tbuckley/cabot-search huggingface dataset:
Convergent Acquisition of Nonembryonic Development in Styelid Ascidians
Authors: Alexandre Alié, Laurel Sky Hiebert, Paul Simion, Marta Scelzo, Maria Mandela Prünster, Sonia Lotito, Frédéric Delsuc, Emmanuel J P Douzery, Christelle Dantec, Patrick Lemaire, Sébastien Darras, Kazuo Kawamura, Federico D Brown, Stefano Tiozzo
Journal: Molecular Biology and Evolution (2018)

Asexual propagation and whole body regeneration are forms of nonembryonic development (NED) widespread across animal phyla and central in life history and evolutionary diversification of metazoans. Whereas it is challenging to reconstruct the gains or losses of NED at large phylogenetic scale, comparative studies could benefit from being conducted at more restricted taxonomic scale, in groups for which phylogenetic relationships are well established. The ascidian family of Styelidae encompasses strictly sexually reproducing solitary forms as well as colonial species that combine sexual reproduction with different forms of NED. To date, the phylogenetic relationships between colonial and solitary styelids remain controversial and so is the pattern of NED evolution. In this study, we built an original pipeline to combine eight genomes with 18 de novo assembled transcriptomes and constructed data sets of unambiguously orthologous genes. Using a phylogenomic super-matrix of 4,908 genes from these 26 tunicates we provided a robust phylogeny of this family of chordates, which supports two convergent acquisitions of NED. This result prompted us to further describe the budding process in the species Polyandrocarpa zorritensis, leading to the discovery of a novel mechanism of asexual development. Whereas the pipeline and the data sets produced can be used for further phylogenetic reconstructions in tunicates, the phylogeny provided here sets an evolutionary framework for future experimental studies on the emergence and disappearance of complex characters such as asexual propagation and whole body regeneration.
Implications of insecticide resistance for malaria vector control with long-lasting insecticidal nets: a WHO-coordinated, prospective, international, observational cohort study
Authors: Immo Kleinschmidt, John Bradley, Tessa Bellamy Knox, Abraham Peter Mnzava, Hmooda Toto Kafy, Charles Mbogo, Bashir Adam Ismail, Jude D Bigoga, Alioun Adechoubou, Kamaraju Raghavendra, Jackie Cook, Elfatih M Malik, Zinga José Nkuni, Michael Macdonald, Nabie Bayoh, Eric Ochomo, Etienne Fondjo, Herman Parfait Awono-Ambene, Josiane Etang, Martin Akogbeto, Rajendra M Bhatt, Mehul Kumar Chourasia, Dipak K Swain, Teresa Kinyari, Krishanthi Subramaniam, Achille Massougbodji, Mariam Okê-Sopoh, Aurore Ogouyemi-Hounto, Celestin Kouambeng, Mujahid Sheikhedin Abdin, Philippa West, Khalid Elmardi, Sylvie Cornelie, Vincent Corbel, Neena Valecha, Evan Mathenge, Luna Kamau, Jonathan Lines, Martin James Donnelly
Journal: The Lancet Infectious Diseases (2018)

Scale-up of insecticide-based interventions has averted more than 500 million malaria cases since 2000. Increasing insecticide resistance could herald a rebound in disease and mortality. We aimed to investigate whether insecticide resistance was associated with loss of effectiveness of long-lasting insecticidal nets and increased malaria disease burden.
Defective Base Excision Repair of Oxidative DNA Damage in Vascular Smooth Muscle Cells Promotes Atherosclerosis
Authors: Aarti Shah, Kelly Gray, Nichola Figg, Alison Finigan, Lakshi Starks, Martin Bennett
Journal: Circulation (2018)

