tbuckley/cabot-search huggingface dataset:
The size and composition of polymeric nanocapsules dictate their interaction with macrophages and biodistribution in zebrafish
Authors: José Crecente-Campo, Jorge Guerra-Varela, Mercedes Peleteiro, Carlha Gutiérrez-Lovera, Iago Fernández-Mariño, Andrea Diéguez-Docampo, África González-Fernández, Laura Sánchez, María José Alonso
Journal: Journal of Controlled Release (2019)
The E3 ubiquitin ligase Itch restricts antigen-driven B cell responses
Authors: Emily K. Moser, Jennifer Roof, Joseph M. Dybas, Lynn A. Spruce, Steven H. Seeholzer, Michael P. Cancro, Paula M. Oliver
Journal: The Journal of Experimental Medicine (2019)

The E3 ubiquitin ligase Itch regulates antibody levels and prevents autoimmune disease in humans and mice, yet how Itch regulates B cell fate or function is unknown. We now show that Itch directly limits B cell activity. While Itch-deficient mice displayed normal numbers of preimmune B cell populations, they showed elevated numbers of antigen-experienced B cells. Mixed bone marrow chimeras revealed that Itch acts within B cells to limit naive and, to a greater extent, germinal center (GC) B cell numbers. B cells lacking Itch exhibited increased proliferation, glycolytic capacity, and mTORC1 activation. Moreover, stimulation of these cells in vivo by WT T cells resulted in elevated numbers of GC B cells, PCs, and serum IgG. These results support a novel role for Itch in limiting B cell metabolism and proliferation to suppress antigen-driven B cell responses.
“Sin taxes”—the language is wrong, but the evidence is clear
Authors: Adam Briggs
Journal: BMJ (2019)

Last week Boris Johnson suggested that a good way to revamp politics after Brexit would be to base “tax policy on clear evidence.”1

He was referring to what he describes as “stealth sin taxes”—taxes on unhealthy food and drink currently exemplified by the soft drink industry levy—and pledged a review into their effectiveness. Aside from any of the potential politics or conflicts of interest underlying these claims, sugary drink taxes are an important piece of any evidence based public health policy.

We all know about the obesity crisis: over a third of 10-11 year olds and two thirds of adults in England are overweight or obese,2 at an estimated cost to the NHS of £6bn (€6.67bn; $7.47bn) in 2014.3 Reversing this crisis is hugely challenging. Crudely speaking, weight gain is caused by eating too much and moving too little, but our diet and activity levels are heavily influenced by social, environmental, and economic conditions,4 as well as the interplay between these and our genetics5 and our physical and mental health. Hence, my colleagues at the Health Foundation have called for cross government action and investment6 on the wider determinants that …
Delayed childhood neurodevelopment and neurosensory alterations in the second year of life in a prospective cohort of ZIKV-exposed children
Authors: Karin Nielsen-Saines, Patrícia Brasil, Tara Kerin, Zilton Vasconcelos, Claudia Raja Gabaglia, Luana Damasceno, Marcos Pone, Liege M. Abreu de Carvalho, Sheila M. Pone, Andrea A. Zin, Irena Tsui, Tania Regina S. Salles, Denise Cotrim da Cunha, Roozemerie Pereira Costa, Jociele Malacarne, Ana Beatriz Reis, Renata Hydee Hasue, Carolina Y. P. Aizawa, Fernanda F. Genovesi, Christa Einspieler, Peter B Marschik, José Paulo Pereira, Stephanie L. Gaw, Kristina Adachi, James D. Cherry, Zhiheng Xu, Genhong Cheng, Maria Elisabeth Moreira
Journal: Nature Medicine (2019)
Development and correlative analysis of a TML assay in specimens with reference MSI and somatic variant results.
Authors: Hestia S. Mellert, Leisa Jackson, Gary Anthony Pestano
Journal: Journal of Clinical Oncology (2019)

