tbuckley/cabot-search huggingface dataset:
Multifunctional Delivery Nanosystems Formed by Degradable Antibacterial Poly(Aspartic Acid) Derivatives for Infected Skin Defect Therapy
Authors: Hai‐Qing Song, Mei‐Yu Shao, Yang Li, Xue‐Jia Ding, Fu‐Jian Xu
Journal: Advanced Healthcare Materials (2018)

Abstract Nucleic acid (NA)‐based therapy is promising for tissue repair, such as skin and bone defect therapy. However, bacterial infections often occur in the process of tissue healing. The ideal treatment of tissue repair requires both anti‐infection and simultaneous tissue healing. The epidermal growth factor (EGF) plays an important role in wound healing processes. In this work, degradable antibacterial gene vectors based on tobramycin (clinically relevant antibiotic) conjugated poly(aspartic acid) (TPT) are proposed as multifunctional delivery nanosystems of plasmid encoding EGF (pEGF) to realize the antibacterial therapy and tissue healing of infected skin defects. TPT has low cytotoxicity and good degradability, which is helpful in the NA delivery process. TPT demonstrates good transfection performances and hemocompatibility, as well as excellent antibacterial activities in vitro. The outstanding pEGF delivery ability of TPT and the bioactivity of expressed EGF facilitate the proliferation of fibroblast cells. The effective in vivo infected skin defect therapy is also demonstrated with TPT/pEGF nanocomplexes, where skin tissue healing is promoted. The present work opens new avenues for the design of multifunctional delivery nanosystems with antibacterial ability to treat infected tissue defect.
Detecting cervical precancer and reaching underscreened women by using HPV testing on self samples: updated meta-analyses
Authors: Marc Arbyn, Sara B Smith, Sarah Temin, Farhana Sultana, Philip Castle
Journal: BMJ (2018)

Abstract Objective To evaluate the diagnostic accuracy of high-risk human papillomavirus (hrHPV) assays on self samples and the efficacy of self sampling strategies to reach underscreened women. Design Updated meta-analysis. Data sources Medline (PubMed), Embase, and CENTRAL from 1 January 2013 to 15 April 2018 (accuracy review), and 1 January 2014 to 15 April 2018 (participation review). Review methods Accuracy review: hrHPV assay on a vaginal self sample and a clinician sample; and verification of the presence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) by colposcopy and biopsy in all enrolled women or in women with positive tests. Participation review: study population included women who were irregularly or never screened; women in the self sampling arm (intervention arm) were invited to collect a self sample for hrHPV testing; women in the control arm were invited or reminded to undergo a screening test on a clinician sample; participation in both arms was documented; and a population minimum of 400 women. Results 56 accuracy studies and 25 participation trials were included. hrHPV assays based on polymerase chain reaction were as sensitive on self samples as on clinician samples to detect CIN2+ or CIN3+ (pooled ratio 0.99, 95% confidence interval 0.97 to 1.02). However, hrHPV assays based on signal amplification were less sensitive on self samples (pooled ratio 0.85, 95% confidence interval 0.80 to 0.89). The specificity to exclude CIN2+ was 2% or 4% lower on self samples than on clinician samples, for hrHPV assays based on polymerase chain reaction or signal amplification, respectively. Mailing self sample kits to the woman’s home address generated higher response rates to have a sample taken by a clinician than invitation or reminder letters (pooled relative participation in intention-to-treat-analysis of 2.33, 95% confidence interval 1.86 to 2.91). Opt-in strategies where women had to request a self sampling kit were generally not more effective than invitation letters (relative participation of 1.22, 95% confidence interval 0.93 to 1.61). Direct offer of self sampling devices to women in communities that were underscreened generated high participation rates (&gt;75%). Substantial interstudy heterogeneity was noted (I 2 &gt;95%). Conclusions When used with hrHPV assays based on polymerase chain reaction, testing on self samples was similarly accurate as on clinician samples. Offering self sampling kits generally is more effective in reaching underscreened women than sending invitations. However, since response rates are highly variable among settings, pilots should be set up before regional or national roll out of self sampling strategies.
Abstract O.38: Fever Patterns in KD Patients after Treatment with IVIG
Authors: Preeti Jaggi, Wei Wang, Beth Printz, Jane Burns, John Kovalchin, Adriana Tremoulet
Journal: Circulation (2015)

