tbuckley/cabot-search huggingface dataset:
Multistage inhibitors of the malaria parasite: Emerging hope for chemoprotection and malaria eradication
Authors: None Poonam, Yash Gupta, Nikesh Gupta, Snigdha Singh, Lidong Wu, Bhupender Singh Chhikara, Manmeet Rawat, Brijesh Rathi
Journal: Medicinal Research Reviews (2018)

Abstract Over time, several exciting advances have been made in the treatment and prevention of malaria; however, this devastating disease continues to be a major global health problem and affects millions of people every year. Notably, the paucity of new efficient drug molecules and the inevitable drug resistance of the malaria parasite, Plasmodium falciparum , against frontline therapeutics are the foremost struggles facing malaria eradication initiatives. According to the malaria eradication agenda, the discovery of new chemical entities that can destroy the parasite at the liver stage, the asexual blood stage, the gametocyte stage, and the insect ookinete stage of the parasite life cycle (i.e., compounds exhibiting multistage activity) are in high demand, preferably with novel and multiple modes of action. Phenotypic screening of chemical libraries against the malaria parasite is certainly a crucial step toward overcoming these crises. In the last few years, various research groups, including industrial research laboratories, have performed large‐scale phenotypic screenings that have identified a wealth of chemical entities active against multiple life stages of the malaria parasite. Vital scientific and technological developments have led to the discovery of multistage inhibitors of the malaria parasite; these compounds, considered highly valuable starting points for subsequent drug discovery and eradication of malaria, are reviewed.
Atmospheric Plasma Deposition of Methacrylate Layers Containing Catechol/Quinone Groups: An Alternative to Polydopamine Bioconjugation for Biomedical Applications
Authors: Urszula Czuba, Robert Quintana, Marie‐Claire De Pauw‐Gillet, Maxime Bourguignon, Maryline Moreno‐Couranjou, Michael Alexandre, Christophe Detrembleur, Patrick Choquet
Journal: Advanced Healthcare Materials (2018)

Abstract Bioconjugation of enzymes on coatings based on polydopamine (PDA) layers is an appealing approach to control biological responses on biomedical implant surfaces. As alternative to PDA wet deposition, a fast, solvent‐free, and dynamic deposition approach based on atmospheric‐pressure plasma dielectric barrier discharge process is considered to deposit on metallic surfaces acrylic‐based interlayers containing highly chemically reactive catechol/quinone groups. A biomimetic approach based on covalent immobilization of Dispersin B, an enzyme with antibiofilm properties, shows the bioconjugation potential of the novel plasma polymer layers. The excellent antibiofilm activity against Staphylococcus epidermidis is comparable to the PDA‐based layers prepared by wet chemical methods with slow deposition rates. A study of preosteoblastic MG‐63 human cell line viability and adhesion properties on plasma polymer layers demonstrates early interaction required for biomedical applications.
Engineering spheroids potentiating cell-cell and cell-ECM interactions by self-assembly of stem cell microlayer
Authors: Yu Bin Lee, Eun Mi Kim, Hayeon Byun, Hyung-kwan Chang, Kwanghee Jeong, Zachary M. Aman, Yu Suk Choi, Jungyul Park, Heungsoo Shin
Journal: Biomaterials (2018)
ETHNIC DIFFERENCES IN ISCHEMIA/BLEEDING RISK TRADE OFF DURING ANTIPLATELET THERAPY POST- DRUG-ELUTING STENT IMPLANTATION: INDIVIDUAL PATIENT LEVEL META-ANALYSIS FROM SEVEN RANDOMIZED CLINICAL TRIALS
Authors: Jeehoon Kang, Kyung Woo Park, Tullio Palmerini, Gregg Stone, Antonio Colombo, Alaide Chieffo, Alexandre Abizaid, Deepak Bhatt, Myeong-Ki Hong, Yangsoo Jang, Marco Valgimigli, Martine Gilard, Marie Morice, Duk-Woo Park, Seung-Jung Park, Ji-Seuk Park, Bon Kwon Koo, Hyo-Soo Kim
Journal: Journal of the American College of Cardiology (2018)
IMPACT OF AVR ON SURVIVAL OF PATIENTS WITH LOW FLOW, LOW GRADIENT AORTIC STENOSIS
Authors: Mohamed-Salah Annabi, Abdellaziz Dahou, Henrique Ribeiro, Ian Burwash, Josep Rodes-Cabau, Jutta Bergler-Klein, Ezequiel Guzzetti, Geraldine Ong, Maurice Enriquez-Sarano, Stefan Orwat, Florent Le Ven, Helmut Baumgartner, Julia Mascherbauer, Gerald Mundigler, Joao Cavalcante, Marie-Annick Clavel, Philippe Pibarot
Journal: Journal of the American College of Cardiology (2018)
由PSENEN始祖突变引起的结合了化脓性汗腺炎与道林-德戈斯(Dowling-Degos)病的表现型
Authors: M. Pavlovsky, O. Sarig, M. Eskin-Schwartz, N. Malchin, R. Bochner, J. Mohamad, A. Gat, A. Peled, A. Hafner, E. Sprecher
Journal: British Journal of Dermatology (2018)

