tbuckley/cabot-search huggingface dataset:
Aspherical, Nanostructured Microparticles for Targeted Gene Delivery to Alveolar Macrophages
Authors: Michael Möhwald, Shashank Reddy Pinnapireddy, Bodo Wonnenberg, Marcel Pourasghar, Marijas Jurisic, Andrea Jung, Claudia Fink‐Straube, Thomas Tschernig, Udo Bakowsky, Marc Schneider
Journal: Advanced Healthcare Materials (2017)

Abstract Introducing novel shapes to particulate carrier systems adds unique features to modern drug and gene delivery. Depending on the route of administration, particle geometry can influence deposition and fate within biological environments. In this work, a template‐assisted engineering technique is applied, providing full control of size and shape in the preparation of aspherical, nanostructured microparticles. Based on the interconnection of nanoparticles, stabilized by a functional layer‐by‐layer (LbL) coating, the resulting cylindrical micrometer architecture is especially qualified for pulmonary delivery. Designed as gene delivery system, plasmid‐DNA (pCMV‐luciferase) and branched polyethylenimine are used to reach both structural integrity of the carrier system and delivery of genes into the cells of interest. Due to their size, particles are exclusively taken up by phagocytes, which also adds a targeting effect to the introduced system. The luciferase expression is demonstrated in macrophages showing increasing levels over a time period of at least 7 d. Furthermore, it is shown for the first time that the expression is depending on the LbL design. From in vivo experiments, corresponding luciferase expression is observed in mice alveolar macrophages. Combining site specific transport with the possibility of genetically engineering immunocompetent phagocytes, the presented system offers promising potential to improve applications for cell‐based immunotherapy.
Abstract P001: HDAC1 Plays an Important Role in the Differentiation of Embryonic Stem Cells and Induced Pluripotent Stem Cells into Cardiovascular Lineages
Authors: Eneda Hoxha, Erin Lambers, Veronica Ramirez, Prasanna Krishnamurthy, Suresh Verma, Melissa Thal, Raj Kishore
Journal: Circulation Research (2011)

Despite advancements in the treatment of myocardial infarction (MI), the majority of patients are at increased risk for developing heart failure due to the loss of cardiomyocytes and microvasculature. Some of the main obstacles in the realization of the full potential of iPS/ES cells arise from incomplete and poorly understood molecular mechanisms and epigenetic modifications that govern their pluripotency and directed differentiation. Real-time array experiments revealed that HDAC1 is highly expressed in pluripotent cells. Additionally the lack of this molecule is embryonic lethal, suggesting it plays a key role in development. Thus, we hypothesized that HDAC1 plays a critical role in directing cardiovascular differentiation of mES and iPS cells in vitro. HDAC1 was knocked down in mES cells (C57BL/6) and iPS cells using a shRNA vector. Differentiation through embryoid body (EB) was induced in wild type mES cells and iPS cells and in their HDAC1-null counterparts and the ability of these cells to differentiate into three early embryonic lineages and more specifically cardiovascular lineage was monitored. EBs lacking HDAC1 differentiated slower and showed delayed suppression of pluripotent genes such as Oct4 and Sox2. ChiP experiments revealed high histone acetylation levels at the promoter regions of these genes during early differentiation. In addition cells lacking HDAC1 showed reduced expression of early markers for all three germ layers. HDAC1-null EBs also showed delayed and reduced spontaneous beating. Expression of cardiomyocite markers as well as markers of other cardiovascular lineages was repressed in HDAC1 -null cells. However, supplementation with BMP2 during early differentiation recovered the ability in the HDAC1-null cells to differentiate into endodermal and mesodermal lineages, but not ectodermal. We propose that HDAC1 plays a critical role in early development and cardiovascular differentiation of mES and iPS cells by repressing pluripotent genes and allowing for expression of early developmental genes such as SOX17 and BMP2. Further research in the molecular mechanisms involved in this process will greatly aid our understanding of the epigenetic circuitry of pluripotency and differentiation in ES and iPS cells.
Novel in vitro booster vaccination to rapidly generate antigen-specific human monoclonal antibodies
Authors: Irene Sanjuan Nandin, Carol Fong, Cecilia Deantonio, Juan A. Torreno-Pina, Simone Pecetta, Paula Maldonado, Francesca Gasparrini, Jose Ordovas-Montanes, Samuel W. Kazer, Svend Kjaer, Daryl W. Borley, Usha Nair, Julia A. Coleman, Daniel Lingwood, Alex K. Shalek, Eric Meffre, Pascal Poignard, Dennis R. Burton, Facundo D. Batista
Journal: The Journal of Experimental Medicine (2017)

