tbuckley/cabot-search huggingface dataset:
Doxorubicin-loaded bacterial outer-membrane vesicles exert enhanced anti-tumor efficacy in non-small-cell lung cancer
Authors: Kudelaidi Kuerban, Xiwen Gao, Hui Zhang, Jiayang Liu, Mengxue Dong, Lina Wu, Ruihong Ye, Meiqing Feng, Li Ye
Journal: Acta Pharmaceutica Sinica B (2020)

More efficient drug delivery system and formulation with less adverse effects are needed for the clinical application of broad-spectrum antineoplastic agent doxorubicin (DOX). Here we obtained outer-membrane vesicles (OMVs), a nano-sized proteoliposomes naturally released by Gram-negative bacteria, from attenuated Klebsiella pneumonia and prepared doxorubicin-loaded O0MVs (DOX-OMV). Confocal microscopy and in vivo distribution study observed that DOX encapsulated in OMVs was efficiently transported into NSCLC A549 cells. DOX-OMV resulted in intensive cytotoxic effects and cell apoptosis in vitro as evident from MTT assay, Western blotting and flow cytometry due to the rapid cellular uptake of DOX. In A549 tumor-bearing BALB/c nude mice, DOX-OMV presented a substantial tumor growth inhibition with favorable tolerability and pharmacokinetic profile, and TUNEL assay and H&E staining displayed extensive apoptotic cells and necrosis in tumor tissues. More importantly, OMVs' appropriate immunogenicity enabled the recruitment of macrophages in tumor microenvironment which might synergize with their cargo DOX in vivo. Our results suggest that OMVs can not only function as biological nanocarriers for chemotherapeutic agents but also elicit suitable immune responses, thus having a great potential for the tumor chemoimmunotherapy.
Identifying IGH disease clones for MRD monitoring in childhood B-cell acute lymphoblastic leukemia using RNA-Seq
Authors: Zhenhua Li, Nan Jiang, Evelyn Huizi Lim, Winnie Hui Ni Chin, Yi Lu, Kean Hui Chiew, Shirley Kow Yin Kham, Wentao Yang, Thuan Chong Quah, Hai Peng Lin, Ah Moy Tan, Hany Ariffin, Jun J. Yang, Allen Eng-Juh Yeoh
Journal: Leukemia (2020)
Abstract 194: Frequency of Mononuclear Diploid Cardiomyocytes Underlies Natural Variation in Heart Regeneration
Authors: Michaela Patterson, Henry Sucov
Journal: Circulation Research (2017)

Strong evidence from the literature supports the model that mononuclear, diploid cardiomyocytes (MNDCMs), a relatively rare population in the adult mammalian heart, are a regeneration-competent population, but this has not previously been subjected to experimental analysis. This project explores the hypothesis that the frequency of MNDCMs in the adult mammalian heart and regenerative potential are two interlinked, variable traits determined by multiple genetic parameters. If so, different individuals will have varying capacity to undergo heart regeneration following injury based on their unique genetic backgrounds. By surveying 120 inbred mouse strains, we found that the percentage of mononuclear cardiomyocytes in the adult mouse heart is a polygenic trait that is surprisingly variable (2.3%-17.0%). We confirmed experimentally that the degree of functional recovery and cardiomyocyte proliferation after permanent coronary artery ligation correlates with MNDCM content. Using genome-wide association, we identify Tnni3k as one gene with natural alleles that influence variation in this composition, and show in an isogenic strain background that Tnni3k knockout results in elevated MNDCM content and elevated cardiomyocyte proliferation after injury. Reciprocal to mammals, zebrafish are known to retain an almost pure MNDCM population through adulthood and are able to efficiently regenerate after adult heart injury. Here, we show that overexpression of Tnni3k in zebrafish promotes cardiomyocyte polyploidization and compromises heart regeneration, indicating a commonality in the regenerative process between the two species. Our results provide support for the requirement of the resident mononuclear diploid subpopulation of cardiomyocytes in heart regeneration. Moreover, our results imply that intrinsic heart regeneration is not uniform and limited in all individuals, but rather is a variable trait subject to the influence of multiple genes.
Mitochondrial DNA Haplogroups and Susceptibility to Neuroblastoma
Authors: Xiao Chang, Marina Bakay, Yichuan Liu, Joseph Glessner, Komal S Rathi, Cuiping Hou, Huiqi Qu, Zalman Vaksman, Kenny Nguyen, Patrick M A Sleiman, Sharon J Diskin, John M Maris, Hakon Hakonarson
Journal: JNCI Journal of the National Cancer Institute (2020)

