tbuckley/cabot-search huggingface dataset:
Enhanced digestion inhibition and mucus penetration of F127-modified self-nanoemulsions for improved oral delivery
Authors: Wenyi Song, Yuting Yang, Miaorong Yu, Quanlei Zhu, Mohammadali Soleimani Damaneh, Haijun Zhong, Yong Gan
Journal: Asian Journal of Pharmaceutical Sciences (2018)

Self-nanoemulsifying systems (SNEs) have excellent ability to improve the solubility of poorly water-soluble drugs (PWSD). However, SNEs are likely to be degraded in gastrointestinal (GIT) when their surface is recognized by lipase/co-lipase enzyme complex, resulting in rapid release and precipitation of encapsulated drugs. The precipitates are then captured and removed by intestinal mucus, reducing the delivery efficacy of SNEs. Herein, the amphiphilic polymer Pluronic® F127 was incorporated into long and short-chain triglycerides (LCT, SCT) based SNEs to diminish the recognition and therefore minimized their degradation by enzymes and clearance by mucus. The SNEs were characterized in terms of particle size, zeta potential and stability. Ex vivo multiple particles tracking studies were performed by adding particle solution into fresh rat mucus. Cellular uptake of SNEs were conducted by using E12 cells, the absorption and distribution in small intestine were also studied after oral administration in male Sprague-Dawley (SD) rats. The in vitro digestion rate of SNEs were found to be in following order SCT-SNE > SCT-F127-SNE > LCT-SNE > LCT-F127-SNE. Moreover, the LCT-F127-SNE was found to be most effective in enhancing cellular uptake, resulting in 3.5-fold, 2.1-fold and 1.7-fold higher than that of SCT-SNE, LCT-SNE and SCT-F127-SNE, respectively. After incubating the SNE with E12 cells, the LCT-F127-SNE exhibited the highest amount regarding both mucus penetration and cellular uptake, with an uptake amount number (via bicinchoninic acid (BCA) analysis) of 3.5-fold, 2.1-fold and 1.7-fold higher than that of SCT-SNE, LCT-SNE and SCT-F127-SNE, respectively. The in vivo results revealed that orally administered LCT-F127-SNE could significantly increase the bioavailability of Cyclosporine A (CsA), which was approximately 2.43-fold, 1.33-fold and 1.80-fold higher than that of SCT-SNE, SCT-F127-SNE and LCT-SNE, respectively. We address in this work that F127-modified SNEs have potentials to improve oral drug absorption by significantly reducing gastrointestinal enzymatic degradation and simultaneously enhancing mucus penetration.
Infographic. Achilles and patellar tendinopathy rehabilitation: strive to implement loading principles not recipes
Authors: Peter Malliaras, Jorge Rodriguez Palomino, Christian J Barton
Journal: British Journal of Sports Medicine (2018)

In 2013, our group published a systematic review of Achilles and patellar tendinopathy rehabilitation programmes.1 Eccentric loading involving slow lengthening muscle contractions was, and among many still is, regarded as the first choice rehabilitation option for these lower limb overuse conditions. The rise in popularity followed Hakan Alfredson’s 1998 publication demonstrating 100% return to preinjury function with isolated eccentric loading in Achilles tendinopathy.2 This publication has had 1072 citations in Google Scholar in February 2018.

However, subsequent studies were not all able to replicate these impressive outcomes. For example, Sayana et al 3 reported that up to 45% with Achilles tendinopathy did not respond to isolated eccentric loading (defined as less than a 10% change in a disease-specific pain and function outcome).

The objective of our 2013 …
I want to enter into foundation year 2 (F2) posts. Are these posts available with radiology as a component?
Authors: Alan Denison
Journal: BMJ (2005)

Have a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone (www.bmjcareers.com/advicezone) for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site.
ZEB1, ZEB2, and the miR-200 family form a counterregulatory network to regulate CD8+ T cell fates
Authors: Tianxia Guan, Claudia X. Dominguez, Robert A. Amezquita, Brian J. Laidlaw, Jijun Cheng, Jorge Henao-Mejia, Adam Williams, Richard A. Flavell, Jun Lu, Susan M. Kaech
Journal: The Journal of Experimental Medicine (2018)

