tbuckley/cabot-search huggingface dataset:
3D bioactive composite scaffolds for bone tissue engineering
Authors: Gareth Turnbull, Jon Clarke, Frédéric Picard, Philip Riches, Luanluan Jia, Fengxuan Han, Bin Li, Wenmiao Shu
Journal: Bioactive Materials (2017)

Bone is the second most commonly transplanted tissue worldwide, with over four million operations using bone grafts or bone substitute materials annually to treat bone defects. However, significant limitations affect current treatment options and clinical demand for bone grafts continues to rise due to conditions such as trauma, cancer, infection and arthritis. Developing bioactive three-dimensional (3D) scaffolds to support bone regeneration has therefore become a key area of focus within bone tissue engineering (BTE). A variety of materials and manufacturing methods including 3D printing have been used to create novel alternatives to traditional bone grafts. However, individual groups of materials including polymers, ceramics and hydrogels have been unable to fully replicate the properties of bone when used alone. Favourable material properties can be combined and bioactivity improved when groups of materials are used together in composite 3D scaffolds. This review will therefore consider the ideal properties of bioactive composite 3D scaffolds and examine recent use of polymers, hydrogels, metals, ceramics and bio-glasses in BTE. Scaffold fabrication methodology, mechanical performance, biocompatibility, bioactivity, and potential clinical translations will be discussed.
CRISPR-Cas9 screen reveals a MYCN-amplified neuroblastoma dependency on EZH2
Authors: Liying Chen, Gabriela Alexe, Neekesh V. Dharia, Linda Ross, Amanda Balboni Iniguez, Amy Saur Conway, Emily Jue Wang, Veronica Veschi, Norris Lam, Jun Qi, W. Clay Gustafson, Nicole Nasholm, Francisca Vazquez, Barbara A. Weir, Glenn S. Cowley, Levi D. Ali, Sasha Pantel, Guozhi Jiang, William F. Harrington, Yenarae Lee, Amy Goodale, Rakela Lubonja, John M. Krill-Burger, Robin M. Meyers, Aviad Tsherniak, David E. Root, James E. Bradner, Todd R. Golub, Charles W.M. Roberts, William C. Hahn, William A. Weiss, Carol J. Thiele, Kimberly Stegmaier
Journal: Journal of Clinical Investigation (2017)

Pharmacologically difficult targets, such as MYC transcription factors, represent a major challenge in cancer therapy. For the childhood cancer neuroblastoma, amplification of the oncogene MYCN is associated with high-risk disease and poor prognosis. Here, we deployed genome-scale CRISPR-Cas9 screening of MYCN-amplified neuroblastoma and found a preferential dependency on genes encoding the polycomb repressive complex 2 (PRC2) components EZH2, EED, and SUZ12. Genetic and pharmacological suppression of EZH2 inhibited neuroblastoma growth in vitro and in vivo. Moreover, compared with neuroblastomas without MYCN amplification, MYCN-amplified neuroblastomas expressed higher levels of EZH2. ChIP analysis showed that MYCN binds at the EZH2 promoter, thereby directly driving expression. Transcriptomic and epigenetic analysis, as well as genetic rescue experiments, revealed that EZH2 represses neuronal differentiation in neuroblastoma in a PRC2-dependent manner. Moreover, MYCN-amplified and high-risk primary tumors from patients with neuroblastoma exhibited strong repression of EZH2-regulated genes. Additionally, overexpression of IGFBP3, a direct EZH2 target, suppressed neuroblastoma growth in vitro and in vivo. We further observed strong synergy between histone deacetylase inhibitors and EZH2 inhibitors. Together, these observations demonstrate that MYCN upregulates EZH2, leading to inactivation of a tumor suppressor program in neuroblastoma, and support testing EZH2 inhibitors in patients with MYCN-amplified neuroblastoma.
Cystic Fibrosis Transmembrane Conductance Regulator Attaches Tumor Suppressor PTEN to the Membrane and Promotes Anti Pseudomonas aeruginosa Immunity
Authors: Sebastián A. Riquelme, Benjamin D. Hopkins, Andrew L. Wolfe, Emily DiMango, Kipyegon Kitur, Ramon Parsons, Alice Prince
Journal: Immunity (2017)
Cancer therapy using self-assembled core-shell nano-particles containing both anti cancer drug and pro-apoptotic Bax gene.
Authors: Jeong-Hee Kim, Woo-Chan Hyung, Yong-Min Huh, Seung-Joo Haam, Kun-Hong Kim
Journal: Cancer Research (2007)