Background: Atherosclerotic plaques demonstrate extensive accumulation of oxidative DNA damage, predominantly as 8-oxoguanine (8oxoG) lesions. 8oxoG is repaired by base excision repair enzymes; however, the mechanisms regulating 8oxoG accumulation in vascular smooth muscle cells (VSMCs) and its effects on their function and in atherosclerosis are unknown. Methods: We studied levels of 8oxoG and its regulatory enzymes in human atherosclerosis, the mechanisms regulating 8oxoG repair and the base excision repair enzyme 8oxoG DNA glycosylase I (OGG1) in VSMCs in vitro, and the effects of reducing 8oxoG in VSMCs in atherosclerosis in ApoE −/− mice. Results: Human plaque VSMCs showed defective nuclear 8oxoG repair, associated with reduced acetylation of OGG1. OGG1 was a key regulatory enzyme of 8oxoG repair in VSMCs, and its acetylation was crucial to its repair function through regulation of protein stability and expression. p300 and sirtuin 1 were identified as the OGG1 acetyltransferase and deacetylase regulators, respectively, and both proteins interacted with OGG1 and regulated OGG1 acetylation at endogenous levels. However, p300 levels were decreased in human plaque VSMCs and in response to oxidative stress, suggesting that reactive oxygen species–induced regulation of OGG1 acetylation could be caused by reactive oxygen species–induced decrease in p300 expression. We generated mice that express VSMC-restricted OGG1 or an acetylation defective version (SM22α-OGG1 and SM22α-OGG1 K-R mice) and crossed them with ApoE −/− mice. We also studied ApoE −/− mice deficient in OGG1 (OGG1 −/− ). OGG1 −/− mice showed increased 8oxoG in vivo and increased atherosclerosis, whereas mice expressing VSMC-specific OGG1 but not the acetylation mutant OGG1 K-R showed markedly reduced intracellular 8oxoG and reduced atherosclerosis. VSMC OGG1 reduced telomere 8oxoG accumulation, DNA strand breaks, cell death and senescence after oxidant stress, and activation of proinflammatory pathways. Conclusions: We identify defective 8oxoG base excision repair in human atherosclerotic plaque VSMCs, OGG1 as a major 8oxoG repair enzyme in VSMCs, and p300/sirtuin 1 as major regulators of OGG1 through acetylation/deacetylation. Reducing oxidative damage by rescuing OGG1 activity reduces plaque development, indicating the detrimental effects of 8oxoG on VSMC function.
Corrigendum to“Effects of compatibility of deproteinized antler cancellous bone with various bioactive factors on their osteogenic potential” [Biomaterials 34 (2013) 9103-9114]
Authors: Xuehui Zhang, Mingming Xu, Lin Song, Yan Wei, Yuanhua Lin, Wentao Liu, Boon C. Heng, Hui Peng, Ying Wang, Xuliang Deng
Journal: Biomaterials (2018)
Private sector hospitals must improve safety, says CQC
Authors: Gareth Iacobucci
Journal: BMJ (2018)

Almost a third of private hospitals in England require improvements to the way they deliver care, and safety is the biggest area of concern, the Care Quality Commission (CQC) has found.

In a report summarising its inspections of 206 independent hospitals in England,1 the regulator said that most were providing good quality care for patients, with 62% rated as “good” and 8% “outstanding.” But it expressed concern at the wide variation around the country, as almost a third were rated as “requires improvement.”

The regulator said that safety was its greatest concern, as 41% of private hospitals were rated as “requires improvement” in this area …
Workforce planners need data on NHS usage, say royal colleges
Authors: Abi Rimmer
Journal: BMJ (2018)

A central source of data on the needs of patients and the availability of staff is vital for future workforce planning, eight royal colleges have said.

In December, Health Education England (HEE) published a draft 10 year workforce strategy.1 It was the first time that an NHS workforce plan looked more than five years ahead and could be key to the future of the service—peers warned in 2017 that poor workforce planning was …
29P Preliminary assessment of a targeted breakpoint NGS assay for ALK gene fusion detection in lung adenocarcinoma samples from Chilean patients
Authors: M. Freire, R. Lizana, L. Ramos, G. Sepúlveda, A. Blanco, S. Chernilo, O. Arén, C. Fernández, R. Armisén
Journal: Journal of Thoracic Oncology (2018)
Compliance with guideline-based empiric antimicrobial therapy for febrile neutropenia in adult Filipino patients and their effect on outcomes.
Authors: Frederic Ivan Leong Ting, Faith Yu Santos, Andrew Ibanez Mallen, Jeanette Jardinico Umali
Journal: Journal of Clinical Oncology (2018)