道林‐德戈斯病是一种罕见的遗传病,在青春期就会开始出现症状,表现为皮肤色素异常(色素沉着),常见于皮肤褶皱处,称为肢端曲侧。家族性化脓性汗腺炎也是一种罕见的遗传病,表现为肢端曲侧出现再生疖。通常在青春期就会开始出现症状。有时,患者身上会同时存在这两种疾病。最近,同时患有化脓性汗腺炎和道林‐德戈斯病的患者被发现名为PSENEN的同一基因存在缺陷。PSENEN的产物是一种蛋白质,它是名为NOTCH的合成物的一部分,后者在皮肤和其他器官发育的过程中起着重要的作用。在此项研究中,我们报告了4个德系犹太人家庭,他们具有两种疾病的临床表现特征。我们发现所有的患者都具有相同的PSENEN基因缺陷,此前这种缺陷从未被发现过。我们检查了该基因周围的区域,发现所有患者的情况都一样。这意味着,所有的患者都拥有来自同一祖先的突变。在研究项目的下一步中,我们希望展示对NOTCH产生实际影响的PSENEN基因缺陷。我们将一位患者的细胞与一位健康人员的细胞进行了对比。我们发现,患者细胞中的PSENEN较少,而当我们在细胞中注入一种当NOTCH处于活跃状态时使细胞发光的特殊元素时,我们发现患者细胞的发光程度要低于健康人员的细胞。总之,在现阶段研究中,我们发现了PSENEN中的一种新型基因缺陷,可能会同时引起两种疾病:道林‐德戈斯病和化脓性汗腺炎。我们还发现,NOTCH在两种疾病中都起着重要的作用。
Can free PSA be used as a biomarker in biochemical recurrence after surgery to predict castrate resistant prostate cancer?
Authors: Hanan Goldberg, Ally Hoffman, Teck Sing Woon, Zachary William Abraham Klaassen, Thenappan Chandrasekar, Douglas Cheung, Alejandro Berlin, Rashid Sayyid, Neil Eric Fleshner
Journal: Journal of Clinical Oncology (2018)

177 Background: PSA produced from prostate cancer (PC) cells escapes proteolytic processing, resulting in a more complexed PSA and a lower %fPSA. Higher %fpsa correlates with lower PC risk. However, the role of fPSA in biochemical recurrence (BCR) after radical prostatectomy (RP) is unknown. Methods: All patients who had BCR after RP and at least one fPSA test, were included. Patients were stratified according to the %fPSA cut-off of 0.15. Multivariable logistic regression analysis was performed to predict covariates associated with a higher %fPSA. Results: A total of 81 men with BCR were found (Table 1). Interestingly, 20% (group 1) vs. 60% (groups 2) become castrate resistant (CRPC), p&lt;0.0001 and the time to reach CRPC state was much shorter in group 2 (33.5 months) vs. group 1 (57.9 months), p=0.05. Additionally, 60% of group 2 patients vs. 32.5% of group 1 patients developed metastasis, p=0.014. Lastly, median survival of 193 months for group 2 patients with no median survival for group 1, Log Rank test p=0.023. Multivariable logistic regression analysis demonstrated that secondary Gleason score of 5 (compared to 3) and %fPSA&gt;0.15 predicted CRPC status (OR 11.63, CI 95% 1.38-97.4, p=0.024, OR 7.99, CI 95% 2-31.95, p=0.003, respectively). Conclusions: %fPSA&gt;0.15 in the setting of BCR confers a more aggressive disease, manifesting in a faster development of CRPC, metastasis and death. Our findings suggest a reversal in the significance of % fPSA values in BCR patients, and should be validated in larger cohorts. [Table: see text]
Fc-Mediated Anomalous Biodistribution of Therapeutic Antibodies in Immunodeficient Mouse Models
Authors: Sai Kiran Sharma, Andrew Chow, Sebastien Monette, Delphine Vivier, Jacob Pourat, Kimberly J. Edwards, Thomas R. Dilling, Dalya Abdel-Atti, Brian M. Zeglis, John T. Poirier, Jason S. Lewis
Journal: Cancer Research (2018)