1414  Due to recent developments in drug delivery system (DDS), cancer drugs, DNA, and/or protein can be delivered to cancer cells efficiently and selectively at the same time. Doxorubicin (DOX) is an anthracycline drug commonly used in cancer chemotherapy, but the dosage of the drug is restricted by its cardiotoxicity and also many cancer cells developed a resistance toward the drug. To overcome or circumvent these problems, we produced self-assembled core-shell nano-particles composed of PLGA [poly (D, L-lactide-co-glycolide)] and PEI (Polyethylenimine). Then, the particles were conjugated with low dose of doxorubicin, pro-apoptotic bax gene, of which expression is regulated by human telomerase reverse transcriptase (hTERT) promoter that are active only in cancer cells, and folic acid for enhancing its specific intracellular delivery to folate receptor overexpressing cancer cells. Bax is a pro-apoptotic gene that activates intrinsic apoptosis pathway. We used HeLa, a human cervical cancer cell line that express moderate level of folate receptor and has high telomerase activity, and used A549, a human lung adenocarcinoma cell line that express low level of receptor and high telomerase activity. When the cells were treated with the nanoparticles conjugated with folate and GFP expressing construct, A549 cells did not show any GFP signal, but HeLa cells showed green fluorescence in approximately 80% of the cells at N/P ratio=16. When we compared the cancer cell killing effect of nanoparticles that are either conjugated with bax gene, folic acid, or doxorubicin alone or conjugated with all of them, HeLa cells were more efficiently killed by all-in-one nanoparticles than by one-in-one. However a little effect was observed when we performed the same experiment with A549 cells.  Taken together, we documented that the core-shell nanoparticles composed of PLGA and PEI are effective for multi-functional drug delivery system and can be used as a powerful tool for cancer therapy. This work was supported by KOSEF through National Core Research Center for Nanomedical Technology (R15-2004-024-00000-0).
Response by Towbin and Jefferies to Letter Regarding Article, “Cardiomyopathies Due to Left Ventricular Noncompaction, Mitochondrial and Storage Diseases, and Inborn Errors of Metabolism”
Authors: Jeffrey A. Towbin, John Lynn Jefferies
Journal: Circulation Research (2017)

Left Ventricular Noncompaction, Mitochondrial and Storage Diseases, and Inborn Errors of Metabolism" notes that although the article describes a significant list of mitochondrial disorders associated with left ventricular noncompaction that there is a longer list of associated mitochondrial disorders. 1Although this may be true, that data are generally weak and the purpose of any review is to be as complete as is reasonable.Therefore, his points are noted, mitochondrial disease is associated with noncompaction and is heterogeneous.
Fate of PEGylated antibody fragments following delivery to the lungs: Influence of delivery site, PEG size and lung inflammation
Authors: Harshad P. Patil, Danielle Freches, Linda Karmani, Gregg A. Duncan, Bernard Ucakar, Jung Soo Suk, Justin Hanes, Bernard Gallez, Rita Vanbever
Journal: Journal of Controlled Release (2017)
La acción de Europa frente a la resistencia antimicrobiana
Authors: M J Struelens
Journal: Eurosurveillance (2004)

En este numero, Wolfgang Witte y sus colegas describen la emergencia en 2002 en Alemania, de casos de infecciones por Staphylococcus aureus resistentes a la meticilina adquiridas en la comunidad produciendo la leucocidina de Panton-Valentine. Su articulo muestra la rapida 
diseminacion geografica en Europa de esta variante muy virulente de un patogeno viejo.
Survival after second primary lung cancer following non-Hodgkin lymphoma: A U.S. population-based study.
Authors: LINA INAGAKI, Kevin C. Ward
Journal: Journal of Clinical Oncology (2014)

