tbuckley/cabot-search huggingface dataset:
In situ monitoring of the structural change of microemulsions in simulated gastrointestinal conditions by SAXS and FRET
Authors: Xia Lv, Shuguang Zhang, Huipeng Ma, Peipei Dong, Xiaodong Ma, Ming Xu, Yan Tian, Zeyao Tang, Jinyong Peng, Haibo Chen, Jianbin Zhang
Journal: Acta Pharmaceutica Sinica B (2018)

Microemulsions are promising drug delivery systems for the oral administration of poorly water-soluble drugs. However, the evolution of microemulsions in the gastrointestinal tract is still poorly characterized, especially the structural change of microemulsions under the effect of lipase and mucus. To better understand the fate of microemulsions in the gastrointestinal tract, we applied small-angle X-ray scattering (SAXS) and fluorescence resonance energy transfer (FRET) to monitor the structural change of microemulsions under the effect of lipolysis and mucus. First, the effect of lipolysis on microemulsions was studied by SAXS, which found the generation of liquid crystalline phases. Meanwhile, FRET spectra indicated micelles with smaller particle sizes were generated during lipolysis, which could be affected by CaCl2, bile salts and lecithin. Then, the effect of mucus on the structural change of lipolysed microemulsions was studied. The results of SAXS and FRET indicated that the liquid crystalline phases disappeared, and more micelles were generated. In summary, we studied the structural change of microemulsions in simulated gastrointestinal conditions by SAXS and FRET, and successfully monitored the appearance and disappearance of the liquid crystalline phases and micelles.
Abstract 18715: Clinical Characteristics of Double Heterozygotes With PCSK9 Gain-of-Function Mutations and LDLR Mutations
Authors: Atsushi Nohara, Masa-aki Kawashiri, Hayato Tada, Mie Yoshida, Mika Mori, Chiaki Nakanishi, Kunimasa Yagi, Akihiro Inazu, Takeshi Kobayashi, Masakazu Yamagishi, Hiroshi Mabuchi
Journal: Circulation (2016)

PCSK9  gene was found as the third causal gene of familial hypercholesterolemia (FH). Gain-of-function mutations in  PCSK9  gene are found in more than 5% of clinical FH in Japan, and this is more frequent than any other countries. We investigated clinical characteristics of gain-of-function PCSK9 mutations as heterozygotes and double heterozygotes with LDLR mutations.   Methods:  A total of 982 clinically diagnosed FH including 41 clinical-homozygotes were investigated for  LDLR ,  PCSK9 , and  APOB  gene. High-resolution melting method followed by Sanger were used for point mutation, and multiplex ligation-dependent probe amplification methods were applied for large rearrangements in LDLR.   Results:  We identified 12 double heterozygotes with  PCSK9  E32K and  LDLR  mutations, double heterozygotes with  PCSK9  V4I and  LDLR , 732 heterozygotes with  LDLR  mutations, 56 heterozygotes with  PCSK9  E32K, and 143 individuals without disease causing mutations.  Double heterozygotes with  PCSK 9 E32K and  LDLR  mutations showed significantly higher LDL-C than heterozygotes with LDLR mutations. (LDL-C 306±111 vs. 268±73,  p  PCSK9  V4I and  LDLR  showed slightly higher LDL-C ( ns ), and none of them were diagnosed as homozygotes. Even 3 of double heterozygotes were diagnosed as clinical homozygotes, they considerably responded to statins because of residual intact LDL receptors.  In comparison between heterozygotes,  PCSK9  carriers showed significantly milder LDL-C ( LDLR  268±73,  PCSK9  198±82, No mutation 198±65 mg/dL,  p  PCSK9  carriers had higher TG compared with  LDLR  mutations (126±94, 150±84, 145±74 mg/dL,  p  PCSK9  (25%, 41%, 36%,  p  LDLR  mutations. Lp(a) levels did not significantly different.   Conclusion:  PCSK9  gain-of-function showed mild LDL-C elevation and wider clinical phenotype compare with relatively equal phenotype of LDLR mutation. PCSK9 carriers showed more hypertriglyceridemia, and this can be attributable to previous kinetic report that PCSK9 regulates also VLDL production.
HIV Population Surveys — Bringing Precision to the Global Response
Authors: Jessica E. Justman, Owen Mugurungi, Wafaa M. El-Sadr
Journal: New England Journal of Medicine (2018)