Long-term immunity depends partly on the establishment of memory CD8+ T cells. We identified a counterregulatory network between the homologous transcription factors ZEB1 and ZEB2 and the miR-200 microRNA family, which modulates effector CD8+ T cell fates. Unexpectedly, Zeb1 and Zeb2 had reciprocal expression patterns and were functionally uncoupled in CD8+ T cells. ZEB2 promoted terminal differentiation, whereas ZEB1 was critical for memory T cell survival and function. Interestingly, the transforming growth factor β (TGF-β) and miR-200 family members, which counterregulate the coordinated expression of Zeb1 and Zeb2 during the epithelial-to-mesenchymal transition, inversely regulated Zeb1 and Zeb2 expression in CD8+ T cells. TGF-β induced and sustained Zeb1 expression in maturing memory CD8+ T cells. Meanwhile, both TGF-β and miR-200 family members selectively inhibited Zeb2. Additionally, the miR-200 family was necessary for optimal memory CD8+ T cell formation. These data outline a previously unknown genetic pathway in CD8+ T cells that controls effector and memory cell fate decisions.
Impact of Incidence and Progression of Diabetic Retinopathy on Vision-Specific Functioning
Authors: Preeti Gupta, Alfred Tau Liang Gan, Ryan Eyn Kidd Man, Eva K. Fenwick, Neelam Kumari, Gavin Tan, Paul Mitchell, Charumathi Sabanayagam, Tien Yin Wong, Ching-Yu Cheng, Ecosse L. Lamoureux
Journal: Ophthalmology (2018)
The immunomodulatory activity of bemcentinib (BGB324): A first-in-class selective oral AXL inhibitor in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome.
Authors: Sonja Loges, Björn Tore Gjertsen, Michael Heuser, Jörg Chromik, Carlos Enrique Vigil, Peter Paschka, I Ben-Batalla, Nuray Akyüz, David Micklem, Anthony Brown, James Lorens, Maxim Kebenko, Melanie Janning, Mascha Binder, Walter M. Fiedler, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2018)

70 Background: The tyrosine kinase AXL acts as suppressive immune checkpoint of the innate immune system. AXL signalling leads to immunosuppression and tumour immune escape by downregulating dendritic cell activity, modulating efferocytosis as well as favouring an immunosuppressive chemokine profile and M-MDSC expansion. Therefore it represents an interesting novel immune oncology target. Bemcentinib (BGB324) is a first-in-class, highly selective and orally bioavailable small molecule AXL inhibitor in phase II clinical development. In pre-clinical models, inhibition of AXL signalling with bemcentinib reversed multiple established immune suppressive mechanisms leading to increased infiltration of CTLs, NK and NKT cells and decreased infiltration of M-MDSCs (Wnuk-Lipinska, 2017). We explored safety, PK, efficacy and the effects of treatment with bemcentinib on the T- and B cell repertoire in patients with relapsed AML or MDS. Methods: BGBC003 (NCT02488408) is an open-label, dose finding study of bemcentinib in patients with R/R AML or MDS. Three dose levels have been explored and a loading dose of 400 mg on days one to three followed by 200 mg daily thereafter has been established as safe and recommended phase 2 dose. The TCRß repertoire was quantified by NGS of DNA isolated from PBMNCs using an Illumina MiSeq sequencer. TCRß genes and the IGH repertoire were analysed with BIOMED2-TCRß-A and –B and BIOMED2-FR1/-FR3 primer pools, respectively. Using genomic DNA as template, the amplicons were tagged with Illumina adapters and indices in two consecutive PCR reactions. Demultiplexing and FastQ formated data output was generated by the MiSeq reporter. Analysis of TCRß and IGH data was performed on a Microsoft Cloud using our in-house analysis pipeline Pippa. Results: Early evidence of antileukemic activity was seen. Diversification of the TCR and IGH repertoire could be detected in peripheral blood at day 21 of therapy compared to pre-treatment in three and two out of five matched samples, respectively. Conclusions: Bemcentinib shows preliminary evidence of immune modulation in AML. Clinical trial information: NCT02488408.
Weekly cabazitaxel in elderly patients (EP) with metastatic castration resistant prostate cancer (mCRPC) progressing after docetaxel treatment: WeCabE, a phase II study.
Authors: Bruno Castagneto, Ilaria Stevani, Roberto Bortolus, Alessandra Bearz, Roberta Buosi, Emanuela Chimienti, Alessandra Guglielmi, Pamela Guglielmini, Sandra Santarossa, Lucia Fratino
Journal: Journal of Clinical Oncology (2018)