Neuroblastoma is a childhood malignancy that arises from the developing sympathetic nervous system. Although mitochondrial dysfunctions have been implicated in the pathophysiology of neuroblastoma, the role of mitochondrial DNA (mtDNA) has not been extensively investigated.A total of 2404 Caucasian children diagnosed with neuroblastoma and 9310 ancestry-matched controls were recruited at the Children's Hospital of Philadelphia. The mtDNA haplogroups were identified from SNP array data of two independent cohorts. We conducted a case-control study to explore potential associations of mtDNA haplogroups with the susceptibility of neuroblastoma. The genetic effect of neuroblastoma was measured by odds ratios (ORs) of mitochondrial haplogroups. All tests were two-sided.Haplogroup K was statistically significantly associated with reduced risk of neuroblastoma in the discovery cohort consisting of 1474 cases and 5699 controls (OR = 0.72, 95% confidence interval [CI] = 0.57 to 0.90; P = 4.8 × 10-3). The association was replicated in an independent cohort (OR = 0.69, 95% CI = 0.53 to 0.92; P = .01) of 930 cases and 3611 controls. Pooled analysis was performed by combining the two data sets. The association remained highly statistically significant after correction for multiple testing (OR = 0.71, 95% CI = 0.59 to 0.84, P = 1.96 × 10-4, Pcorrected = .002). Further analysis focusing on neuroblastoma subtypes indicated haplogroup K was more associated with high-risk neuroblastoma (OR = 0.57, 95% CI = 0.43 to 0.76; P = 1.46 × 10-4) than low-risk and intermediate-risk neuroblastoma.Haplogroup K is an independent genetic factor associated with reduced risk of developing neuroblastoma in European descents. These findings provide new insights into the genetic basis of neuroblastoma, implicating mitochondrial DNA encoded proteins in the etiology of neuroblastoma.
Maternal and fetal outcomes following exposure to duloxetine in pregnancy: cohort study
Authors: Krista F Huybrechts, Brian T Bateman, Ajinkya Pawar, Lily G Bessette, Helen Mogun, Raisa Levin, Hu Li, Stephen Motsko, Maria Fernanda Scantamburlo Fernandes, Himanshu P Upadhyaya, Sonia Hernandez-Diaz
Journal: BMJ (2020)