A critical benchmark in the development of antibody-based therapeutics is demonstration of efficacy in preclinical mouse models of human disease, many of which rely on immunodeficient mice. However, relatively little is known about how the biology of various immunodeficient strains impacts the in vivo fate of these drugs. Here we used immunoPET radiotracers prepared from humanized, chimeric, and murine mAbs against four therapeutic oncologic targets to interrogate their biodistribution in four different strains of immunodeficient mice bearing lung, prostate, and ovarian cancer xenografts. The immunodeficiency status of the mouse host as well as both the biological origin and glycosylation of the antibody contributed significantly to the anomalous biodistribution of therapeutic monoclonal antibodies in an Fc receptor-dependent manner. These findings may have important implications for the preclinical evaluation of Fc-containing therapeutics and highlight a clear need for biodistribution studies in the early stages of antibody drug development.Significance: Fc/FcγR-mediated immunobiology of the experimental host is a key determinant to preclinical in vivo tumor targeting and efficacy of therapeutic antibodies. Cancer Res; 78(7); 1820-32. ©2018 AACR.
Wearable Biosensors: Disposable <i>Morpho menelaus</i> Based Flexible Microfluidic and Electronic Sensor for the Diagnosis of Neurodegenerative Disease (Adv. Healthcare Mater. 5/2018)
Authors: Zhenzhu He, Abdelrahman Elbaz, Bingbing Gao, Junning Zhang, Enben Su, Zhongze Gu
Journal: Advanced Healthcare Materials (2018)

A disposable Morpho menelaus based wearable biosensor with integration of a microfluidic system and electronic networks is presented in article number 1701306 by Zhongze Gu and co-workers. The excellent structural and optical characteristics of the Morpho menelaus are exploited for flexible sensors, which enable biochemical-physiological hybrid monitoring of neurodegenerative disease for the early diagnosis.
Myocarditis in Patients Treated With Immune Checkpoint Inhibitors
Authors: Syed S. Mahmood, Michael G. Fradley, Justine V. Cohen, Anju Nohria, Kerry L. Reynolds, Lucie M. Heinzerling, Ryan J. Sullivan, Rongras Damrongwatanasuk, Carol L. Chen, Dipti Gupta, Michael C. Kirchberger, Magid Awadalla, Malek Z.O. Hassan, Javid J. Moslehi, Sachin P. Shah, Sarju Ganatra, Paaladinesh Thavendiranathan, Donald P. Lawrence, John D. Groarke, Tomas G. Neilan
Journal: Journal of the American College of Cardiology (2018)
The impact of neoadjuvant chemotherapy (NAC) on conditional survival (CS) among patients with muscle-invasive bladder cancer (MIBC).
Authors: Nikhil Waingankar, Rachel Jia, Bart Ferket, François Audenet, Reza Mehrazin, John Sfakianos, Madhu Mazumdar, Matt D. Galsky
Journal: Journal of Clinical Oncology (2018)