300 Background: Docetaxel (Doc) and Cabazitaxel (Cab) every 3 weeks with daily prednisone are standard first and second line chemotherapies in mCRPC. In daily practice, many mCRPC pts are aged &gt; 65 years and around 20% are aged &gt; 75years. MATuRITY registry shows that taxanes therapy provides EP with increased chances of surviving even in case of frailty. EP unfit due to their comorbidities are at risk of AE related to the chemo-treatment, so an appropriate adjustment of the dosage and schedule should be take into account. According to SIOG guidelines, G-8 Screening Tool represents a key tool to identify a suitable subset of EP able to receive cab. Methods: WeCabE enrolled mCRPC EP ≥ 70 and &lt; 85 years, G8 Score 8-14, PS 0-2. Cab was administered at a dose of 8mg /m2 (10mg/m2 if well tolerated) for 4 out 5 weeks Use of G-CSF was allowed. Median PFS, primary endpoint, was evaluated according to PCWG-2. Secondary endpoints were: PSA Response, ORR, OS, Safety, Geriatric assessment (Minimal Data Set according with Elderly Task Force EORTC) on outcomes. PSA response, safety, impact of the treatment on pain and G8 score pre and post cab were analysed. Results: At time of this analysis 14 EP enrolled in WeCabE were analysed. Median age was 78 years, 35.7% of pts were 80-85 years. Median number of cycles received, in pts who ended treatment was 4. Overall 55.6% of pts reached a PSA response while 33.3% achieved a stability. 42.8% of pts ended therapy without a worsening/rising of symptoms, 42.8% and 14.4% showed, respectively, mild and severe pain at end of cab. G8 best score improvement during treatment was 1.28 (median). The most common AE G 3-4 was fatigue (20%) while G1-2 toxicities were diarrhea (40%) and fatigue (60%). Only one pt experienced neutropenia and anemia G3-4. Conclusions: These preliminary results confirm the usefulness of G8 tool to identify elderly mCRPC pts suitable to receive chemotherapy. It suggests that weekly cabazitaxel, in elderly mCRPC, is effective including in very old pts ( &gt; 80 ), with a manageable safety profile. Additional results will be presented at ASCO GU meeting. Trial partially supported by Sanofi Genzyme Clinical trial information: 2014-001647-20.
Patients’ interests will be “at heart” of training changes, review group says
Authors: Marika Davies
Journal: BMJ (2015)

The interests of patients will be “at the heart” of any changes to medical training, says the group deciding how the recommendations of the Shape of Training review will be implemented.

The Shape of Training Steering Group, which was set up to consider how to take forward the recommendations of the Shape of Training reviews, has issued a statement outlining its plans. The group said that proposed changes to training would need to be “properly considered, modelled and costed, and consulted upon” before any changes were made. “Patients’ interests will be at the heart of any proposals,” the group said.

The group also intends to expand its membership to include representation from the BMA, employers, patients, and trainee doctors. In addition, a mapping exercise will be carried out by the Academy of Medical Royal Colleges to look at the extent to which medical royal colleges have, or can develop, generic components of their …
Cynical Acumen: The Anarchic Guide to Clinical Medicine
Authors: Patrick Hutt
Journal: BMJ (2006)

John Larkin

Radcliffe, 2005, £19.95, 152 pages

ISBN: 1 85775 787 4

Rating: ★★★★/5



My memories of bedside teaching are mixed. Sometimes it was good. Sometimes it was bad. Most of the time it never happened, “Why don't you go and have a coffee and come back in an hour?” I kept waiting and returning, hoping that someone would simplify the chaos of medicine.

Cynical Acumen is a book written by a bedside enthusiast. John Larkin works from the premise, “The purpose …
Age-Dependent Cellular and Behavioral Deficits Induced by Molecularly Targeted Drugs Are Reversible
Authors: Joseph Scafidi, Jonathan Ritter, Brooke M. Talbot, Jorge Edwards, Li-Jin Chew, Vittorio Gallo
Journal: Cancer Research (2018)