Vaccines remain the most effective tool to prevent infectious diseases. Here, we introduce an in vitro booster vaccination approach that relies on antigen-dependent activation of human memory B cells in culture. This stimulation induces antigen-specific B cell proliferation, differentiation of B cells into plasma cells, and robust antibody secretion after a few days of culture. We validated this strategy using cells from healthy donors to retrieve human antibodies against tetanus toxoid and influenza hemagglutinin (HA) from H1N1 and newly emergent subtypes such as H5N1 and H7N9. Anti-HA antibodies were cross-reactive against multiple subtypes, and some showed neutralizing activity. Although these antibodies may have arisen as a result of previous influenza infection, we also obtained gp120-reactive antibodies from non–HIV-infected donors, indicating that we can generate antibodies without prior antigenic exposure. Overall, our novel approach can be used to rapidly produce therapeutic antibodies and has the potential to assess the immunogenicity of candidate antigens, which could be exploited in future vaccine development.
Role of 92 gene cancer classifier assay in neuroendocrine tumor of unknown primary.
Authors: Aman Chauhan, Leaundra Murray, Arun Kumar Arumugam Raajasekar, Zin Myint, Lowell Brian Anthony
Journal: Journal of Clinical Oncology (2017)

e15696 Background: Neuroendocrine tumor of unknown primary constitutes about 10-15 % of all neuroendocrine tumors. Identification of primary site can helps alter the management. Sunitinib is FDA approved for management of pancreatic neuroendocrine tumors, everolimus is approved for gastroenteropancreatic and bronchial NETs, immune checkpoint inhibitors are active in Merkel cell carcinoma and MIBG treatment is standard of care for pheochromocytoma. Methods: Patients with neuroendocrine tumor with unknown primary were identified from Markey Cancer Center database over a five-year period (2012-2016). Patient who underwent 92-gene reverse transcriptase polymerase chain reaction cancer classification assay (BioTheranostics Tissue Type ID) were analyzed. IRB approval was obtained. Results: 56 patients with neuroendocrine tumors with unknown primary were identified. Median age of cohort was 61 years. 28/56 patients were males. 92 gene cancer ID assay was used in 38 out of 56 patients. Primary site of tumor was identified with &gt; 95% certainty in 36 out of 38 patients. The test reported pancreatic NET as the primary site for 10 patients, gastrointestinal NETs for 14 patients, bronchial carcinoid for 5, large call NEC for 3, Merkel cell carcinoma for two and pheochromocytoma in one patient. Conclusions: Tissue type ID was able to identify a primary site in NETs of unknown primary in majority (94.7%) of cases. The result had direct implication in management of patients with regards to FDA approved treatment options in 13/38 patients (pNETs, merkel cell and pheochromocytoma).
Effectiveness and Safety of Dementia Care Management in Primary Care
Authors: Jochen René Thyrian, Johannes Hertel, Diana Wucherer, Tilly Eichler, Bernhard Michalowsky, Adina Dreier-Wolfgramm, Ina Zwingmann, Ingo Kilimann, Stefan Teipel, Wolfgang Hoffmann
Journal: JAMA Psychiatry (2017)