124 Background: Treatment of late-stage non-small cell lung cancer has been greatly impacted by the advances in immunotherapy. Molecular biomarkers such as tumor mutation load (TML or TMB) and micro-satellite instability (MSI) may identify patients with NSCLC that are more likely to respond to immune checkpoint inhibitors. In this report, we describe the development of and NGS-based assay for the robust detection of TML and somatic variants simultaneously using a targeted assay that covers 1.7 Mb of the genome. Methods: Initial feasibility included reference control cell-lines, HCC1143 and NIST8398, as well as FFPE (formalin-fixed, paraffin-embedded) samples from lung and colorectal tumors. In development, eight FFPE specimens from patients with late stage cancer and a reference MSI status were evaluated. FFPE slides were extracted using the MagMax FFPE DNA/RNA Ultra kit, and nucleic acid quality was assessed using qPCR. Extracted DNA was processed through the Oncomine TML Assay with a minimum input of 30 ng of DNA per specimen. Automated library and template preparation were performed followed by sequencing on the Ion GeneStudio S5 Plus system using replicate 540 chips. Eight samples with barcoded adapters were multiplexed per chip. Tumor mutation analysis and variant calling was performed using the Oncomine TML v2.0 workflow. Results: The time from FFPE extraction to result was 96 hours, and all samples passed QC metrics. TML scores ranged from 14.4-36.04 mutations/Mb for all samples with MSI-high reference results. A very high level of inter-chip concordance was also observed (R 2 =0.990). Additionally, the variant caller function within the TML workflow was used to detect BRAF V600E mutations with 100% concordance to reference testing results. Conclusions: The accurate quantification of somatic mutations paired with fast turn-around time and robust automated workflow is ideal for assessing the tumor mutation load as well as hotspot mutations from limited (FFPE) samples.
First-in-human phase I clinical trial of QBI-139, a human ribonuclease variant, in solid tumors.
Authors: Laura E. Strong, John A. Kink, Baigen Mei, Mark N. Shahan, Ronald T. Raines
Journal: Journal of Clinical Oncology (2012)

TPS3113 Background: RNA has been recognized as a drug target for cancer therapy, as evidenced by the ongoing clinical trials of RNAi and antisense therapies. An alternative approach that circumvents the delivery and stability issues of RNAi and antisense is to harness the activity of naturally occurring enzymes that degrade RNA. Variants of human ribonucleases (RNase) have been generated with diminished binding to their natural inhibitor inside cells, which allows the new proteins to kill cancer cells. QBI-139, a variant that retains 95% sequence identity to a naturally occurring RNase, has demonstrated efficacy as both a single agent and in combination against multiple tumor types in in vivo models of human cancer. A first in human phase I trial was designed and initiated for QBI-139. Methods: Since QBI-139 showed efficacy against multiple cancers in model systems, a first in human phase I trial was designed for patients with advanced solid tumors (NCT00818831). Patients receive QBI-139 by intravenous infusion once weekly for a cycle of three weeks. In the absence of disease progression or unacceptable toxicity, treatment can continue on the twenty one day cycle. The trial is a standard 3+3 design with cohorts of three to six patients receiving escalating doses of QBI-139 until the maximum tolerated dose (MTD) and/or recommended phase II dose is determined. The inclusion/exclusion criteria are typical for the patient population. Forty three patients have been treated to date (January 2012) without identification of dose limiting toxicity. The starting dose in the clinical trial was 3 mg/m 2 while the most recently completed cohort was treated with a dose of 50.4 mg/m 2 . Dose escalation is ongoing. The primary outcome is to evaluate the toxicity and tolerability of QBI-139 in patients with advanced refractory solid tumors. This information will allow for identification of the maximum tolerated dose. Clinical exposure levels are being monitored by measuring the pharmacokinetics of QBI-139. Tumor response to QBI-139 will be measured using RECIST criteria. Since QBI-139 demonstrated broad efficacy in model systems, another outcome of the phase I trial may be identification of the indications for the next stage of clinical development.
Abstract P070: Dyslipidemic Adolescent and Adult African Americans Have Similar Cardio-Metabolic Risk
Authors: Puneet K Tung, Samuel Gidding, Scott W Keith, Stephanie DeLoach, Bonita Falkner
Journal: Circulation (2013)