Abstract Objective To evaluate the risk of adverse maternal and infant outcomes following in utero exposure to duloxetine. Design Cohort study nested in the Medicaid Analytic eXtract for 2004-13. Setting Publicly insured pregnancies in the United States. Participants Pregnant women 18 to 55 years of age and their liveborn infants. Interventions Duloxetine exposure during the etiologically relevant time window, compared with no exposure to duloxetine, exposure to selective serotonin reuptake inhibitors, exposure to venlafaxine, and exposure to duloxetine before but not during pregnancy. Main outcome measures Congenital malformations overall, cardiac malformations, preterm birth, small for gestational age infant, pre-eclampsia, and postpartum hemorrhage. Results Cohort sizes ranged from 1.3 to 4.1 million, depending on the outcome. The number of women exposed to duloxetine varied by cohort and exposure contrast and was around 2500-3000 for early pregnancy exposure and 900-950 for late pregnancy exposure. The base risk per 1000 unexposed women was 36.6 (95% confidence interval 36.3 to 36.9) for congenital malformations overall, 13.7 (13.5 to 13.9) for cardiovascular malformations, 107.8 (107.3 to 108.3) for preterm birth, 20.4 (20.1 to 20.6) for small for gestational age infant, 33.6 (33.3 to 33.9) for pre-eclampsia, and 23.3 (23.1 to 23.4) for postpartum hemorrhage. After adjustment for measured potential confounding variables, all baseline characteristics were well balanced for all exposure contrasts. In propensity score adjusted analyses versus unexposed pregnancies, the relative risk was 1.11 (95% confidence interval 0.93 to 1.33) for congenital malformations overall and 1.29 (0.99 to 1.68) for cardiovascular malformations. For preterm birth, the relative risk was 1.01 (0.92 to 1.10) for early exposure and 1.19 (1.04 to 1.37) for late exposure. For small for gestational age infants the relative risks were 1.14 (0.92 to 1.41) and 1.20 (0.83 to 1.72) for early and late pregnancy exposure, respectively, and for pre-eclampsia they were 1.12 (0.96 to 1.31) and 1.04 (0.80 to 1.35). The relative risk for postpartum hemorrhage was 1.53 (1.08 to 2.18). Results from sensitivity analyses were generally consistent with the findings from the main analyses. Conclusions On the basis of the evidence available to date, duloxetine is unlikely to be a major teratogen but may be associated with an increased risk of postpartum hemorrhage and a small increased risk of cardiac malformations. While continuing to monitor the safety of duloxetine as data accumulate over time, these potential small increases in risk of relatively uncommon outcomes must be weighed against the benefits of treating depression and pain during pregnancy in a given patient. Trial registration EUPAS 15946.
Hypokalemia Promotes Arrhythmia by Distinct Mechanisms in Atrial and Ventricular Myocytes
Authors: Kiarash Tazmini, Michael Frisk, Alexandre Lewalle, Martin Laasmaa, Stefano Morotti, David B. Lipsett, Ornella Manfra, Jonas Skogestad, Jan M. Aronsen, Ole M. Sejersted, Ivar Sjaastad, Andrew G. Edwards, Eleonora Grandi, Steven A. Niederer, Erik Øie, William E. Louch
Journal: Circulation Research (2020)

Hypokalemia occurs in up to 20% of hospitalized patients and is associated with increased incidence of ventricular and atrial fibrillation. It is unclear whether these differing types of arrhythmia result from direct and perhaps distinct effects of hypokalemia on cardiomyocytes.To investigate proarrhythmic mechanisms of hypokalemia in ventricular and atrial myocytes.Experiments were performed in isolated rat myocytes exposed to simulated hypokalemia conditions (reduction of extracellular [K+] from 5.0 to 2.7 mmol/L) and supported by mathematical modeling studies. Ventricular cells subjected to hypokalemia exhibited Ca2+ overload and increased generation of both spontaneous Ca2+ waves and delayed afterdepolarizations. However, similar Ca2+-dependent spontaneous activity during hypokalemia was only observed in a minority of atrial cells that were observed to contain t-tubules. This effect was attributed to close functional pairing of the Na+-K+ ATPase and Na+-Ca2+ exchanger proteins within these structures, as reduction in Na+ pump activity locally inhibited Ca2+ extrusion. Ventricular myocytes and tubulated atrial myocytes additionally exhibited early afterdepolarizations during hypokalemia, associated with Ca2+ overload. However, early afterdepolarizations also occurred in untubulated atrial cells, despite Ca2+ quiescence. These phase-3 early afterdepolarizations were rather linked to reactivation of nonequilibrium Na+ current, as they were rapidly blocked by tetrodotoxin. Na+ current-driven early afterdepolarizations in untubulated atrial cells were enabled by membrane hyperpolarization during hypokalemia and short action potential configurations. Brief action potentials were in turn maintained by ultra-rapid K+ current (IKur); a current which was found to be absent in tubulated atrial myocytes and ventricular myocytes.Distinct mechanisms underlie hypokalemia-induced arrhythmia in the ventricle and atrium but also vary between atrial myocytes depending on subcellular structure and electrophysiology.
Airway Microbes modulate Allergic Airway Inflammation through Secreted Leukocyte Proteinase Inhibitor
Authors: Natalia Jaeger, Ryan McDonough, Ariel Hernandez-Leyva, Anne Rosen, Naomi Wilson, Emilie Russler-Germain, Jiani Chai, Leonard Bacharier, Chyi-Song Hsieh
Journal: Journal of Allergy and Clinical Immunology (2020)
Improving detection of higher-risk or locally advanced disease features in stage I and II renal cell carcinoma.
Authors: Nathan Miller, Ithaar Derweesh, Michael Y. Liu, Aaron Bradshaw, Raksha Dutt, Cathrine Keiner, Margaret Frances Meagher, Fady Ghali, Devin Patel, Fang Wan, Masoud Shiehmorteza
Journal: Journal of Clinical Oncology (2020)