Dementia care management (DCM) can increase the quality of care for people with dementia. Methodologically rigorous clinical trials on DCM are lacking.To test the effectiveness and safety of DCM in the treatment and care of people with dementia living at home and caregiver burden (when available).This pragmatic, general practitioner-based, cluster-randomized intervention trial compared the intervention with care as usual at baseline and at 12-month follow-up. Simple 1:1 randomization of general practices in Germany was used. Analyses were intent to treat and per protocol. In total, 6838 patients were screened for dementia (eligibility: 70 years and older and living at home) from January 1, 2012, to March 31, 2016. Overall, 1167 (17.1%) were diagnosed as having dementia, and 634 (9.3%) provided written informed consent to participate.Dementia care management was provided for 6 months at the homes of patients with dementia. Dementia care management is a model of collaborative care, defined as a complex intervention aiming to provide optimal treatment and care for patients with dementia and support caregivers using a computer-assisted assessment determining a personalized array of intervention modules and subsequent success monitoring. Dementia care management was targeted at the individual patient level and was conducted by 6 study nurses with dementia care-specific qualifications.Quality of life, caregiver burden, behavioral and psychological symptoms of dementia, pharmacotherapy with antidementia drugs, and use of potentially inappropriate medication.The mean age of 634 patients was 80 years. A total of 407 patients received the intended treatment and were available for primary outcome measurement. Of these patients, 248 (60.9%) were women, and 204 (50.1%) lived alone. Dementia care management significantly decreased behavioral and psychological symptoms of dementia (b = -7.45; 95% CI, -11.08 to -3.81; P < .001) and caregiver burden (b = -0.50; 95% CI, -1.09 to 0.08; P = .045) compared with care as usual. Patients with dementia receiving DCM had an increased chance of receiving antidementia drug treatment (DCM, 114 of 291 [39.2%] vs care as usual, 31 of 116 [26.7%]) after 12 months (odds ratio, 1.97; 95% CI, 0.99 to 3.94; P = .03). Dementia care management significantly increased quality of life (b = 0.08; 95% CI, 0 to 0.17; P = .03) for patients not living alone but did not increase quality of life overall. There was no effect on potentially inappropriate medication (odds ratio, 1.86; 95% CI, 0.62 to 3.62; P = .97).Dementia care management provided by specifically trained nurses is an effective collaborative care model that improves relevant patient- and caregiver-related outcomes in dementia. Implementing DCM in different health care systems should become an active area of research.clinicaltrials.gov Identifier: NCT01401582.
ROCK as a molecular bond connecting coronary microvascular and cardiac remodelling
Authors: Daphne Merkus, Johnathan D Tune
Journal: Cardiovascular Research (2017)

__This editorial refers to ‘Enhanced endothelin-1/Rho-kinase signaling and coronarymicrovascular dysfunction in hypertensive myocardial hypertrophy’ by S.H. Tsai et al., pp. 1329–1337.__  

Communication between cardiomyocytes and the coronary microvasculature is imperative for adequate cardiac function. The high metabolic rate of the heart requires sufficient myocardial oxygen delivery through the coronary microvasculature, which is accomplished by adjusting coronary microvascular resistance. Coronary microvascular resistance is modulated by a variety of factors including extravascular compressive forces and the regulation ofmicrovascular tone, which involves the interplay between metabolic, myogenic, neurohumoral, and endotheliumderived factors. Together these mechanisms modulate coronary blood flow and act to sustain an adequate balance between myocardial oxygen delivery (supply) and metabolism (demand). [...]
A case of endoscopic hemostasis using double-balloon endoscopy for an intestinal hemorrhage in a giant incisional hernia
Authors: Takashi Taida, Tomoo Nakagawa, Yuki Ohta, Shinsaku Hamanaka, Kenichiro Okimoto, Daisuke Maruoka, Tomoaki Matsumura, Makoto Arai
Journal: Endoscopy (2017)

A 62-year-old man was referred to Chiba University Hospital with melena. He had previously suffered from severe peritonitis due to appendicitis and consequently had a giant abdominal incisional hernia. Although his appearance was pale due to a hemoglobin concentration of 6.9 g/dL, his vital signs were stable. His abdomen was distended in the right side because of, not only the hernia, but also his severe obesity; he had a body mass index of 42.3 kg/m2 ([Fig. 1]).
Analysis of “double-hit” lymphoma cases by genetic subtype.
Authors: Daniel Jeffrey Landsburg, Adam Matthew Petrich, Jeremy S. Abramson, Aliyah Sohani, Oliver W. Press, Ryan Daniel Cassaday, Julio C. Chavez, Kevin W. Song, Andrew David Zelenetz, Mitul Gandhi, Namrata Mahendra Shah, Timothy Fenske, Jesse Jasso, L Jeffrey Medeiros, David T Yang, Chadi Nabhan
Journal: Journal of Clinical Oncology (2015)