Background: African Americans (AA) are at increased risk for developing diabetes mellitus. However, they are known to have lower triglycerides (TG) and higher high density lipoprotein-cholesterol (HDL-C) than other ethnic groups. Among AA, it is thought that adolescents are at lower cardiovascular risk and have lower levels of metabolic co-variants than adults, but there are no studies directly comparing adolescents and adults. Objective: To compare AA adolescents to adults with regard to the relationships of adiposity-related lipid risk markers (TG/HDL ratio and non HDL-C) with body mass index (BMI), waist circumference (WC), homeostasis model of insulin resistance (HOMA), and serum high sensitivity C-Reactive Protein (hsCRP). Methods: Healthy AAs (283 adolescents, 484 adults) were recruited from the same urban community. To create TG/HDL strata, adult tertiles were established. Non HDL-C strata were based on ATP III/NHLBI expert guidelines. Adolescents and adults in the low, middle and high strata were compared with regard to BMI, WC, HOMA, and hsCRP. Results: As both TG/HDL ratio and non HDL-C strata increased, BMI, WC, HOMA, and hsCRP increased in both adolescents and adults (Tables). Among 16% (44/283) of adolescents and 33% (161/484) of adults having a TG/HDL ratio above 2.028 (High group), BMI, WC, and hsCRP were similar in both age groups (Table 1). In 8% (22/283) of adolescents and 12% (60/484) of adults having an elevated non HDL-C (HIgh group), BMI, WC, and hsCRP were also similar (Table 2). HOMA was higher in adolescents, but after accounting for this age difference, was significantly associated with the high TG/HDL ratio and non HDL-C strata. Slopes of these relationships were steeper in adolescents than adults, therefore adolescents in the lower lipid strata had lower BMI, WC, HOMA, and hsCRP. Conclusions: Elevated TG/HDL ratio and non HDL-C are associated with similar levels of metabolic risk in adolescent and adult AAs. The relationship between HOMA and dyslipidemia is stronger in adolescent versus adult AAs.
Granulocyte transfusions in patients with skin and soft tissues infections and leukemia: Are they useful?
Authors: Yamil Michelen, Hagop M. Kantarjian, Farhad Ravandi, Naveen Pemmaraju, Tapan M. Kadia, Marina Konopleva, Srdan Verstovsek, Naval Guastad Daver, Guillermo Garcia-Manero, Heidi Krause, Courtney Denton Dinardo, Jan Andreas Burger, Alessandra Ferrajoli, William G. Wierda, Jorge E. Cortes, Fleur M. Aung
Journal: Journal of Clinical Oncology (2019)

7022 Background: Granulocyte transfusions (GTX) have been proposed to improve clinical outcome of neutropenic patients (pts) with serious infections. We evaluated the impact of unirradiated GTX in pts with skin and soft tissue infections (SSTI) and leukemia. Methods: We did a retrospective analysis of pts with leukemia and SSTI that received GTX from 2014 to 2018. We analyzed infection outcome and changes in ANC after GTX. Donors were mobilized using G-CSF plus oral dexamethasone 12 hours prior to apheresis. Results: Twenty-seven pts received 141 GTX for 33 SSTI. Transfusions were unirradiated, except for 10 (7%) radiated units administered due to availability. Twenty pts were male (74%); median age was 59 yrs (20–83 yrs). Hematologic diagnoses included AML (23, 70%), MDS (3, 9%), ALL (3, 9%), CLL (2, 6%), CML (1, 3%), and MF (1, 3%). In 24 (73%) SSTI, pts had a baseline ANC&lt;0.5 x10 9 /L, 3 (9%) had ANC between 0.51x10 9 L to 0.99 x 10 9 L, and 6 (18%) with ANC &gt;1 x10 9 /L. After GTX, ANC increased in 99 (70%) cases by a median of 0.7 x 10 9 /L (0.02 to 10.03) with a median peak time of 9 hrs (4 to114 hrs), with a median time from GTX to first drop of 34 hrs (10 to 136 hrs). ANC decreased in 27 (19%) (by a median -0.5 x 10 9 /L,-0.02 to -2.41). There was no change of ANC in 15 (11%). Improvement was determined by reduction in fever and inflammation, or resolution of SSTI 7 days after first GTX. Twenty-seven (82%) episodes improved. In those improved, ANC remained &lt;1.5x10 9 /L in 15 (56%) episodes after last GTX and after improvement. Main adverse reactions were fever in 21% (29), and respiratory complications in 6% (9) (pulmonary effusion, respiratory distress and acute hypoxemia). One pt (3%) required intubation. There was no transfusion-related GVHD. Cumulative survival from first GTX on each SSTI by Kaplan-Meier Survival was 82% (8) at 30 days, 49% (17) at 90 days, 41% (17) at 180 days, and 24% (12) at 360 days. Eight of this pts died of infections, 4 of which were SSTI described on this paper. Conclusions: GTX have a beneficial effect on clinical improvement in patients with SSTI and underlying hematological malignancies and severe neutropenia. It can be safely administered without GVHD. Further prospective studies are warranted.
Laser eye procedure is safe and effective as an early treatment for glaucoma
Authors: Rob Cook, Vaughan Thomas, Rosie Martin
Journal: BMJ (2019)