e18757 Background: Febrile neutropenia (FN) is a common complication of immunocompromised patients –whether due to infection, cancer, drug-induced, or other bone marrow failure states. With the incidence of patients with immunocompromised states on the rise, this life threatening complication is also increasing. The importance of initiating the appropriate empiric antibiotic therapy can prove to be lifesaving, thus we examined how the initial choice of antibiotics influenced patient outcomes. Objective: This study aimed to determine the effect of adherence to guideline-based antimicrobial therapy for adult febrile neutropenia patients in terms of patient outcomes. Design: Retrospective Cross-Sectional Analytical Study Methods: This is a 10-year cross-sectional analytical study which was conducted by doing a retrospective chart review involving adult patients with FN from 2007 to 2016. We determined use of guideline-based antibiotics, examined the factors that influenced adherence, and investigated the effect of initial treatment on patient outcome. Results: Among the 257 adult patients with FN included in the study, guideline-based antibiotics were administered to 65%. On multivariate analysis, the most powerful predictor of adherence to guideline-based antibiotics was the type of risk (p = 0.000), with high risk patients thrice more likely to be given guideline-based antibiotics. Other predictors were physician specialty (p = 0.036) and hematologic malignancy (p = 0.045). This study showed that among low risk patients with FN, a trend towards patient discharge was observed (OR 1.18, CI = 0.16 – 8.63). However overall, adherence to guideline-based empiric antibiotic in treating adult FN patients did not correlate to patient discharge (p = 0.134, OR 0.557, 95% CI = 0.260-1.205). Conclusions: In summary, our data suggest that adherence to guideline-based antibiotics in managing adult Filipino patients with febrile neutropenia does not correlate to better outcomes such as patient discharge. Significant factors associated with adherence to guideline-based antibiotics are physician specialty, hematologic malignancy, and type of risk.
Erratum: A mutation in the extracellular cysteine-rich repeat region of the β3 subunit activates integrins α(IIb)β3 and α(v)β3 (Blood (1999) 93:8 (2559-2568))
Authors: H. Kashiwagi, Y. Tomiyama, S. Tadokoro, S. Honda, M. Shiraga, H. Mizutani, M. Handa, Y. Kurata, Y. Matsuzawa, S. J. Shattil
Journal: Blood (1999)
Effect of ASXL1 on the stemness of colorectal cancer initiating cells.
Authors: Taichi Isobe, Mark A. Zarnegar, Omar Ibrahim Abdel-Wahab, Michael F. Clarke
Journal: Journal of Clinical Oncology (2018)

683 Background: Impaired cellular differentiation causes uncontrolled proliferation of stem cells and can be a cause of oncogenesis. The epigenome regulates the expression of genes that are essential for cellular differentiation. On the other hand, chromosomal abnormalities are common in colorectal cancer cells. We hypothesize that epigenetic disorders caused by chromosomal abnormalities may result in oncogenesis. Methods: The Cancer Genome Atlas (TCGA) database was investigated to identify epigenetic regulating genes affected by chromosomal abnormalities. Patient-derived colorectal cancer cells were obtained from consented patients to validate these findings. Results: The amplification of Chr20q11 is the most frequent chromosomal alteration in left-sided colonic and rectal cancers. ASXL1, a recruiter of PRC2, is coded in Chr20q11 and has upregulated expression in many cases. Excessive expression of ASXL1 may cause oncogenesis as PRC2 trimethylates histone H3 on lysine 27 (H3K27me3), an epigenetic mark of transcriptional silencing. Immunofluorescence revealed that the ASXL1 protein was located in the nuclei of colorectal cancer cells that did not express differentiation markers. This finding was consistent with the finding that ASXL1 highly expressed at the bottom of crypts where undifferentiated cells exist in normal colonic epithelium. Knockdown of ASXL1 in colorectal cancer cells reduced the levels of H3K27me3 and diminished organoid formation in vitro. Knockdown of ASXL1 in patient-derived cancer cells obtained from clinical specimens impaired the tumorigenicity of cancer initiating cells in vivo and increased the expression of differentiation markers. Murine colonic tumor cells from Apc Min mice highly expressed ASXL1, while homozygous Asxl 1 knockout reduced the occurrence of tumors in vivo. Many putative genes regulated by ASXL1 are identified by gene expression analysis and ChIP-sequencing. Conclusions: High expression of ASXL1 initiates oncogenesis and maintains the stemeness of colorectal cancer cells.
227P Stereotactic body radiotherapy with helical tomotherapy for lung tumors: A single-center experience
Authors: V. Figlia, F. Cuccia, V. Valenti, A. Tripoli, G. Terranova, A. Lo Casto, G. Failla, T. Cucchiara, G. Mortellaro, G. Ferrera
Journal: Journal of Thoracic Oncology (2018)
Abstract 10234: A Randomized Comparison of Sirolimus- versus Paclitaxel-Eluting Stent Implantation in Patients with Diabetes Mellitus: 4-Year Clinical Outcomes of DES-DIABETES Trial
Authors: Hyun-Sook Kim, Seung-Whan Lee, Seong-Wook Park, Young-Hak Kim, Duk-Woo Park, Cheol Whan Lee, Seung-Jung Park, Kyoung-Suk Rhee, Jae-Hwan Lee, June Hong Kim
Journal: Circulation (2010)