520 Background: Achieving a pathologic complete response (pCR) with NAC for MIBC is associated with a favorable prognosis. Patients with pathologic residual disease (pRD) generally have poor outcomes. However, prognosis after radical cystectomy (RC) improves with ongoing survivorship. Whether the difference in prognosis of patients with pCR and pRD is sustained over time has not been explored. Methods: We queried the National Cancer Database for patients who received NAC and RC for clinically localized MIBC (cT2-T4aN0M0) between 2002-2010. We identified patients with pCR (&lt;/= pTis) and pRD. Using Kaplan-Meier analysis, we assessed CS up to 5 years given survivorship of 0-4 years using log-rank test with multiple comparison adjustment. Results: The cohort comprised 1,554 patients (pCR: 314, pRD: 1,240). The median follow up was 2.38 (0.04-9.60) and 2.76 (0.01-9.97) years for pCR and pRD, respectively. Patients with pCR had lower stage (cT2= 79% vs. 72%; cT3= 14% vs. 18%; cT4= 7% vs. 10%), more recent diagnosis (2010: 31% vs. 19%), and were more often treated at a high-volume center (&gt;15 RC/year: 61% vs. 49%). Patients with pCR had improved CS relative to those with pRD with survivorship up to 3 years, but the benefit associated with pCR becomes attenuated from 4 years post-RC (Table). Conclusions: MIBC patients with pRD after NAC have worse CS up to years 3 post-RC, but this difference diminishes after 4 years. These findings may inform patient counseling, surveillance intensity, and novel adjuvant approaches for patients with pRD, and are subject to confirmation with a forthcoming multivariable analysis. Probability of surviving to X years (95% CI). [Table: see text]
Consultant delivered care improves outcomes and should become the norm, say royal colleges
Authors: Helen Jaques
Journal: BMJ (2012)

Consultant delivered care improves patients’ outcomes and increases the efficiency of care, a major review of the topic by the Academy of Medical Royal Colleges has concluded.

The academy recommends that consultant delivered care should be available to all patients throughout the whole day and the whole week, although it cautions that a different approach to consultants’ working patterns will be needed to achieve this.

“This review provides real evidence that patients are likely to have better outcomes to their care and resources will be used more effectively when medical care is delivered by consultants,” said Terence Stephenson, vice chairman of the academy and leader of the steering group. “The weight of evidence makes it clear that it can no longer be acceptable for some patients to …
The Specialist Registrar and New Consultant Handbook (3rd edn)
Authors: Rachel Hooke
Journal: BMJ (2007)

We hear that the transition from junior doctor to consultant is not an automatically smooth progression, particularly with non-clinical concepts. Dealing with colleagues can be a thorny issue at any stage, but particularly so at consultant level. For the first time in your life, you have full responsibility for your patients and your team. You are also more accountable to NHS management. There is concern that doctors coming through the new system will be less prepared than those of yesteryear.

This book goes some …
Recruitment “disaster” may occur if Shape of Training review is poorly implemented, trainees say
Authors: Abi Rimmer
Journal: BMJ (2014)

Poor implementation of last year’s major review of postgraduate medical education and training could have “a disastrous impact” on the future recruitment of doctors, trainees have warned. 

Doctors on the trainee committees of four royal medical colleges have published a joint statement in response to the UK-wide Shape of Training review, which was led by David Greenaway, vice chancellor of Nottingham University, and published in October 2013.1 The trainees welcomed many aspects of the review, including its recommendations for broad based training and increased flexibility during training. But they warned that …
OUTCOMES AFTER TRANSCATHETER MITRAL VALVE REPAIR IN PATIENTS WITH CHRONIC KIDNEY DISEASE: AN ANALYSIS OF 5,241 PATIENTS IN THE UNITED STATES
Authors: Binita Shah, Sreekanth Vemulapalli, Pratik Manandhar, Nicholas Amoroso, Tania Ruiz-Maya, Cezar Staniloae, Muhamed Saric, Mathew Williams
Journal: Journal of the American College of Cardiology (2018)
GPs returning to practice are being asked to work for free, reports BMA
Authors: Helen Jaques
Journal: BMJ (2013)

Some GPs who return to practice after a career break are not being paid a salary, whereas others receive pay as low as £50 a session, research by the BMA has found.

The union’s unpublished survey of deaneries and health boards in the United Kingdom highlights the wide variation in provision and payment for GPs who want to return to work through the GP induction and refresher (I+R) scheme.

The I+R scheme allows GPs who have been away from UK practice for two years or more to return safely and confidently to general practice. GPs on the scheme—most of whom have taken time out to work abroad or start a family—spend between three and six months working supervised in a training practice. 