1536 Background: Cancer survivors are known to have a higher risk of developing second primary cancer (SPC). While Hodgkin lymphoma attracts more attention, non-Hodgkin lymphoma (NHL) survivors account for a larger population of those who develop SPC, and lung cancer accounts for the largest risk of SPC among NHL-survivors. Although a follow-up care plan for cancer survivors has been recommended, concrete guidelines for screening for SPC have not been established. Methods: Study patients were identified from the SEER program from 1990 through 2009. A total of 863 NHL survivors who developed second primary lung cancer and 3,452 patients among 232,202 first primary lung cancer patients without a history of malignancy were randomly sampled and included in the analysis. The overall survival (OS) between the two groups were compared using a Log-rank test, followed by subset analysis for estimated survival among patients with localized stage lung cancer, in which OS was significantly different, using Cox proportional hazard regression, controlling for sex, race, year of diagnosis, age at diagnosis, histology, tumor grade and marital status. Results: NHL survivors experienced significantly inferior survival after lung cancer compared to patients without a history of malignancy at localized stage disease: 5-year OS was 33.0% vs. 44.8% (p < 0.001), whereas the survival did not differ significantly for regional stage: 13.9% vs. 19.2% (p = 0.38), and distant stage: 0% vs. 2.9% (p = 0.10). The subset analysis for patients with localized stage showed that the adjusted Hazard Ratio for death among NHL survivors was 1.38 (95% CI, 1.10-1.73; p = 0.005). Conclusions: NHL survivors were shown to have inferior survival when diagnosed with localized stage lung cancer compared to the general population. Because NHL survivors may not benefit from screening, the promotion of lung cancer screening to reduce mortality among NHL survivors warrants careful assessment.
Abstract 17903: Novel Esterase-Activated Hydrogen Sulfide Donors Attenuate Myocardial Ischemia/Reperfusion Injury
Authors: Zhen Li, Chelsea L Organ, Yueqin Zheng, Binghe Wang, David J Lefer
Journal: Circulation (2016)

Background: Hydrogen sulfide (H2S) protects against acute myocardial ischemia/reperfusion (MI/R) injury and heart failure by ameliorating oxidative stress and attenuating cell death. A major limita...
Opioids are not just an American problem
Authors: Meghna Jani, William G Dixon
Journal: BMJ (2017)

The rise in opioid prescriptions and mortality in the US1 has shone a light on similar concerns in the UK. Opioid prescriptions for non-cancer pain rose by about 60% in the UK from 2000 to 2010.2

With more use comes a larger burden of side effects, dependency, and divergence. The number of deaths related to opioid misuse in England and Wales …
Identifying and Targeting Sporadic Oncogenic Genetic Aberrations in Mouse Models of Triple-Negative Breast Cancer
Authors: Hui Liu, Charles J. Murphy, Florian A. Karreth, Kristina B. Emdal, Forest M. White, Olivier Elemento, Alex Toker, Gerburg M. Wulf, Lewis C. Cantley
Journal: Cancer Discovery (2017)

Triple-negative breast cancers (TNBC) are genetically characterized by aberrations in
Similar outcome of allogeneic stem cell transplantation after myeloablative and sequential conditioning regimen in patients with refractory or relapsed acute myeloid leukemia: A study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire
Authors: Justine Decroocq, Raphaël Itzykson, Stéphane Vigouroux, Mauricette Michallet, Ibrahim Yakoub‐Agha, Anne Huynh, Florence Beckerich, Felipe Suarez, Patrice Chevallier, Stéphanie Nguyen‐Quoc, Marie‐Pierre Ledoux, Laurence Clement, Yosr Hicheri, Gaëlle Guillerm, Jérôme Cornillon, Nathalie Contentin, Martin Carre, Natacha Maillard, Mélanie Mercier, Mohamad Mohty, Yves Beguin, Jean‐Henri Bourhis, Amandine Charbonnier, Charles Dauriac, Jacques‐Olivier Bay, Didier Blaise, Eric Deconinck, Charlotte Jubert, Nicole Raus, Regis Peffault de Latour, Nathalie Dhedin
Journal: American Journal of Hematology (2017)

