, Marco Ladetto, Wolfgang Hiddemann, Robert E Marcus, Eva Kimby, Michael Herold, Sabine De Bedout, Tina Nielsen, Franck Morschhauser, Mathias Rummel, Anton Hagenbeek, Umberto Vitolo, Gilles A. Salles, Daniel Sargent
Journal: Blood (2016)
Enhanced EGFR Targeting Activity of Plasmonic Nanostructures with Engineered GE11 Peptide
Authors: Francesca Biscaglia, Senthilkumar Rajendran, Paolo Conflitti, Clara Benna, Roberta Sommaggio, Lucio Litti, Simone Mocellin, Gianfranco Bocchinfuso, Antonio Rosato, Antonio Palleschi, Donato Nitti, Marina Gobbo, Moreno Meneghetti
Journal: Advanced Healthcare Materials (2017)

Abstract Plasmonic nanostructures show important properties for biotechnological applications, but they have to be guided on the target for exploiting their potentialities. Antibodies are the natural molecules for targeting. However, their possible adverse immunogenic activity and their cost have suggested finding other valid substitutes. Small molecules like peptides can be an alternative source of targeting agents, even if, as single molecules, their binding affinity is usually not very good. GE11 is a small dodecapeptide with specific binding to the epidermal growth factor receptor (EGFR) and low immunogenicity. The present work shows that thousands of polyethylene glycol (PEG) chains modified with lysines and functionalized with GE11 on clusters of naked gold nanoparticles, obtained by laser ablation in water, achieves a better targeting activity than that recorded with nanoparticles decorated with the specific anti‐EGFR antibody Cetuximab (C225). The insertion of the cationic spacer between the polymeric part of the ligand and the targeting peptide allows for a proper presentation of GE11 on the surface of the nanosystems. Surface enhanced resonance Raman scattering signals of the plasmonic gold nanoparticles are used for quantifying the targeting activity. Molecular dynamic calculations suggest that subtle differences in the exposition of the peptide on the PEG sea are important for the targeting activity.
An evaluation of the chronic lymphocytic leukemia (CLL) international prognostic index as a prognostic tool in patients with relapsed/refractory CLL in idelalisib phase 3 randomized studies.
Authors: Jacob Drobnyk Soumerai, Jacqueline Claudia Barrientos, Michael Hallek, Thomas J. Kipps, Jeffrey Alan Jones, Stephan Stilgenbauer, Guan Xing, Nai-Shun Yao, Loic Ysebaert, Andrew David Zelenetz
Journal: Journal of Clinical Oncology (2016)

7513 Background: The International Prognostic Index for patients (pts) with CLL (CLL-IPI) is a validated scoring system with prognostic value for overall survival (OS) in untreated CLL, but it has not been studied in relapsed/refractory (R/R) CLL (Kutsch et al. J Clin Oncol.33 (suppl), 2015). The CLL-IPI is a risk-weighted model comprising the risk factors age (relative weight, 1), stage (1), del(17p)/TP53 mutation (−17p/TP53M) (4), IGHV mutation status (2), and β2-microglobulin (2). We hypothesized that idelalisib (IDELA), an agent active in CLL with −17p/TP53M, can overcome the negative impact of high CLL-IPI risk on OS. Methods: The CLL-IPI score was analyzed in 460 pts with R/R CLL treated with IDELA + rituximab (R) vs placebo + R (NCT01539512) or IDELA + ofatumumab (O) vs O (NCT01659021). Subgroup analyses of OS were performed in 274 pts treated with IDELA + R or + O (IDELA cohort) and in 186 pts treated with R or O alone (control). Median OS was estimated for low, intermediate, high, and very high CLL-IPI risk groups using the Kaplan-Meier method. The log-rank test was used to compare survival distributions across groups and estimate hazard ratios (HRs) for OS. Results: At a median follow-up of 14.7 months, the CLL-IPI score was validated in the pooled cohort of all pts with R/R CLL, with significant differences in OS across CLL-IPI risk groups (P=0.0001; table). In the subgroup analysis, the CLL-IPI score was prognostic for OS in the control (P=0.0007) but not IDELA cohort (P=0.0859). Conclusions: Although low-risk pts are uncommon in the R/R setting, the CLL-IPI score is prognostic of OS in R/R CLL. IDELA partially overcomes the negative impact on OS of very high-risk disease driven by −17p/TP53M. Analyses of data derived from another phase 3 study are ongoing. Clinical trial information: NCT01659021, NCT01539512.OS CLL-IPI Low (0–1) Intermediate (2–3) High (4–6) Very High (7–10) All (N=460) n=6 n=38 n=228 n=188 HR (95% CI) 0 0.22 (0.08–0.6) 0.57 (0.4–0.8) 1 Log-rank test P=0.0001 IDELA cohort (n=274) n=4 n=20 n=141 n=109 HR (95% CI) 0 0.37 (0.11–1.21) 0.67 (0.41–1.09) 1 Log-rank test P=0.0859 Control (n=186) n=2 n=18 n=87 n=79 HR (95% CI) 0 0.09 (0.01–0.64) 0.42 (0.28–0.77) 1 Log-rank test P=0.0007