The study Gazzard G, Konstantakopoulou G, Garway-Heath E, et al. Selective laser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma (LiGHT): a multicentre randomised controlled trial. Lancet 2019; doi: 10.1016/S0140-6736(18)32213-X . This project was funded by the NIHR Health Technology Assessment Programme (project number 09/104/40) and was sponsored by the Moorfields Eye Hospital NHS Foundation Trust. To read the full NIHR Signal, go to https://discover.dc.nihr.ac.uk/content/signal-000774/early-glaucoma-laser-eye-treatment-trabeculoplasty
A pipeline to detect antibody-targetable cancer stem cell proteins.
Authors: Raffaele A Calogero, Stefania Lanzardo, Laura Conti, Federica Cavallo
Journal: Journal of Clinical Oncology (2012)

e13527 Background: Monoclonal antibody represents an ideal tool to develop highly specific drugs. However, the efficacy of antibody-based drugs is strongly dependent by the effect that the protein targeted will have on the disease cell. Particularly interesting, as target for antibody therapy, are oncoantigens (OAs), i.e., surface tumor antigen that supports tumor growth. Methods: We have developed a two steps pipeline that allows identifying moAbs directed against e.g., cancer stem cells (CSC) OAs. First step: we compare transcription profiles, derived by tumor cell line grown as epithelial monolayer, with those derived by spheroids generated using the same cell line. Since spheroids are enriched in CSCs, genes up-modulated in spheroids are putative targets for antibody-targeting. Putative targets are ranked on the basis of their oncological potential and low expression in normal tissues. Top ranking targets are then tested in animal model. If vaccination inducing antibody response is able to reduce tumour growth and/or metastasis formation targets are proficient for the second step: they are used to vaccinate BALB/c mice. IgG expressing cells are isolated and libraries of the heavy (HV) and light variable (LV) chains are sequenced. Bioinformatics is then used to detect enriched VH and VL, which are transformed in single-chain antibodies to test target binding efficacy. Results: Using our pipeline we have identified, as associated to HER2+ breast cancer cell, TMPRSS4. This protein is involved in metastasis and invasion and, in hepatocellular carcinoma, it is over-expression leads to epithelial-mesenchymal transition. We are now evaluating if antibodies raised against TMPRSS4 are able to inhibit metastasis formation in BALB/c mice. On the basis of these results we will move to the second step of the pipeline. Conclusions: We have designed a pipeline that allows identification of CSC associated proteins suitable as targets for antibody-driven therapy.
Mycosis fungoides and Sézary syndrome: 2019 update on diagnosis, risk‐stratification, and management
Authors: Alexandra C. Hristov, Trilokraj Tejasvi, Ryan A. Wilcox
Journal: American Journal of Hematology (2019)