Objectives:  We compared 4-year efficacy and safety of sirolimus-eluting stent (SES) and paclitaxel-eluting stent (PES) in patients with diabetes mellitus (DM).   Background:  Four-year comparison of SES with PES in diabetic patients has not been evaluated in a randomized manner.   Methods:  This prospective, multicenter, randomized study compared SES (n=200) and PES (n=200) implantation in diabetic patients. We evaluated 4-year major adverse cardiac events (MACE) including death, myocardial infarction (MI), and target lesion revascularization (TLR).   Results:  The 2 groups had similar baseline characteristics. At 2 years, TLR (3.5% vs. 11.0%, HR: 0.30, 95% CI, 0.13 to 0.71, p=0.006) and MACE (3.5% vs. 12.5%, HR: 0.27, 95% CI, 0.11 to 0.61, p=0.002) were significantly lower in SES versus PES group with no difference of death or MI. At 4 years there were no differences in death (3.0% vs. 5.0%, p=0.445) or MI (1.5% vs. 1.0%, p=0.999) between SES and PES group. TLR (7.5% vs. 12.0%, HR: 0.54, 95% CI, 0.28 to 1.05, p=0.069) and MACE (11.0% vs. 16.0%, HR: 0.61, 95% CI, 0.35 to 1.05, p=0.076) were statistically not different between SES and PES group. At multivariate Cox regression, postprocedural minimal lumen diameter (MLD) were independent predictor of 4-year TLR (HR: 0.24, 95% CI, 0.10 to 0.55, p=0.0008) and MACE (HR: 0.38, 95% CI, 0.20 to 0.71, p=0.0027).   Conclusions:  Superiority of SES over PES during 2 years was attenuated between 2 year and 4 years in diabetic patients. Larger postprocedural MLD was independent predictor of the improved long-term clinical outcomes.
Effects of TTI-621 (SIRPαFc) on CD47 and serum cytokines associated with phagocytosis in subjects with relapsed, refractory hematologic malignancies: Pharmacodynamic findings from a first-in-human clinical trial.
Authors: Lisa Johnson, Raju K. Pillai, Rebecca L. King, Stephen Maxted Ansell, Robert W. Chen, Ian Flinn, Michael B. Maris, Meghan Irwin, Eric L. Sievers, Penka S. Petrova, Robert A. Uger
Journal: Journal of Clinical Oncology (2017)