625 Background: Pathologically upstaged T3a renal cell carcinoma (RCC) carries higher oncologic risk than corresponding preoperative clinical stage and presents unique risks from a treatment planning standpoint due to reduced clinician awareness of locally aggressive disease. We sought to identify imaging criteria that predict risk of pathological upstaging of clinical T1 and T2 RCC to T3a and to assess accuracy of CT in detecting T3a RCC. Methods: Single institution retrospective analysis of patients who underwent surgery for RCC. A propensity-score matching process was used to match upstaged patients with non-upstaged (control) patients in a 1:2 fashion. Preoperative CT images were reviewed in a blinded fashion by 2 radiologists for presence of T3a stage imaging criteria. Multivariable analyses assessed risk conferred by imaging features and sensitivity analysis assessed accuracy in detecting T3a RCC. Results: After exclusions, 231 patients were analyzed (mean age 61 years, upstaged 83/control 148, mean tumor size 6.4 cm). In 71/83 (86%) of upstaged tumors, the presence of sinus fat invasion (SFI), perinephric fat invasion (PFI), or venous invasion (VI) was found. The presence of all three was not observed in any non-upstaged tumor. The following features were associated with upstaging: tumor necrosis (OR 2.1, p=0.017), irregular tumor edge (OR 2.9, p&lt;0.001), thickened perirenal fascia (OR 2.6, p=0.001), perinephric stranding (OR 1.8, p=0.043), increased perinephric vascularity (OR 2.02, p=0.021), and perinephric nodules (OR 3.4, p=0.020). The SE/SP for tumor necrosis, irregular tumor edge, thickened perirenal fascia, perinephric stranding, increased perinephric vascularity, and perinephric nodules were 42%/74%, 74%/50%, 48%/74%, 70%/44%, 70%/46%, and 13%/96%, respectively. Conclusions: Upstaged T3a RCC contained several preoperative imaging attributes which were 2-3 times more likely to be present than in non-upstaged tumors. Of these, irregular tumor edge had highest sensitivity, and perinephric nodules had highest specificity. These features should elevate clinical suspicion for T3a disease and may be used to develop a novel risk scoring system. Further investigation is requisite.
Surgical learning curve for robotic multiplex partial nephrectomy: The National Cancer Institute Experience.
Authors: Siobhan Telfer, Sandeep Gurram, Patrick H. Gomella, Winston Li, Gennady Bratslavsky, Adam R. Metwalli, W. Marston Linehan, Mark Wayne Ball
Journal: Journal of Clinical Oncology (2020)