Abstract Disease Overview Cutaneous T‐cell lymphomas (CTCL) are a heterogenous group of T‐cell neoplasms involving the skin, the majority of which may be classified as Mycosis fungoides (MF) or Sézary syndrome (SS). Diagnosis The diagnosis of MF or SS requires the integration of clinical and histopathologic data. Risk‐Adapted Therapy TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a “risk‐adapted,” multi‐disciplinary approach to treatment. For patients with disease limited to the skin, skin‐directed therapies are preferred, as both disease‐specific and overall survival for these patients is favorable. In contrast, patients with advanced‐stage disease with significant nodal, visceral or blood involvement are generally approached with systemic therapies. These include biologic‐response modifiers, histone deacetylase (HDAC) inhibitors, or antibody‐based strategies, in an escalating fashion. In highly‐selected patients, allogeneic stem‐cell transplantation may be considered, as this may be curative in some patients.
Correction to: Circular RNA YAP1 inhibits the proliferation and invasion of gastric cancer cells by regulating the miR-367-5p/p27 Kip1 axis
Authors: Hui Liu, Yuan Liu, Zhaolian Bian, Jing Zhang, Rui Zhang, Xiaoyu Chen, Yanxia Huang, Yang Wang, Jinshui Zhu
Journal: Molecular Cancer (2019)

After the publication of this work [1], a spelling error was found: the ID of the circRNA, termed circYAP1, in the original publication was misspelled as "has_circ_0002320".
A phase II trial with the combination of plinabulin (plin) pegfilgrastim (peg): Evaluation of the reversal of peg’s immune-suppressive potential by the addition of plin to peg.
Authors: Douglas W. Blayney, Stephan Ogenstad, Yuankai Shi, Ji Feng Feng, Qingyuan Zhang, Tao Sun, Lihua Du, Lan Huang, Ramon Mohanlal
Journal: Journal of Clinical Oncology (2019)

4 Background: Peg is a long-acting G-CSF used for prevention of Chemotherapy Induced Neutropenia (CIN). Peg stimulates granulopoiesis in bone marrow and causes a temporary overshoot in absolute neutrophil count (ANC). High NLR is a negative prognostic marker in esophageal, renal cancer and melanoma (Zhou, Nature 2016; Ma, Nature 2018). Decreased Lymphocyte-to Monocyte Ratio (LMR) is another negative prognostic marker (Sierzega; Ann Surg Onc 2017). Peg single agent (SA), but not Plin SA, increased NLR, and decreased LMR (Blayney ESMO 2018) after Docetaxel (Doc). We analyzed whether Plin added to Peg would reverse Peg’s immune-suppressive potential by analyzing NLR and LMR with Peg SA and with Plin+Peg. Methods: NLR and LMR were calculated in cycle 1 of Ph2 study BPI-2358-106 with either Peg SA (6 mg; n = 22), Plin SA (20 mg/m2; n = 15) or Peg 6 mg and Plin 20 mg/m2 (Peg+Plin; n = 21). NLR and LMR were calculated after day (D) 8, since Peg increases leukocytes after D8, and were performed through D15. Plin was given D1 of chemotherapy (Doc, Doxorubicin, Cyclophosphamide) in Breast Cancer patients (pts); Peg was given D2. Results: The percentage (%) of pts with grade 4 neutropenia was lowered from 59% with Peg SA to 38% by adding Plin to Peg. The % of pts with an ANC exceeding upper limit of normal (8x10E9/L) was lowered from 50% with Peg SA to 31%, by adding Plin to Peg. The table summarizes the % of patients with NLR ≥ 5 and LMR ≤3.2 over time with Peg SA, Plin SA and Peg+Plin. Peg-induced immune-suppressive NLR and or LMR levels occurred in 50% or more of pts, and in a significantly lower % of pts by adding Plin to Peg (p &lt; 0.0076 for NLR and p &lt; 0.073 for LMR on D13). Conclusions: Peg, but not Plin generates a potentially deleterious NLR and LMR which was significantly reversed by the addition of Plin to Peg. The Peg+Plin combination improves efficacy for CIN and reversed Peg’s potentially immune-suppressive NLR and MLR phenotype. Clinical trial information: NCT03294577. [Table: see text]
Significant differences in outcome between Immunoscore categories in stage I colon cancer patients
Authors: J. Galon, F. Hermitte, B. Mlecnik, F. Marliot, C. Bifulco, A. Lugli, I. Nagtegaal, A. Hartmann, M. Van den Eynde, M. Roehrl, P. Ohashi, E. Zavadova, T. Torigoe, P. Patel, Y. Wang, Y. Kawakami, F. Marincola, P. Ascierto, B. Fox, F. Pagès
Journal: Annals of Oncology (2019)
Causal clarity and deeper dimensions in microbiota-gut-brain research
Authors: Katarzyna B. Hooks, Jan Pieter Konsman, Maureen A. O'Malley
Journal: Behavioral and Brain Sciences (2019)