112 Background: CD47 delivers an anti-phagocytic (“do not eat”) signal by binding SIRPα on macrophages and is overexpressed on many cancers enabling immune surveillance evasion. TTI-621 is a decoy receptor that promotes phagocytosis of tumors by blocking CD47 and engaging activating FcR on macrophages. A first-in-human, phase 1a, open label, multicenter study (NCT02663518) evaluating safety and tolerability of weekly, intravenous infusions of TTI-621 was conducted. As of October 12, 2016, 18 subjects were treated with TTI-621 with doses of 0.05-0.3 mg/kg. Multiple pharmacodynamic and hematologic assessments were performed to characterize the effects of TTI-621 and better understand the mechanism of action. Methods: Serial blood draws were analyzed for CD47 receptor occupancy (RO), complete blood counts, cytokines, T cell repertoire changes and CD47, SIRPα and FcR sequences. CD47 expression, macrophage and T cell infiltration was assessed on biopsies by IHC. Results: Peripheral CD47 levels varied considerably between subjects and were inversely correlated with RO. A maximum of 80% RO was achieved on peripheral leukocytes. Circulating monocytes, neutrophils, and lymphocytes were transiently decreased at the end of the TTI-621 infusion and generally returned to baseline levels by 24 to 72 hours. Platelet counts decreased immediately after TTI-621 infusions, typically recovering to baseline levels prior to the subsequent treatment cycle. Hemoglobin levels did not meaningfully change during treatment. Cytokines associated with macrophage activation or phagocytosis, notably MIP-1α, MIP-1β, TNF-α and IP-10 were elevated in a dose dependent manner. Conclusions: Systemic administration of TTI-621 leads to CD47 blockade and dose dependent increases in cytokines associated with phagocytosis, temporally associated with reversible thrombocytopenia, suggesting enhanced macrophage mediated clearance of circulating platelets followed by a robust marrow regenerative response. Enrollment into multiple expansion cohorts addressing a wide range of hematopoietic cancers is ongoing. Clinical trial information: NCT02663518.
Early experience with delamanid-containing regimens in the treatment of complicated multidrug-resistant tuberculosis in Hong Kong
Authors: Kwok-Chiu Chang, Eric Chung-Ching Leung, Wing-Sze Law, Wai-Man Leung, Lai-Bun Tai, Shuk-Nor Lee, Fai-Man Lam, Chi-Hung Chau, Thomas Yun-Wing Mok, Wing-Wai Yew, Chi-Chiu Leung
Journal: European Respiratory Journal (2018)

Hong Kong is an intermediate tuberculosis (TB) burden region with a disease notification rate of 60.5 per 100 000 population in 2015. With the use of supervised treatment since 1970s and the use of drug susceptibility testing (DST) for guiding use of TB drugs for several decades [1], TB drug resistance rates in Hong Kong have declined and the multidrug-resistant (MDR)-TB rate has been kept at ∼1%. Successful control of MDR-TB was partly attributable to judicious use of ofloxacin and later levofloxacin in the 1990s [2, 3], the introduction of linezolid in the 2000s [4] among patients with fluoroquinolone-resistant MDR-TB or extensively drug-resistant (XDR)-TB, with intermittent dosing to enable its prolonged use [5], and selective use of delamanid among patients with complicated MDR-TB since 2012. To echo our support for using delamanid in the treatment of MDR-TB [6, 7], we would like to report our early experience in Hong Kong regarding the use of delamanid-containing regimens among patients with pre-XDR-TB (MDR-TB with bacillary resistance to either fluoroquinolone or second-line injectable agents) or XDR-TB. It is probably safe to give delamanid beyond 6 months, with once-daily dosing after the first 1–2 months <http://ow.ly/zoCv30jyCj0>
Resection of pancreatic cancer following induction chemotherapy.
Authors: Walid Labib Shaib, Layal Sayegh, Olatunji Alese, Shishir Maithel, Kenneth Cardona, Juan Sarmiento, Astrid Belalcazar, Andrew Ip, Yuesheng Qu, Mehmet Akce, Chao Zhang, Christina Sing-Ying Wu, Zhengjia Chen, Bassel F. El-Rayes
Journal: Journal of Clinical Oncology (2018)