Up until 2006, the I+R scheme in England was funded by the Department …
Whole-genome sequencing of multiple myeloma reveals oncogenic pathways are targeted somatically through multiple mechanisms
Authors: Phuc H. Hoang, Sara E. Dobbins, Alex J. Cornish, Daniel Chubb, Philip J. Law, Martin Kaiser, Richard S. Houlston
Journal: Leukemia (2018)

Multiple myeloma (MM) is a biologically heterogeneous malignancy, however, the mechanisms underlying this complexity are incompletely understood. We report an analysis of the whole-genome sequencing of 765 MM patients from CoMMpass. By employing promoter capture Hi-C in naïve B-cells, we identify cis-regulatory elements (CREs) that represent a highly enriched subset of the non-coding genome in which to search for driver mutations. We identify regulatory regions whose mutation significantly alters the expression of genes as candidate non-coding drivers, including copy number variation (CNV) at CREs of MYC and single-nucleotide variants (SNVs) in a PAX5 enhancer. To better inform the interplay between non-coding driver mutations with other driver mechanisms, and their respective roles in oncogenic pathways, we extended our analysis identifying coding drivers in 40 genes, including 11 novel candidates. We demonstrate the same pathways can be targeted by coding and non-coding mutations; exemplified by IRF4 and PRDM1, along with BCL6 and PAX5, genes that are central to plasma cell differentiation. This study reveals new insights into the complex genetic alterations driving MM development and an enhanced understanding of oncogenic pathways.
King-Devick concussion test performs poorly as a screening tool in elite rugby union players: a prospective cohort study of two screening tests versus a clinical reference standard
Authors: Gordon Ward Fuller, Matthew J Cross, Keith A Stokes, Simon P T Kemp
Journal: British Journal of Sports Medicine (2018)

Background The King-Devick (KD) test is an objective clinical test of eye movements that has been used to screen for concussion. We characterised the accuracy of the KD test and the World Rugby Head Injury Assessment (HIA-1) screening tools as methods of off-field evaluation for concussion after a suspicious head impact event. Methods A prospective cohort study was performed in elite English rugby union competitions between September 2016 and May 2017. The study population comprised consecutive players identified with a head impact event with the potential to result in concussion. The KD test was administered off-field, alongside the World Rugby HIA-1 screening tool, and the results were compared with the preseason baseline. Accuracy was measured against a reference standard of confirmed concussion, based on the clinical judgement of the team doctor after serial assessments. Results 145 head injury events requiring off-field medical room screening assessments were included in the primary analysis. The KD test demonstrated a sensitivity of 60% (95% CI 49.0 to 70) and a specificity of 39% (95% CI 26 to 54) in identifying players subsequently diagnosed with concussion. Area under the receiver operating characteristic curve for prolonged KD test times was 0.51 (95% CI 0.41 to 0.61). The World Rugby HIA-1 off-field screening tool sensitivity did not differ significantly from the KD test (sensitivity 75%, 95% CI 66 to 83, P=0.08), but specificity was significantly higher (91%, 95% CI 82 to 97, P&lt;0.001). Although combining the KD test and the World Rugby HIA-1 multimodal screening assessment achieved a significantly higher sensitivity of 93% (95% CI 86% to 97%), there was a significantly lower specificity of 33% (95% CI 21% to 48%), compared with the HIA-1 test alone. Conclusions The KD test demonstrated limited accuracy as a stand-alone remove-from-play sideline screening test for concussion. As expected with the addition of any parallel test, combination of the KD test with the HIA-1 off-field screening tool provided improved sensitivity in identifying concussion, but at the expense of markedly lower specificity. These results suggest that it is unlikely that the KD test will be incorporated into multimodal off-field screening assessments for concussion at the present time.
Receptor-targeted aptamer-siRNA conjugate-directed transcriptional regulation of HIV-1
Authors: Jiehua Zhou, Daniel Lazar, Haitang Li, Xin Xia, Sangeetha Satheesan, Paige Charlins, Denis O'Mealy, Ramesh Akkina, Sheena Saayman, Marc S. Weinberg, John J. Rossi, Kevin V. Morris
Journal: Theranostics (2018)