Newly developed targeted anticancer drugs inhibit signaling pathways commonly altered in adult and pediatric cancers. However, as these pathways are also essential for normal brain development, concerns have emerged of neurologic sequelae resulting specifically from their application in pediatric cancers. The neural substrates and age dependency of these drug-induced effects in vivo are unknown, and their long-term behavioral consequences have not been characterized. This study defines the age-dependent cellular and behavioral effects of these drugs on normally developing brains and determines their reversibility with post-drug intervention. Mice at different postnatal ages received short courses of molecularly targeted drugs in regimens analagous to clinical treatment. Analysis of rapidly developing brain structures important for sensorimotor and cognitive function showed that, while adult administration was without effect, earlier neonatal administration of targeted therapies attenuated white matter oligodendroglia and hippocampal neuronal development more profoundly than later administration, leading to long-lasting behavioral deficits. This functional impairment was reversed by rehabilitation with physical and cognitive enrichment. Our findings demonstrate age-dependent, reversible effects of these drugs on brain development, which are important considerations as treatment options expand for pediatric cancers.Significance: Targeted therapeutics elicit age-dependent long-term consequences on the developing brain that can be ameliorated with environmental enrichment. Cancer Res; 78(8); 2081-95. ©2018 AACR.
Patient Characteristics Associated With Severe Hypoglycemia in a Type 2 Diabetes Cohort in a Large, Integrated Health Care System From 2006 to 2015
Authors: Anita D. Misra-Hebert, Kevin M. Pantalone, Xinge Ji, Alex Milinovich, Tanujit Dey, Kevin M. Chagin, Janine M. Bauman, Michael W. Kattan, Robert S. Zimmerman
Journal: Diabetes Care (2018)

OBJECTIVE To identify severe hypoglycemia events, defined as emergency department visits or hospitalizations for hypoglycemia, in patients with type 2 diabetes receiving care in a large health system and to identify patient characteristics associated with severe hypoglycemia events. RESEARCH DESIGN AND METHODS This was a retrospective cohort study from January 2006 to December 2015 using the electronic medical record in the Cleveland Clinic Health System (CCHS). Participants included 50,439 patients with type 2 diabetes receiving care in the CCHS. Number of severe hypoglycemia events and associated patient characteristics were identified. RESULTS The incidence proportion of severe hypoglycemia increased from 0.12% in 2006 to 0.31% in 2015 (P = 0.01). Compared with patients who did not experience severe hypoglycemia, those with severe hypoglycemia had similar median glycosylated hemoglobin (HbA1c) levels. More patients with severe hypoglycemia versus those without had a prior diagnosis of nonsevere hypoglycemia (9% vs. 2%, P &amp;lt; 0.001). Logistic regression confirmed an increased odds for severe hypoglycemia with insulin, sulfonylureas, increased number of diabetes medications, history of nonsevere hypoglycemia (odds ratio [OR] 3.01, P &amp;lt; 0.001), HbA1c &amp;lt;6% (42 mmol/mol) (OR 1.95, P &amp;lt; 0.001), black race, and increased Charlson comorbidity index. Lower odds of severe hypoglycemia were noted with higher BMI and use of metformin, dipeptidyl peptidase 4 inhibitors, and glucagon-like peptide 1 agonists. CONCLUSIONS In this retrospective study of patients with type 2 diabetes with severe hypoglycemia, patient characteristics were identified. Patients with severe hypoglycemia had previous nonsevere hypoglycemia diagnoses more frequently than those without. Identifying patients at high risk at the point of care can allow for change in modifiable risk factors and prevention of severe hypoglycemia events.
Applying ethical standards to guide shared decision-making with youth athletes
Authors: Clare L Ardern, Hege Grindem, Guri Ranum Ekås, Romain Seil, Michael McNamee
Journal: British Journal of Sports Medicine (2018)

Despite the vast quantity of information available to patients, parents and clinicians, high-quality information and knowledge remains in relatively short supply.1 The benefits of an active lifestyle are incontrovertible. However, youth athletes have substantial risk for sports-related injuries to the musculoskeletal system and the brain.2 3 These potential dangers are known to clinicians who are helping youth athletes and their parents make sound decisions about injury management and sports participation. In the face of these challenges, how does the clinician fulfil his or her duty of care to youth athletes?