406 Background: Survival of resectable pancreas cancer (RPC) treated with resection and adjuvant therapy is 22-28 months (mo). Locally advanced unresectable pancreatic cancer (LAPC) treated with combination chemotherapy have a median survival of 24 mo. The objective of this project is to evaluate the effect of neoadjuvant treatment on survival outcome of localized PC. Methods: Charts of localized PC patients treated at Emory University from 2009 to 2016 were reviewed. Information on demographics, stage and treatment was collected. Survival rates were estimated by Kaplan-Meier method and compared with log-rank test. A Cox proportional hazard model was fitted to estimate the adjusted effect of treatment on overall survival(OS). Results: A total of 415 patients were included; 144 RPC, 158 borderline resectable (BRPC) and 108 LAPC. Stage was determined at the multidisciplinary conference. The median age was 67.7 years (30-92); 49% male, and 63% Caucasians. The median OS for RPC, BRPC, and LAPC was 16.9, 14.6 and 10.9 mo, respectively. Stage, type of chemotherapy and age were significant predictors of OS after adjusting for gender, race, age, surgery, stage, chemotherapy, margins and radiation. Of the 144 RPC, 137 underwent surgery and 3 received neoadjuvant treatment; 73 RPC were followed in outside facility with missing follow up data. Of the 71 RPC treated at Emory; 91% received adjuvant gemcitabine. Of the 158 BRPC, 84 underwent surgery; 44 received FOLFIRINOX neoadjuvant therapy, 23 received gemcitabine/nab-paclitaxel, and 16 received gemcitabine single agent. BRPC patients who underwent resection had a median OS of 18.5 mo (95%CI: 14.2, 26.4), significantly longer than RPC (P = 0.044). Combination chemotherapy was significantly associated with improved OS at 36 mo (38.9%) when compared to single agent gemcitabine (6.3% at 36 mo) (p = 0.009). BRPC patients who received FOLFORINOX and surgery had a median OS of 31.5 mo. Conclusions: Overall survival of BRPC patients who undergo resection after FOLFIRINOX is significantly improved (more than doubled) compared to upfront resection for RPC. Preoperative therapy provides the best approach for systemic disease early in the course of treatment.
53P Lung cancer: Beyond EGFR and ALK dichotomy
Authors: C.T. Satheesh, A.D. Bhatt, M. Singhal, R. Aarthi, K. Shubham, G. Madhura, V. Maka, R. Naik, S. Iyer, G. Shafi
Journal: Journal of Thoracic Oncology (2018)
84P Patterns of care for patients with small cell lung cancer: A survey of German radiation oncology institutions on recommendations for prophylactic cranial irradiation
Authors: C. Eze, O. Roengvoraphoj, M. Dantes, R. Abdo, N-S. Schmidt-Hegemann, C. Belka, F. Manapov
Journal: Journal of Thoracic Oncology (2018)
144PD Leptomeningeal metastases in EGFR-mutated non-small cell lung carcinoma: Management after tyrosine kinase inhibitors
Authors: R. Flippot, E. Auclin, P. Biondani, E. Le Rhun, D. Planchard, C. Caramella, C. Le Pechoux, L. Lacroix, L. Mezquita, B. Besse
Journal: Journal of Thoracic Oncology (2018)
The Importance of Body Composition in Explaining the Overweight Paradox in Cancer—Counterpoint
Authors: Bette J. Caan, Elizabeth M. Cespedes Feliciano, Candyce H. Kroenke
Journal: Cancer Research (2018)

Abstract Despite a greater risk of cancer associated with higher BMI, overweight (BMI 25–&amp;lt;30 kg/m2) and class I obese (BMI 30–&amp;lt;35 kg/m2) patients often have a paradoxically lower risk of overall mortality after a cancer diagnosis, a phenomenon called the “obesity paradox.” Only when patients exceed a BMI ≥35 kg/m2 are elevations in mortality risk consistently noted. This paradox has been dismissed as the result of methodologic bias, which we will describe and debate here. However, even if such bias influences associations, there is growing evidence that body composition may in part explain the paradox. This phenomenon may more accurately be described as a BMI paradox. That is, BMI is a poor proxy for adiposity and does not distinguish muscle from adipose tissue, nor describe adipose tissue distribution. Low muscle mass is associated with higher risk of recurrence, overall and cancer-specific mortality, surgical complications, and treatment-related toxicities. Patients with who are overweight or obese have on average higher levels of muscle than their normal-weight counterparts. Also, there is some evidence that patients with moderate levels of subcutaneous adipose tissue may have lower mortality. More research utilizing body composition is needed to clarify the effects of adiposity on cancer mortality. Cancer Res; 78(8); 1906–12. ©2018 AACR.