Objective: To determine if fever patterns in the first 36 hours after completion of intravenous immunoglobulin (IVIG) for Kawasaki disease (KD), with or without additional infliximab, can predict eventual resistance to treatment and coronary artery abnormalities (CAA). Study design: Subjects with acute KD enrolled in a clinical trial of infliximab plus IVIG (n=96) versus placebo plus IVIG (n=94) had temperatures taken axillary and either oral or rectal every 6 hours after completion of IVIG infusion. Fever was defined as any temperature &gt; 38.0 o C and resistance to treatment was defined as persistent or recrudescent fever ≥36 hours after completion of IVIG. CAA was defined as a Z-score &gt;2.5 based on the maximum internal diameters of the proximal right coronary or left anterior descending artery. Multivariable logistic regression was performed to predict two outcomes (resistance to treatment and development of CAA) by the variables of presence of fever at 0-12, 12-24, and 24-36 hours post IVIG. All analyses were controlled for treatment, age, and sex. Results: After completion of IVIG, 131 subjects (68.9%) had no fever. There was no difference in the median time to defervescence between the infliximab + IVIG group (n=96) versus the IVIG alone group (n= 94). Subjects who had at least one fever at 24-36 hours post-IVIG had a higher probability of having a fever at least 36 hours post-IVIG (p&lt;0.0001, odds ratio=30.6 [95%CI 6.7-139.8]), although 11% of those who eventually responded to treatment also had fever between 24-36 hours post-completion of IVIG. Subjects who had at least one fever within the first 12 hours post-IVIG had a higher likelihood of having CAA (odds ratio=3.782, p=0.037)). Of those with CAA (n=51), 43 (84%) had abnormalities on the initial baseline echocardiogram. Conclusion: Fevers in the first 12 hours after completion of IVIG are associated with CAA, which can be demonstrated on the initial echocardiogram in the majority of CAA+ subjects. Fever 24-36 hours after IVIG completion is associated with subsequent resistance to treatment, but also occurred in 11% of responders. Our data suggest that patterns of fever can be useful as prognostic indicators of disease outcome in KD patients.
TEM8 and CMG2 expression in normal and cancerous prostate tissues
Authors: Micaela Vargas, G. Chaudry
Journal: Cancer Research (2008)

4257  Tumor endothelial marker 8 (TEM8) shows enhanced expression in endothelia of colon carcinomas, determined by serial analysis of gene expression (SAGE). Capillary morphogenesis gene 2 (CMG2) shows elevated expression during in vitro induction of capillary-like tubulation in collagen matrices. Thus, both genes have been suggested to be potential novel players in neo-vasculature formation. Notably, TEM8 appears important for vasculature of tumors. Both genes exhibit differential splicing, which results in multiple isoforms of the proteins, some single-pass integral membrane proteins, others secreted. The extracellular portions of TEM8 and CMG2 contain von Willebrand Factor A domain, and within it a metal ion dependent adhesion site. The secreted forms typically diverge in sequence right before the transmembrane segment in the membrane-bound forms. Although the precise mechanisms by which these proteins function are unclear, it is known that collagen α3 (VI) interacts with TEM8, and collagen IV and laminin interact with CMG2. However, the functional significance of these interactions is unclear. The only definitively known function of TEM8 and CMG2 is that they serve as anthrax toxin receptors.  A comprehensive expression profile of TEM8 and CMG2, notably the variant-specific profile, is unavailable. In as much as a gene can function in a process specific manner by differential expression of its variants, it is imperative that expression of each variant be determined to discern any correlation with a normal or pathological state. To that end, we have assessed expression of all TEM8 and CMG2 variants in a large number of normal human tissues, as well as cancer cells. To do so we used variant specific primers and semi-quantitative nested PCR. We report here that both TEM8 and CMG2 variants show tissue-specific and developmental expression. Both genes have certain variants that show near ubiquitous expression, and others that show highly selective expression. TEM8V3, a secreted form, is ubiquitous, while V2 and V4, both membrane-bound, show selective expression. V1 (membrane-bound) and V5 (secreted) were only in prostate. CMG2-488 and 489, both membrane-bound, show broad expression, but CMG2-322, a secreted form, shows highly selective expression. CMG2-386, another membrane-bound form, was absent from all tissues studied. We are now studying the expression of all variants in paired normal and cancerous prostate tissues. Our initial results show that TEM8V3, ubiquitous in all normal tissues, is absent from cancerous prostate tissue. But CMG2-488 was strongly expressed in the same tissue. We think it likely that the two genes exhibit expression profiles in cancerous tissues different from those in normal tissues, and that such differences may prove useful in diagnosis.
Not just correlative: a new pathway defines how an ALDH2 SNP contributes to atherosclerosis
Authors: Andrew A. Gibb, John W. Elrod
Journal: Journal of Clinical Investigation (2018)