660 Background: Multiplex partial nephrectomy (MPN) remains the standard of care for hereditary and bilateral kidney tumors. Our institution is an international referral center for the management of hereditary renal cell carcinoma, and therefore has considerable experience with MPN. The objective of this study was to evaluate surgical learning curve for MPN among multiple surgeons at a single institution over an 11-year period. Methods: Retrospective review of a prospectively maintained registry of patients who underwent MPN from 2007-present. The first 100 consecutive surgeries of 3 NIH fellowship trained Urologic Oncologists were identified and evaluated in quartiles. Surgical outcome measures including operative duration (OD), estimated blood loss (EBL), number of tumors resected, and complication rate were chosen as surrogate markers of learning curve. Differences in individual surgeon outcomes were evaluated and variables including re-do surgery and surgical approach were considered. Significant differences found among quartiles or among surgeon were evaluated with multivariate logistic regression analysis. Results: A total of 300 MPN's were identified. In the quartile analysis, there were no significant differences in OD, EBL, numbers of tumors resected or rates of complication. Among surgeon factors, there were differences in surgical approach and EBL (table). In a multivariate analysis of factors associated with EBL, open approach (95%CI 245-831), p &lt; 0.0001) and number of tumors (95%CI 43-82), p &lt; 0.0001) were independently associated. No factors were associated increased rate of complication. Conclusions: As surgeons progressed through their first 100 operations, no true learning curve was appreciated, with similar outcomes in each quartile. Among surgeon factors, open surgical approach appears to drive difference in EBL.[Table: see text]
Health care team and treatment decision-making experiences among prostate cancer patients.
Authors: Nicole E. Nicksic, Melissa F. Miller, Kelly Clark, Alexandra Katherine Zaleta
Journal: Journal of Clinical Oncology (2020)

57 Background: Treatment by a multidisciplinary healthcare team can improve patient outcomes, but not all prostate cancer (PC) patients may access multiple providers. This study explored whether differences in healthcare team at treatment were associated with PC treatment type and decision-making. Methods: Of 311 PC patients enrolled in the Cancer Support Community’s Cancer Experience Registry online, 160 (32% ever metastatic, 28% had recurrence, median 3 years since diagnosis) indicated which specialists comprised their healthcare team during treatment (urologist versus a specialist team including 2-5 doctors, 70% of which included urologists). We examined PC treatment decision-making using chi-square tests, independent sample t-tests, and linear regression. Results: The majority were not experiencing symptoms of PC at diagnosis (69%); 58% were diagnosed after a routine check-up. More PC patients with advanced disease at diagnosis had a team of specialists, whereas those diagnosed at stages 1 or 2 typically only saw a urologist ( p&lt;0.01). Most first received care at a private urology practice (44%) compared to 27% for current treatment. Treatment discussions varied by treatment for urologist-only (28%) versus a team of specialists (72%): chemotherapy (16% vs 36%, p=.01), surgery (89% vs 65%, p&lt;.01), radiation (82% vs 80%, p=.75), hormones (36% vs 75%, p&lt;.001), and active surveillance (51% vs 23%, p&lt;.001). More patients who had seen only a urologist had surgery (95% vs 43%, p&lt;.001); those seeing a specialty team tended to undergo other treatments, such as chemotherapy (4% vs 30%, p=.001), radiation (12% vs 83%, p&lt;.001), and hormones (27% vs 77%, p&lt;.001). After controlling for stage at diagnosis, those treated only by a urologist had lower treatment regret ( β=0.22, p&lt;.01). Conclusions: Advanced PC patients more often treated by a specialist team and discuss different treatment options vs. those followed by a urologist only. While effects were small, care provider type was associated with treatment regret and confidence. Healthcare teams could improve the patient experience by increasing communication surrounding navigating myriad treatment options. Clinical trial information: NCT02333604.
DNA-methylation-mediated activating of lncRNA SNHG12 promotes temozolomide resistance in glioblastoma
Authors: Chenfei Lu, Yutian Wei, Xiefeng Wang, Zhuoran Zhang, Jianxing Yin, Wentao Li, Lijiu Chen, Xiao Lyu, Zhumei Shi, Wei Yan, Yongping You
Journal: Molecular Cancer (2020)