Abstract Our analysis of microbiota-gut-brain (MGB) research took MGB to task for some of its methods, concepts, and interpretations. Commentators then raised numerous issues about the neuroscientific and microbiome aspects of MGB and how it can be understood as a field. We respond by addressing the dimensionality (scope and depth) and causal focus of MGB.
Why What You May Not Know About Fecal Immunochemical Testing Matters
Authors: Andrew W. Swartz
Journal: Annals of Internal Medicine (2019)

Letters16 July 2019Why What You May Not Know About Fecal Immunochemical Testing MattersAndrew W. Swartz, MDAndrew W. Swartz, MDYukon-Kuskokwim Delta Regional Hospital, Bethel, Alaska (A.W.S.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L19-0265 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:In his editorial endorsing fecal immunochemical testing (FIT), Allison (1) adopts the most optimistic perspective of the evidence to conclude that FIT has an effect similar to that of colonoscopy. However, a more conservative interpretation yields a different conclusion. Meta-analysis of 5 large randomized controlled trials with intention-to-screen analysis has shown that flexible sigmoidoscopy consistently prevented colorectal cancer (CRC) and reduced the risk for death (that is, all-cause mortality) despite examining only one half of the colon. These are landmark outcomes by themselves. However, regression analysis of these outcomes also shows a clear dose–response relation between preventing ...References1. Allison J. Why what you may not know about fecal immunochemical testing matters. Ann Intern Med. 2019;170:341-3. [PMID: 30802903]. doi:10.7326/M19-0301 LinkGoogle Scholar2. Swartz AW, Eberth JM, Josey MJ, et al. Reanalysis of all-cause mortality in the U.S. Preventive Services Task Force 2016 evidence report on colorectal cancer screening. Ann Intern Med. 2017;167:602-3. [PMID: 28828493]. doi:10.7326/M17-0859 LinkGoogle Scholar3. Swartz AW, Eberth JM, Strayer SM. Preventing colorectal cancer or early diagnosis: which is best? A re-analysis of the U.S. Preventive Services Task Force evidence report. Prev Med. 2019;118:104-12. [PMID: 30367971] doi:10.1016/j.ypmed.2018.10.014 CrossrefMedlineGoogle Scholar4. Imperiale TF, Gruber RN, Stump TE, et al. Performance characteristics of fecal immunochemical tests for colorectal cancer and advanced adenomatous polyps. A systematic review and meta-analysis. Ann Intern Med. 2019;170:319-29. [PMID: 30802902]. doi:10.7326/M18-2390 LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: Yukon-Kuskokwim Delta Regional Hospital, Bethel, Alaska (A.W.S.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L19-0265. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoWhy What You May Not Know About Fecal Immunochemical Testing Matters James Allison Why What You May Not Know About Fecal Immunochemical Testing Matters James Allison Metrics 16 July 2019Volume 171, Issue 2Page: 151KeywordsColonColonoscopyColorectal cancerColorectal cancer screeningDisclosureFlexible sigmoidoscopyHematologic testsMortalityRegression analysisRelative risk ePublished: 16 July 2019 Issue Published: 16 July 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...