Individuals with the rs671 SNP in the gene encoding aldehyde dehydrogenase 2 (ALDH2) are at increased risk of cardiovascular disease (CVD); however, it has been unclear if this mutation contributes to CVD development. In this issue of the JCI, Zhong et al. perform an elegant set of experiments that reveal a pathway wherein the ALDH2 rs671 mutant is phosphorylated by AMPK and translocates to the nucleus where it represses the transcription of a lysosomal H+ pump subunit that is critical for lipid degradation and foam cell formation, as occurs in atherosclerosis. The discovery of this pathway may explain how subjects harboring ALDH2 rs671 are at a greater risk for numerous other disease states and thereby provide new targets for therapeutic intervention.
Long non-coding RNA DANCR stabilizes HIF-1α and promotes metastasis by interacting with NF90/NF45 complex in nasopharyngeal carcinoma
Authors: Xin Wen, Xu Liu, Yan-Ping Mao, Xiao-Jing Yang, Ya-Qin Wang, Pan-Pan Zhang, Yuan Lei, Xiao-Hong Hong, Qing-Mei He, Jun Ma, Na Liu, Ying-Qin Li
Journal: Theranostics (2018)

Long noncoding RNAs (lncRNAs) play an important role in the development and progression of cancers. However, the clinical significances of lncRNAs and their functions and mechanisms in nasopharyngeal carcinoma (NPC) remain largely unclear. Methods: Quantitative RT-PCR was used to determine DANCR expression and Kaplan-Meier curves were used to evaluate its prognostic value. RNA sequencing followed by bioinformatic analysis was performed to determine the potential function of DANCR. In vitro and in vivo experiments were conducted to investigate its biological effects. DANCR-interacting proteins were identified by RNA pull-down assay followed by mass spectrometry and western blotting, and then confirmed by RNA immunoprecipitation (RIP) assays. Results: Our previous microarray analysis identified a metastasis-associated lncRNA DANCR. Here, we found that DANCR was upregulated in NPC, especially in those with lymph lode metastasis, and its upregulation could predict poor survival. We then constructed a prognostic predictive model. RNA sequencing followed by bioinformatic analysis revealed that DANCR was responsible for NPC metastasis and hypoxia phenotype. Functional studies showed that DANCR promoted NPC cell invasion and metastasis in vitro and in vivo. Further investigation suggested that DANCR could increase HIF-1α mRNA stability through interacting with the NF90/NF45 complex. Additionally, overexpression of HIF-1α in DANCR knockdown cells restored its suppressive effects on NPC cell migration and invasion. Conclusions: Taken together, our results suggest that DANCR acts as a prognostic biomarker and increases HIF-1α mRNA stability by interacting with NF90/NF45, leading to metastasis and disease progression of NPC.
Diagnosis and Treatment of Chronic Myelomonocytic Leukemias in Adults
Authors: Raphael Itzykson, Pierre Fenaux, David Bowen, Nicholas C.P. Cross, Jorge Cortes, Theo De Witte, Ulrich Germing, Francesco Onida, Eric Padron, Uwe Platzbecker, Valeria Santini, Guillermo F. Sanz, Eric Solary, Arjan Van de Loosdrecht, Luca Malcovati
Journal: HemaSphere (2018)

Chronic myelomonocytic leukemia (CMML) is a disease of the elderly, and by far the most frequent overlap myelodysplastic/myeloproliferative neoplasm in adults. Aside from the chronic monocytosis that remains the cornerstone of its diagnosis, the clinical presentation of CMML includes dysplastic features, cytopenias, excess of blasts, or myeloproliferative features including high white blood cell count or splenomegaly. Prognosis is variable, with several prognostic scoring systems reported in recent years, and treatment is poorly defined, with options ranging from watchful waiting to allogeneic stem cell transplantation, which remains the only curative therapy for CMML. Here, we present on behalf of the European Hematology Association and the European LeukemiaNet, evidence- and consensus-based guidelines, established by an international group of experts, from Europe and the United States, for standardized diagnostic and prognostic procedures and for an appropriate choice of therapeutic interventions in adult patients with CMML.
Beyond Parenting: The Responsibility of Multidisciplinary Health Care Providers in Early Intervention Policy Guidance
Authors: Kristin Canavera, Liza-Marie Johnson, Jennifer Harman
Journal: The American Journal of Bioethics (2018)