Abstract Background Accumulating evidence shows that long noncoding RNAs (lncRNAs) are important regulator molecules involved in diverse biological processes. Acquired drug resistance is a major challenge in the clinical treatment of glioblastoma (GBM), and lncRNAs have been shown to play a role in chemotherapy resistance. However, the underlying mechanisms by which lncRNA mediates TMZ resistance in GBM remain poorly characterized. Methods Quantitative reverse transcription PCR (qRT-PCR) and fluorescence in situ hybridization assays were used to detect small nucleolar RNA host gene 12 (SNHG12) levels in TMZ-sensitive and TMZ-resistant GBM cells and tissues. The effects of SNHG12 on TMZ resistance were investigated through in vitro assays (western blots, colony formation assays, flow cytometry assays, and TUNEL assays). The mechanism mediating the high expression of SNHG12 in TMZ-resistant cells and its relationships with miR-129-5p, mitogen-activated protein kinase 1 (MAPK1), and E2F transcription factor 7 (E2F7) were determined by bioinformatic analysis, bisulfite amplicon sequencing, methylation-specific PCR, dual luciferase reporter assays, chromatin immunoprecipitation assays, RNA immunoprecipitation assays, immunofluorescence, qRT-PCR, and western blot. For in vivo experiments, an intracranial xenograft tumor mouse model was used to investigate SNHG12 function. Results SNHG12 was upregulated in TMZ-resistant cells and tissues. Overexpression of SNHG12 led to the development of acquired TMZ resistance, while knockdown of SNHG12 restored TMZ sensitivity. An abnormally low level of DNA methylation was detected within the promoter region of SNHG12, and loss of DNA methylation made this region more accessible to the Sp1 transcription factor (SP1); this indicated that methylation and SP1 work together to regulate SNHG12 expression. In the cytoplasm, SNHG12 served as a sponge for miR-129-5p, leading to upregulation of MAPK1 and E2F7 and endowing the GBM cells with TMZ resistance. Disinhibition of MAPK1 regulated TMZ-induced cell apoptosis and the G1/S cell cycle transition by activating the MAPK/ERK pathway, while E2F7 dysregulation was primarily associated with G1/S cell cycle transition. Clinically, SNHG12 overexpression was associated with poor survival of GBM patients undergoing TMZ treatment. Conclusion Our results suggest that SNHG12 could serve as a promising therapeutic target to surmount TMZ resistance, thereby improving the clinical efficacy of TMZ chemotherapy.
Abstract 12593: Impact of Intraoperative Methylprednisolone on Neurodevelopmental Outcomes in Neonates Undergoing Cardiac Surgery
Authors: Sinai C Zyblewski, Renee H Martin, Virginia B Shipes, Kasey Hamlin-Smith, Andrew M Atz, Scott M Bradley, Minoo N Kavarana, William T Mahle, Allen D Everett, Eric M Graham
Journal: Circulation (2019)

Introduction: Neurodevelopmental impairment is the most significant consequence for survivors of critical congenital heart disease. This study sought to determine if intraoperative methylprednisolo...
Twenty miles per hour speed zones reduce the danger to pedestrians and cyclists
Authors: Rob Cook, Peter Davidson, Rosie Martin
Journal: BMJ (2020)

The study Cleland LC, McComb L, Kee F, et al. Effects of 20 mph interventions on a range of public health outcomes: a meta-narrative evidence synthesis. J Transp Health 2019. doi: 10.1016/j.jth.2019.100633 . This project was funded by the NIHR Policy Research Programme (project number 17/149/19). To read the full NIHR Signal, go to: https://discover.dc.nihr.ac.uk/content/signal-000853/twenty-mph-speed-zones-reduce-the-danger-to-pedestrians-and-cyclists