Patients with acute myeloid leukemia (AML) in relapse or refractory to induction therapy have a dismal prognosis. Allogeneic hematopoietic stem cell transplantation is the only curative option. In these patients, we aimed to compare the results of a myeloablative transplant versus a sequential approach consisting in a cytoreductive chemotherapy followed by a reduced intensity conditioning regimen and prophylactic donor lymphocytes infusions. We retrospectively analyzed 99 patients aged 18-50 years, transplanted for a refractory (52%) or a relapsed AML not in remission (48%). Fifty-eight patients received a sequential approach and 41 patients a myeloablative conditioning regimen. Only 6 patients received prophylactic donor lymphocytes infusions. With a median follow-up of 48 months, 2-year overall survival was 39%, 95% confidence interval (CI) (24-53) in the myeloablative group versus 33%, 95% CI (21-45) in the sequential groups (P = .39), and 2-year cumulative incidence of relapse (CIR) was 57% versus 50% respectively (P = .99). Nonrelapse mortality was not higher in the myeloablative group (17% versus 15%, P = .44). In multivariate analysis, overall survival, CIR and nonrelapse mortality remained similar between the two groups. However, in multivariate analysis, sequential conditioning led to fewer acute grade II-IV graft versus host disease (GVHD) (HR for sequential approach = 0.37; 95% CI: 0.21-0.65; P < .001) without a significant impact on chronic GVHD (all grades and extensive). In young patients with refractory or relapsed AML, myeloablative transplant and sequential approach offer similar outcomes except for a lower incidence of acute GvHD after a sequential transplant.
Correlative analyses of milieu inflammatory cytokines in preneoplastic oral leukoplakia
Authors: Nelson Rhodus, Beverly Wuertz, Kate Cole, Carol Dunn, Eva Szabo, Frank Ondrey
Journal: Cancer Research (2007)

1678   Non invasive diagnostic biomarkers in saliva are an attractive area of investigation in oral and other cancers. The human oral carcinogenesis milieu typically contains proinflammatory cytokines stimulated chronically by the genotoxic and pro-inflammatory effects of tobacco carcinogens. Previously, we have demonstrated that proinflammatory cytokines could be analyzed in a variety of oral cavity-derived fluids from patients with oral cancers and other lesions. In the present study, we analyzed correlations between levels of proangiogenic IL-6, IL-8, and VEGF in saliva and serum in patients with preneoplastic oral leukoplakia. Twenty patients with preneoplastic leukoplakia were examined, biopsied, and lesions bi dimensionally measured. Saliva, saline oral rinse and serum were collected and IL-6, 8, and VEGF were analyzed by ELISA. Milieu (salivary) cytokine levels were 3 to 10 fold higher than serum levels for all three proangiogenic cytokines. A significant correlation was found between VEGF levels in saliva compared to levels in saline oral rinse and serum (p= 0.0004 and 0.0496). For IL-8, there was significant correlation between levels in saliva and saline oral rinse (p=0.0142), but not in serum. In this study, IL-6 levels were much lower and no significant correlation was seen between saliva, saline oral rinse and serum levels. IL-8 and VEGF, but not IL-6, were coordinately upregulated in saliva specimens (p
Progression and regression of women with biopsy-confirmed normal cervical epithelium or cervical intraepithelial neoplasia grade 1: a 15-year population-based cohort study in China
Authors: Shang-Ying Hu, Rezhake Remila, Qian Zhang, Li Dong, Li Zhang, Rui-Mei Feng, Xue-Lian Zhao, Feng Chen, Xun Zhang, Qin-Jing Pan, Wen-Hua Zhang, Jun-Fei Ma, You-Lin Qiao, Fang-Hui Zhao
Journal: The Lancet (2017)
Sources of Parent-Offspring Resemblance for Major Depression in a National Swedish Extended Adoption Study
Authors: Kenneth S. Kendler, Henrik Ohlsson, Kristina Sundquist, Jan Sundquist
Journal: JAMA Psychiatry (2017)