Moral responsibility in early intervention (EI) policy guidance is discussed and analyzed in the target article by Mortimer and colleagues (Mortimer et al. 2018), with emphasis on the role of paren...
Abstract #3961: Galectin-3 mediates resistance to radiotherapy through the activation of p-ERK independent of Ras activation
Authors: Areej El-Jawahri, Tim Lautenschlaeger, Disha Patel, Arnab Chakravarti
Journal: Cancer Research (2009)

Purpose: We investigated the role and underlying mechanisms of Gal-3 in mediating radiation resistance in Glioblastoma (GBM) through modulating the MAPK pathway. Experimental Design: First, we investigated Gal-3 expression in GBM cell lines (U87, LN18, LN229) following radiation using western blot analysis and RT-PCR. Then, we created stable (lentiviral shRNA) Gal-3 knockdown cell lines (Gal-3KD). We then evaluated the radiosensitivity, apoptosis, and cell viability of control cell lines treated by non-targeting (NT) vectors as compared to gal-3KD using clonogenic survival assay, MTT cell viability, Annexin V/PI apoptosis assay, COMET assay, and cell cycle analysis. Signaling cascades were evaluated using Western blot and a GTP-ras pull down assay. Gal-3 binding interactions were identified using co-immunoprecipitation. Gal3-KD and NT cell lines were also transiently transfected with constitutively active MEK (MEK-2DD plasmid was obtained from Dr. Brugge) and signaling cascades were subsequently analyzed using western blotting. Results: Gal-3 expression was induced in all GBM cell lines following irradiation as shown by Western blotting and quantitative PCR. Gal-3KD cell lines showed increased radiosensitivity to radiation therapy as compared to controls with decreased clonogenic survival, decreased cell viability, increased DNA damage, increased apoptosis, and increased cell cycle arrest in G1 and G2. Gal-3KD cell lines showed reduced p-ERK at baseline followed by a minimal induction of p-ERK with irradiation as compared to controls which have a high level of p-ERK. Overall p-Akt, ERK and Ras-GTP levels were equivalent in Gal-3 KD and controls. When Gal-3 KD cells were transiently transfected with constitutively active MEK, a minimal increase in p-ERK levels was seen as compared to controls. Gal-3 co-immunoprecipitated with ERK. Conclusion: Gal-3 expression is induced by irradiation in GBM and appears to mediate radiation resistance by modulating the MAPK pathway and is associated with adverse clinical outcomes. Knocking down Gal3 in our in vitro models was found to enhance radiosensitivity and suppress p-ERK expression despite equivalent Ras-GTP levels suggesting Gal-3 regulates p-ERK expression independent of k-ras activation. P-ERK levels were only minimally rescued with a constitutively active MEK construct, and ERK co-immunoprecipitated with Gal-3 further supporting a possible direct novel interaction between Gal-3 and ERK in GBM cell lines that is essential for the expression of p-ERK and radiation resistance in GBMs.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3961.
Fractionating Blunted Reward Processing Characteristic of Anhedonia by Over-Activating Primate Subgenual Anterior Cingulate Cortex
Authors: Laith Alexander, Philip L.R. Gaskin, Stephen J. Sawiak, Tim D. Fryer, Young T. Hong, Gemma J. Cockcroft, Hannah F. Clarke, Angela C. Roberts
Journal: Neuron (2018)