presence of nonprofit manufacturers will bring increased competition to areas of the generic-drug market where market failure is prevalent, which will motivate for-profit manufacturers to reduce prices and stabilize supply.The complex nature of market failures for generic drugs implies that a single alternative business model cannot address all aspects of this problem.We believe that Project Rx may drive other non-profit and for-profit manufacturers to enter generic-drug markets, compete among themselves, and collectively improve market efficiency and broaden access to generic drugs.
<i>Gata3</i> hypermethylation and <i>Foxp3</i> hypomethylation are associated with sustained protection and bystander effect following epicutaneous immunotherapy in peanut‐sensitized mice
Authors: L. Mondoulet, V. Dioszeghy, F. Busato, C. Plaquet, V. Dhelft, K. Bethune, L. Leclere, C. Daviaud, M. Ligouis, H. Sampson, C. Dupont, J. Tost
Journal: Allergy (2018)

Epicutaneous immunotherapy (EPIT) is a promising method for treating food allergies. In animal models, EPIT induces sustained unresponsiveness and prevents further sensitization mediated by Tregs. Here, we elucidate the mechanisms underlying the therapeutic effect of EPIT, by characterizing the kinetics of DNA methylation changes in sorted cells from spleen and blood and by evaluating its persistence and bystander effect compared to oral immunotherapy (OIT).BALB/c mice orally sensitized to peanut proteins (PPE) were treated by EPIT using a PPE-patch or by PPE-OIT. Another set of peanut-sensitized mice treated by EPIT or OIT were sacrificed following a protocol of sensitization to OVA. DNA methylation was analyzed during immunotherapy and 8 weeks after the end of treatment in sorted cells from spleen and blood by pyrosequencing. Humoral and cellular responses were measured during and after immunotherapy.Analyses showed a significant hypermethylation of the Gata3 promoter detectable only in Th2 cells for EPIT from the 4th week and a significant hypomethylation of the Foxp3 promoter in CD62L+ Tregs, which was sustained only for EPIT. In addition, mice treated with EPIT were protected from subsequent sensitization and maintained the epigenetic signature characteristic for EPIT.Our study demonstrates that EPIT leads to a unique and stable epigenetic signature in specific T-cell compartments with downregulation of Th2 key regulators and upregulation of Treg transcription factors, likely explaining the sustainability of protection and the observed bystander effect.
Improvement in Ulcerative Necrobiosis Lipoidica After Janus Kinase–Inhibitor Therapy for Polycythemia Vera
Authors: Jonathan J. Lee, Joseph C. English
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
Trial in progress: A multicenter phase II study of pembrolizumab in patients with advanced small bowel adenocarcinomas.
Authors: Katrina Pedersen, Michael J. Overman, Nathan R. Foster, Sunnie S. Kim, Tanios S. Bekaii-Saab, Janet E. Murphy, Patrick McKay Boland, Howard S. Hochster, Thorvardur Ragnar Halfdanarson, Richard H. Wilson, Jack Welch, Robert R. McWilliams
Journal: Journal of Clinical Oncology (2018)