8543 Background: “Double-hit” lymphoma (DHL), defined as a B cell non-Hodgkin lymphoma harboring rearrangements in c-MYC as well as BCL2 and/or BCL6, carries a poor prognosis. Here we report characteristics and outcomes of DHL patients (pts) by genetic subtype. Methods: From our previously-described database of DHL pts (Blood 2014 124:2354-61), we identified cases which underwent cytogenetic testing for c-MYC as well as both BCL2 and BCL6 rearrangements. Cohorts were defined by the presence (+) or absence (-) of rearrangements: c-MYC+/BCL2+/BCL6- (BCL2-DHL), c-MYC+/BCL2-/BCL6+ (BCL6-DHL) and c-MYC+/BCL2+/BCL6+ (THL). Therapy was given at the discretion of the treating physician. Results: Data from 117 cases were included. Pts with BCL6-DHL were more likely to have extranodal disease as compared to BCL2-DHL (p=0.04) and THL (p=0.04) pts. Treatment received and outcomes are described in Table. Univariate analysis revealed that elevated LDH, stage ≥3 disease, IPI ≥4 and bone marrow involvement in BCL2-DHL pts and IPI ≥4 and bone marrow involvement in THL pts predicted for inferior overall survival (OS). Conclusions: Analysis of the largest reported series of BCL2-DHL, BCL6-DHL and THL pts by genetic subtype did not reveal significant differences in outcome, potentially due to small cohort sizes. Nevertheless, high rates of primary refractory disease and relapse seen across all subtypes provides a rationale for offering novel therapeutic approaches to these pts in the front-line setting. Treatment received and outcomes. DHL subtype p value BCL2-DHL (n=76) BCL6-DHL (n=16) THL (n=25) BCL2-DHL vs. BCL6-DHL BCL2-DHL vs. THL BCL6-DHL vs. THL Receipt of DE1 55% 44% 65% 0.42 0.35 0.19 Complete response (CR1) 54% 75% 46% 0.17 0.49 0.10 If receiving DE1 55% 86% 63% 0.22 0.77 0.37 Stem cell transplant (SCT) in CR1 36% 22% 55% 0.47 0.31 0.18 Primary refractory disease 32% 13% 33% 0.14 1.0 0.25 If receiving DE1 25% 14% 14% 1.0 0.71 1.0 Relapse (if responding) 42% 50% 23% 0.75 0.33 0.23 If receiving DE1 36% 33% 25% 0.67 0.29 1.0 Median OS (months)2 34.8 14.5 17.2 0.89 0.69 0.90 If receiving DE1 37.5 12.1 NYR3 0.67 0.91 0.84 1DE=dose-escalated front-line chemotherapy (EPOCH, hyperCVAD, CODOX-M/IVAC). 2Median length of follow-up 12.0 months (range 0.1-85.6). 3Not yet reached.
Improving Revised International Prognostic Scoring System (IPSS-R) Pre-Allogeneic Stem Cell Transplant Does Not Translate into Better Post-Transplant Outcomes for Patients with Myelodysplastic Syndromes
Authors: Musa Alzahrani, Maryse M Power, Emilie Nevill, Yasser Abou Mourad, Michael J Barnett, Raewyn Broady, Donna L. Forrest, Alina S. Gerrie, Donna E. Hogge, Stephen H. Nantel, David Sanford, Heather J. Sutherland, Cynthia L. Toze, Kevin W. Song, Kevin W. Song, Thomas J. Nevill, Sujaatha Narayanan
Journal: Blood (2016)
Characterization of background noise in capture-based targeted sequencing data
Authors: Gahee Park, Joo Kyung Park, Seung-Ho Shin, Hyo-Jeong Jeon, Nayoung K. D. Kim, Yeon Jeong Kim, Hyun-Tae Shin, Eunjin Lee, Kwang Hyuck Lee, Dae-Soon Son, Woong-Yang Park, Donghyun Park
Journal: Genome biology (2017)

Targeted deep sequencing is increasingly used to detect low-allelic fraction variants; it is therefore essential that errors that constitute baseline noise and impose a practical limit on detection are characterized. In the present study, we systematically evaluate the extent to which errors are incurred during specific steps of the capture-based targeted sequencing process. We removed most sequencing artifacts by filtering out low-quality bases and then analyze the remaining background noise. By recognizing that plasma DNA is naturally fragmented to be of a size comparable to that of mono-nucleosomal DNA, we were able to identify and characterize errors that are specifically associated with acoustic shearing. Two-thirds of C:G > A:T errors and one quarter of C:G > G:C errors were attributed to the oxidation of guanine during acoustic shearing, and this was further validated by comparative experiments conducted under different shearing conditions. The acoustic shearing step also causes A > G and A > T substitutions localized to the end bases of sheared DNA fragments, indicating a probable association of these errors with DNA breakage. Finally, the hybrid selection step contributes to one-third of the remaining C:G > A:T and one-fifth of the C > T errors. The results of this study provide a comprehensive summary of various errors incurred during targeted deep sequencing, and their underlying causes. This information will be invaluable to drive technical improvements in this sequencing method, and may increase the future usage of targeted deep sequencing methods for low-allelic fraction variant detection.
Parent-Based Therapy Helps Children Lose Weight
Authors: Anita Slomski
Journal: JAMA (2017)