Gene-based therapies represent a promising therapeutic paradigm for the treatment of HIV-1, as they have the potential to maintain sustained viral inhibition with reduced treatment interventions.Such an option may represent a long-term treatment alternative to highly active antiretroviral therapy.Methods: We previously described a therapeutic approach, referred to as transcriptional gene silencing (TGS), whereby small noncoding RNAs directly inhibit the transcriptional activity of HIV-1 by targeting sites within the viral promoter, specifically the 5' long terminal repeat (LTR).TGS differs from traditional RNA interference (RNAi) in that it is characterized by concomitant silent-state epigenetic marks on histones and DNA.To deliver TGS-inducing RNAs, we developed functional RNA conjugates based on the previously reported dual function of the gp120 (A-1) aptamer conjugated to 27-mer Dicer-substrate anti-HIV-1 siRNA (dsiRNA), LTR-362. Results:We demonstrate here that high levels of processed guide RNAs localize to the nucleus in infected T lymphoblastoid CEM cell line and primary human CD4+ T-cells.Treatment of the aptamer-siRNA conjugates induced TGS with an ~10-fold suppression of viral p24 levels as measured at day 12 post infection.To explore the silencing efficacy of aptamer-siRNA conjugates in vivo, HIV-1-infected humanized NOD/SCID/IL2 rγ null mice (hu-NSG) were treated with the aptamer-siRNA conjugates.Systemic delivery of the A-1-stick-LTR-362 27-mer siRNA conjugates suppressed HIV-1 infection and protected CD4+ T cell levels in viremia hu-NSG mice.Principle conclusions: Collectively these data suggest that the gp120 aptamer-dsiRNA conjugate design is suitable for systemic delivery of small RNAs that can be used to suppress HIV-1.
Diagnosis, treatment and prevention of ankle sprains: update of an evidence-based clinical guideline
Authors: Gwendolyn Vuurberg, Alexander Hoorntje, Lauren M Wink, Brent F W van der Doelen, Michel P van den Bekerom, Rienk Dekker, C Niek van Dijk, Rover Krips, Masja C M Loogman, Milan L Ridderikhof, Frank F Smithuis, Sjoerd A S Stufkens, Evert A L M Verhagen, Rob A de Bie, Gino M M J Kerkhoffs
Journal: British Journal of Sports Medicine (2018)

This guideline aimed to advance current understandings regarding the diagnosis, prevention and therapeutic interventions for ankle sprains by updating the existing guideline and incorporate new research. A secondary objective was to provide an update related to the cost-effectiveness of diagnostic procedures, therapeutic interventions and prevention strategies. It was posited that subsequent interaction of clinicians with this guideline could help reduce health impairments and patient burden associated with this prevalent musculoskeletal injury. The previous guideline provided evidence that the severity of ligament damage can be assessed most reliably by delayed physical examination (4-5 days post trauma). After correct diagnosis, it can be stated that even though a short time of immobilisation may be helpful in relieving pain and swelling, the patient with an acute lateral ankle ligament rupture benefits most from use of tape or a brace in combination with an exercise programme.New in this update: Participation in certain sports is associated with a heightened risk of sustaining a lateral ankle sprain. Care should be taken with non-steroidal anti-inflammatory drugs (NSAIDs) usage after an ankle sprain. They may be used to reduce pain and swelling, but usage is not without complications and NSAIDs may suppress the natural healing process. Concerning treatment, supervised exercise-based programmes preferred over passive modalities as it stimulates the recovery of functional joint stability. Surgery should be reserved for cases that do not respond to thorough and comprehensive exercise-based treatment. For the prevention of recurrent lateral ankle sprains, ankle braces should be considered as an efficacious option.
LOW-DOSE RECOMBINANT TISSUE-TYPE PLASMINOGEN ACTIVATOR (RT-PA) THROMBOLYSIS AND ORAL FACTOR XA INHIBITOR AS ADJUNCTIVE TREATMENT IN HIGH-RISK PULMONARY EMBOLISM (PE)
Authors: Vicente Jimenez Franco, José Gildardo Paredes-Vázquez, Marcos Ibarra, Carlos Sanchez-Diaz, Felipe Valdes, Hernan Azpiri
Journal: Journal of the American College of Cardiology (2018)