Anhedonia is a core symptom of depression, but the underlying neurobiological mechanisms are unknown. Correlative neuroimaging studies implicate dysfunction within ventromedial prefrontal cortex, but the causal roles of specific subregions remain unidentified. We addressed these issues by combining intracerebral microinfusions with cardiovascular and behavioral monitoring in marmoset monkeys to show that over-activation of primate subgenual anterior cingulate cortex (sgACC, area 25) blunts appetitive anticipatory, but not consummatory, arousal, whereas manipulations of adjacent perigenual ACC (pgACC, area 32) have no effect. sgACC/25 over-activation also reduces the willingness to work for reward. 18F-FDG PET imaging reveals over-activation induced metabolic changes in circuits involved in reward processing and interoception. Ketamine treatment ameliorates the blunted anticipatory arousal and reverses associated metabolic changes. These results demonstrate a causal role for primate sgACC/25 over-activity in selective aspects of impaired reward processing translationally relevant to anhedonia, and ketamine's modulation of an affective network to exert its action.
Financial burden at end of life: Findings from interviews with caregivers of patients with cancer.
Authors: Cara L. McDermott, Ruth Engelberg, Scott David Ramsey, J. Randall Curtis, Cossette Woo, Helene Starks
Journal: Journal of Clinical Oncology (2018)

14 Background: Studies have described financial burden during and after cancer treatment, but little data are available on financial burden to patients and caregivers at end of life. We conducted a qualitative study with bereaved caregivers and discussed the impact of cancer-associated medical and nonmedical costs on family finances. Methods: From October-December 2017, we audio-recorded semi-structured phone interviews with 35 adults who were primary caregivers for a family member who died with cancer (July-December 2016). We asked about ability to meet costs of care. Drawing from previous studies, we defined substantial financial burden as incurring debt, selling assets or draining savings to meet health care costs. Two analysts coded transcripts using qualitative content analysis and summarized results as major themes. Results: Patients ranged from 30-88 years old, caregivers 34-85. Most caregivers were white (91%), female (63%) and spouses (89%). Ten patients (29%) were insured commercially, 24 (69%) had Medicare, and one (2%) had Medicaid. Ten caregivers (29%) reported substantial financial burden, irrespective of patients’ insurance coverage. Issues associated with substantial financial burden were: 1) insurance hurdles: “my husband’s dying and…I have to run interference with insurance companies, which is frustrating;” 2) limited financial resources: “It is hard when…you really don't have a lot of savings because…you never really made a lot of money” and 3) financial burden that continues after the patient’s death : “I went broke, basically, looking after my parents.” “We lost two incomes and we had to live on our savings.” Three other caregivers noted their family did not experience financial burden because they switched health insurance plans or had a supplemental insurance plan. Conclusions: In this pilot study of caregivers of advanced cancer patients, a substantial portion of commercially insured patients and Medicare enrollees with limited savings and income reported financial burden associated with cancer treatment and end-of-life care that persisted after the patient’s death. Future research is needed to determine best ways to mitigate financial burden among patients and their survivors.
Statistical compared to clinical significance and the risk of misattribution
Authors: Nicholas T. Vozoris, Peter C. Austin, Paula A. Rochon
Journal: European Respiratory Journal (2018)

We thank M. Ekström and colleagues for their interest in our study [1] and for their comments. The central concepts that M. Ekström and colleagues express in their correspondence are that our findings of increased respiratory-related morbidity and mortality in association with new serotonergic antidepressant use among older adults with chronic obstructive pulmonary disease (COPD) "likely reflect the underlying illness(es) and other unmeasured factors rather than an actual drug effect". Propensity score matching and stratification are methods that help minimise the risk of confounding and misattribution in observational studies <http://ow.ly/DY0n30mrtQF>
Haematological immune-related adverse events induced by anti-PD-1 or anti-PD-L1 immunotherapy: a descriptive observational study
Authors: Nicolas Delanoy, Jean-Marie Michot, Thibault Comont, Nora Kramkimel, Julien Lazarovici, Romain Dupont, Stéphane Champiat, Claude Chahine, Caroline Robert, Charles Herbaux, Benjamin Besse, Aude Guillemin, Christine Mateus, Patricia Pautier, Philippe Saïag, Emanuela Madonna, Marie Maerevoet, Jean-Christophe Bout, Charlotte Leduc, Pascal Biscay, Gilles Quere, Charlée Nardin, Mikael Ebbo, Laurence Albigès, Grégoire Marret, Virginie Levrat, Cécile Dujon, Jacques Vargaftig, Salim Laghouati, Laure Croisille, Anne-Laure Voisin, Bertrand Godeau, Christophe Massard, Vincent Ribrag, Aurélien Marabelle, Marc Michel, Olivier Lambotte
Journal: The Lancet Haematology (2018)