The aim of this editorial is to illustrate how different ethical standards can help guide better shared decisions in sports medicine clinical practice. Youth athletes are a particularly vulnerable group because their life plans are still developing. Adding to this complexity is an increasing trend towards professionalisation in youth sport. When arriving at a decision in a clinical dilemma, one or several ethical standards may help the decision-making team evaluate if a decision is ethically justifiable. The 2018 International Olympic Committee consensus on paediatric ACL injury4 outlined six ethical standards (box 1) that may apply to different situations in sports medicine clinical practice.Box 1 
### Six ethical standards that can apply to sports medicine clinical scenarios

1.  Best interests 5: what is in the youth athlete’s best long-term interests.

2.  Harm principle 6: a threshold below which the clinician should not acquiesce to a parent-led …
Voxtalisib (XL765) in patients with relapsed or refractory non-Hodgkin lymphoma or chronic lymphocytic leukaemia: an open-label, phase 2 trial
Authors: Jennifer R Brown, Mehdi Hamadani, John Hayslip, Ann Janssens, Nina Wagner-Johnston, Oliver Ottmann, Jon Arnason, Hervé Tilly, Michael Millenson, Fritz Offner, Nashat Y Gabrail, Siddhartha Ganguly, Sikander Ailawadhi, Siddha Kasar, Arnon P Kater, Jeanette K Doorduijn, Lei Gao, Joanne J Lager, Bin Wu, Coumaran Egile, Marie José Kersten
Journal: The Lancet Haematology (2018)
Public health directors must report directly to council chief executives, says Faculty of Public Health
Authors: Abi Rimmer
Journal: BMJ (2014)

The Faculty of Public Health has called on local authorities in England to ensure that directors of public health report directly to the authorities’ chief executive officers.

Responsibility for public health was transferred from the NHS to local authorities in April 2013. Since then local authorities have been required to appoint a director of public health who is directly responsible to their chief executive …
Filippo Pacini—A Life of Achievement
Authors: Aria Shakeri
Journal: JAMA Dermatology (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2
Authors: Joao Incio, Jennifer A. Ligibel, Daniel T. McManus, Priya Suboj, Keehoon Jung, Kosuke Kawaguchi, Matthias Pinter, Suboj Babykutty, Shan M. Chin, Trupti D. Vardam, Yuhui Huang, Nuh N. Rahbari, Sylvie Roberge, Dannie Wang, Igor L. Gomes-Santos, Stefan B. Puchner, Christopher L. Schlett, Udo Hoffmman, Marek Ancukiewicz, Sara M. Tolaney, Ian E. Krop, Dan G. Duda, Yves Boucher, Dai Fukumura, Rakesh K. Jain
Journal: Science Translational Medicine (2018)

Anti-vascular endothelial growth factor (VEGF) therapy has failed to improve survival in patients with breast cancer (BC). Potential mechanisms of resistance to anti-VEGF therapy include the up-regulation of alternative angiogenic and proinflammatory factors. Obesity is associated with hypoxic adipose tissues, including those in the breast, resulting in increased production of some of the aforementioned factors. Hence, we hypothesized that obesity could contribute to anti-VEGF therapy's lack of efficacy. We found that BC patients with obesity harbored increased systemic concentrations of interleukin-6 (IL-6) and/or fibroblast growth factor 2 (FGF-2), and their tumor vasculature was less sensitive to anti-VEGF treatment. Mouse models revealed that obesity impairs the effects of anti-VEGF on angiogenesis, tumor growth, and metastasis. In one murine BC model, obesity was associated with increased IL-6 production from adipocytes and myeloid cells within tumors. IL-6 blockade abrogated the obesity-induced resistance to anti-VEGF therapy in primary and metastatic sites by directly affecting tumor cell proliferation, normalizing tumor vasculature, alleviating hypoxia, and reducing immunosuppression. Similarly, in a second mouse model, where obesity was associated with increased FGF-2, normalization of FGF-2 expression by metformin or specific FGF receptor inhibition decreased vessel density and restored tumor sensitivity to anti-VEGF therapy in obese mice. Collectively, our data indicate that obesity fuels BC resistance to anti-VEGF therapy via the production of inflammatory and angiogenic factors.
FEASIBILITY AND EFFECTIVENESS OF A SHOCK TEAM APPROACH IN REFRACTORY CARDIOGENIC SHOCK: PRELIMINARY RESULTS
Authors: Iosif Taleb, Anwar Tandar, Antigoni Koliopoulou, Stephen McKellar, Jose Nativi, Omar Wever-Pinzon, Edward Gilbert, James Fang, Josef Stehlik, Joseph Tonna, Byung-Soo Ko, Theophilus Owan, Homam Ibrahim, Craig Selzman, Frederick Welt, Stavros Drakos
Journal: Journal of the American College of Cardiology (2018)