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<i>Diabetes Care</i>: Change Is Constant, Part 2
Authors: William T. Cefalu
Journal: Diabetes Care (2017)

On 1 July 2011, I began my initial duties as Editor in Chief of Diabetes Care . In my initial Editor’s Commentary titled “ Diabetes Care : Change Is Constant” (1), I outlined the current status of the journal and what I had learned from the outstanding editors and associate editors who came before me. I described how, as an editorial team, we had prepared to take on the enormous duties that lay before us by studying the strategies that former editorial teams used to advance the journal. We evaluated what had worked, what didn’t work, and provided a narrative on our anticipated challenges. We initiated actions to address and keep abreast of changing times, increased competition from other journals now focused on diabetes, and the issues related to alterations in research funding and health care delivery that would likely drive the content for the journal. During my tenure as Editor in Chief, our editorial team kept you, our readers, well informed with regular updates on our progress, format changes, and views on controversial topics. With dedication and vision, as well as the expertise from the editorial office, the editorial team, and the American Diabetes Association (ADA) Publishing office, we were successful in sustaining the upward trajectory of the journal. The journal's latest impact factor for 2016 is 11.857—its highest impact factor ever—which is an increase from 8.934 in 2015. Diabetes Care , without question, is at its highest level in relevance and remains the world’s premier journal focused solely on diabetes care and clinical research.

Given the success of the journal as outlined above and the fact that our “team” (i.e., editorial committee, editorial office, and publications staff) felt we still had “creative ideas to make the journal better and considerable energy to bring these ideas to fruition,” we …
Abstract P313: Genetic Deletion of Pim Causes Premature Cardiac Senescence
Authors: Shabana Din, Michael McGregor, Brandi Bailey, Sadia Mohsin, Daniele Avitabile, Natalie Gude, Mark A Sussman
Journal: Circulation Research (2011)

Rationale: Cardiac aging is defined as increased cellular senescence and loss of survival signaling within cardiomyocytes and the cardiac stem cell population. To prevent myocardial, aging it is important to reverse the characteristic aging phenotype. Pim-1 is a cardioprotective kinase downstream of AKT, and has been shown to be pro-proliferative and anti-apoptotic. Pim-1 mediated antagonism of myocardial aging will lead to a decrease in cardiac senescence, maintain contractile performance, and prolong the lifespan of an organism. Objective: Demonstrate that myocardial senescence is antagonized by Pim-1 mediated signaling and loss of Pim-1 activity leads to premature aging of the myocardium and associated decline in cardiac performance. Methods and Results: Pim Triple KnockOut (PTKO) mice, in which all three isoforms of Pim are genetically deleted, develop premature phenotypic hallmarks of myocardial senescence. Elevated levels of the tumor suppressor p53 and senescence marker p16 are present in hearts of PTKO mice at two months of age. Increased p16 expression is consistent with observed induction of Ets-1, a transcription factor that activates p16 transcription in PTKO mice. Levels of Id1 and Id2, positive transcriptional regulators of the cell cycle, are decreased in hearts of PTKO mice. Hemodynamic analyses reveal impaired cardiac function in PTKO mice at two months of age. Conversely, cardiac specific overexpression of Pim1-kinase attenuates the senescent phenotype. Hypoxia treatment of neonatal rat cardiomyocytes infected with Pim-1 encoding adenovirus results in reduction of p16 accumulation as seen by qRT-PCR. Pim-1 overexpression increases expression of c-myc, thereby upregulating Id2 and inhibits p16 induced senescence. Cardiac Pim-1 transgenic mice show a delay in the onset of senescence as evidenced by decreased frequency of p16 positive cells in the myocardium. Conclusion: Pim-1 inhibits cardiac senescence and is important for maintaining cardiac function. Therefore, selective manipulation of Pim-1 should be pursued as a therapeutic target to promote and extend myocardial cellular lifespan and function.
French comment on article Endoscopic submucosal dissection for early rectal neoplasia: experience from a European center1 Dissection sous-muqueuse endoscopique pour les lésions rectales superficielles: retour d’expérience d’un centre européen
Journal: Endoscopy (2017)

La résection curative endoscopique est une option thérapeutique pour les larges lésions rectales non pédiculées (LNPCPs). La dissection sous-muqueuse endoscopique (ESD) permet une résection monobloc mais l’expérience en ESD est limitée en dehors des pays asiatiques. Le but de cette étude était d’évaluer le rôle de l’ESD dans le traitement des lésions rectales superficielles dans un centre européen (Klinikum Augsburg, Allemagne).