Twin studies have assessed sibling resemblance for major depression (MD) but cannot address sources of resemblance across generations.To clarify the relative importance of genetic and rearing effects on the parent-offspring resemblance for MD.This Swedish population register-based study examined parents and children from the following 5 family types: intact (2 041 816 offspring), adoptive (14 104 offspring), not-lived-with (NLW) father (116 601 offspring), stepfather (67 826 offspring), and triparental (29 205 offspring). The 5 family types permitted quantification of parent-offspring resemblance for genes plus rearing, genes-only, and rearing-only associations. Treated MD was assessed from national primary care, specialist care, and inpatient registries. Data were collected from January 1, 1960, through December 31, 2016.Diagnosis of MD vs no diagnosis in parents.Registration for MD.The study population included 2 269 552 offspring (51.5% male and 48.5% female; median age, 42; range, 26-56 years). The weighted tetrachoric correlations for MD across family types and across mothers and fathers were r = 0.17 (95% CI, 0.16-0.17) for genes plus rearing, r = 0.08 (95% CI, 0.06-0.09) for genes-only, and r = 0.08 (95% CI, 0.07-0.09) for rearing-only parent-child associations. Only the genes plus rearing association differed significantly between mothers (weighted tetrachoric correlation, r = 0.18; 95% CI, 0.18-0.18) and fathers (weighted tetrachoric correlation, r = 0.15; 95% CI, 0.15-0.16). In triparental families, the parent-offspring correlations for MD were estimated at r = 0.19 (95% CI, 0.17-0.22) for mothers in the genes plus rearing association, r = 0.10 (95% CI, 0.07-0.13) for NLW fathers in the genes-only association, and r = 0.08 (95% CI, 0.05-0.11) for stepfathers in the rearing-only association. In adoptive families, the effect of affected biological and affected adoptive parents on adoptee risk for MD was additive. In intact families, parental MD diagnosed by specialists in hospital or outpatient settings and primary care physicians affected equally the risk for MD in offspring.The parent-offspring resemblance for treated MD arises from genetic factors and rearing experiences to an approximately equal extent. Both forms of cross-generational transmission act additively on the risk for MD in the offspring.
Polymyxin B-immobilized hemoperfusion and mortality in critically ill adult patients with sepsis/septic shock: a systematic review with meta-analysis and trial sequential analysis
Authors: Tomoko Fujii, Riki Ganeko, Yuki Kataoka, Toshi A. Furukawa, Robin Featherstone, Kent Doi, Jean-Louis Vincent, Daniela Pasero, René Robert, Claudio Ronco, Sean M. Bagshaw
Journal: Intensive Care Medicine (2017)
US tax bill could destroy central pillar of Obamacare
Authors: Owen Dyer
Journal: BMJ (2017)

The tax reform bill passed by Senate Republicans this week threatens to strip 13 million Americans of their health insurance coverage through a provision eliminating the Affordable Care Act’s individual mandate, a rule requiring most US residents to have health insurance or pay a penalty.

By adding younger and healthier customers who otherwise would not seek insurance to the risk pool, the individual mandate is Obamacare’s principal mechanism for keeping insurance premiums down for older patients and people with pre-existing conditions.

The Congressional Budget Office, which has scored the tax bill’s likely effects, found that repealing the mandate would make four million people uninsured by 2019 and 13 million by 2027. It would drive up premiums by 10% a year, it found.1 …
Nkx2-2as Suppression Contributes to the Pathogenesis of Sonic Hedgehog Medulloblastoma
Authors: Yimeng Zhang, Ting Wang, Shan Wang, Yanlu Xiong, Rui Zhang, Xiang Zhang, Jing Zhao, An-Gang Yang, Lei Wang, Lintao Jia
Journal: Cancer Research (2017)

Abstract Aberrant Hedgehog signaling and excessive activation of the Gli family of transcriptional activators are key drivers of medulloblastoma (MB), the most common human pediatric brain malignancy. MB originates mainly from cerebellar granule neuron progenitors (CGNP), but the mechanisms underlying CGNP transformation remain largely obscure. In this study, we found that suppression of the noncoding RNA Nkx2-2as promoted Sonic Hedgehog (Shh)-potentiated MB development. Nkx2-2as functioned as a competing endogenous RNA against miR-103 and miR-107, sequestering them and thereby derepressing their tumor suppressive targets BTG2 and LATS1 and impeding cell division and migration. We also found that Nkx2-2as tethered miR-548m and abrogated its LATS2 targeting activity. Shh signaling impaired Nkx2-2as expression by upregulating the transcriptional repressor FoxD1. In clinical specimens of Shh-subgroup MB, we validated coordinated expression of the aforementioned proteins. Notably, exogenous expression of Nkx2-2as suppressed tumorigenesis and prolonged animal survival in MB mouse models. Our findings illuminate the role of noncoding RNAs in Hedgehog signaling and MB occurrence, with implications for identifying candidate therapeutic targets for MB treatment. Significance: These findings illuminate the role of noncoding RNAs in Hedgehog signaling and an interplay between the Hedgehog and Hippo pathways in medulloblastoma pathogenesis. Cancer Res; 78(4); 962–73. ©2017 AACR.
DNA Base Editing Could Reverse Most Disease-Causing Point Mutations
Authors: Jennifer Abbasi
Journal: JAMA (2017)

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