TPS535 Background: Small bowel adenocarcinoma (SBA) is a rare malignancy, possibly because of the high rate of immunosurveillance in baseline small bowel function, and is frequently diagnosed in late stages. Due to these factors, there is no consistent standard of care for metastatic disease beyond first-line where several prospective studies have confirmed activity of FOLFOX/CAPOX. Historically, second-line treatment of SBA has been extrapolated from colon/gastric cancer. Recent studies suggest that SBA has a distinct genomic profile, including higher incidence of microsatellite instability, compared to gastric and colon cancers. Additionally, the tumor microenvironment reflects a greater degree of PD-L1 expression and infiltration by lymphocytes. Immune checkpoint inhibitors have not previously been tested in SBA unselected for MSI status. Methods: The study is a phase 2, multicenter, single-arm clinical trial of pembrolizumab (200 mg IV every 3 weeks) for patients with unresectable or metastatic SBA refractory to first-line chemotherapy. Forty patients with any tumor mismatch repair status will be enrolled at 8 US sites as part of the ACCRU network and International Rare Cancer Initiative (IRCI) with a primary objective to assess the confirmed response rate (H 0 p &lt; 10%, H A : p &gt; 30%) to pembrolizumab. Secondary endpoints include PFS, OS, and adverse events. Correlative aims include assessing blood and tissue biomarkers (i.e. PD-L1, MSI-H/MSS status, cfDNA, mutation burden, etc.) for association with clinical benefit. An interim analysis will be performed to assess efficacy after 18 patients become evaluable. The study is open with 16 patients enrolled at time of submission. Clinical trial information: NCT02949219.
Considerations When Calculating Data Completeness
Authors: Wendy C. King, Steven H. Belle, Anita P. Courcoulas
Journal: JAMA Surgery (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 Surgery 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 Surgery journal
PCSK9 expression in the ischaemic heart and its relationship to infarct size, cardiac function, and development of autophagy
Authors: Zufeng Ding, Xianwei Wang, Shijie Liu, Jiwani Shahanawaz, Sue Theus, Yubo Fan, Xiaoyan Deng, Sichang Zhou, Jawahar L Mehta
Journal: Cardiovascular Research (2018)

Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a novel therapy to treat hypercholesterolaemia and related cardiovascular diseases. This study determined if PCSK9 can regulate infarct size, cardiac function, and autophagy during ischaemia. Mice hearts were subjected to left coronary artery (LCA) occlusion. There was intense expression of PCSK9 in the zone bordering the infarct area in association with marked cardiac contractile dysfunction in the wild-type mice. This region also revealed intense autophagy. To assess the role of PCSK9 in the evolution of infarct size and function and development of autophagy, we used wild-type mice pre-treated with two different PCSK9 inhibitors (Pep2-8 and EGF-A) or mice lacking PCSK9 gene. Both strategies resulted in smaller infarcts and improved cardiac function following LCA ligation. PCSK9 inhibition also markedly reduced autophagy. Relationship between myocardial ischaemia and PCSK9 expression and autophagy was examined in cultured mouse cardiomyocytes. Exposure of cardiomyocytes to hypoxia resulted in prompt PCSK9 expression and autophagy signals; both were blocked by HIF-1α siRNA. Further, treatment of cardiomyocytes with recombinant PCSK9 during hypoxia induced, and treatment with PCSK9 siRNA reduced, autophagy suggesting a possible role of PCSK9 in the determination of autophagy. Other studies revealed activation of ROS-ATM-LKB1-AMPK axis as a possible mechanism of PCSK-induced autophagy. Hearts of humans with recent infarcts also showed expression of PCSK9 and autophagy in the border zone—similar to that in the infarcted mouse heart. PCSK9 is up-regulated in the ischaemic hearts and determines development of infarct size, cardiac function, and autophagy.
Long non-coding RNA NEAT1-modulated abnormal lipolysis via ATGL drives hepatocellular carcinoma proliferation
Authors: Xirui Liu, Yingjian Liang, Ruipeng Song, Guangchao Yang, Jihua Han, Yaliang Lan, Shangha Pan, Mingxi Zhu, Yao Liu, Yan Wang, Fanzheng Meng, Yifeng Cui, Jiabei Wang, Bo Zhang, Xuan Song, Zhaoyang Lu, Tongsen Zheng, Lianxin Liu
Journal: Molecular Cancer (2018)

Abnormal metabolism, including abnormal lipid metabolism, is a hallmark of cancer cells. Some studies have demonstrated that the lipogenic pathway might promote the development of hepatocellular carcinoma (HCC). However, the role of the lipolytic pathway in HCC has not been elucidated. We compared levels of adipose triglyceride lipase (ATGL) in human HCC and healthy liver tissues by real time PCR, western blot and immunohistochemistry. We measured diacylglycerol(DAG) and free fatty acid (FFA) levels in HCC cells driven by the NEAT1-ATGL axis and in HCC tissues. We also assessed the effects of ATGL, DAG, FFA, and NEAT1 on HCC cells proliferation in vitro and in an orthotopic xenograft HCC mouse model. We also performed a luciferase reporter assay to investigate the interaction between NEAT1/ATGL and miR-124-3p. We found that the lipolytic enzyme, ATGL is highly expressed in human HCC tissues and predicts poor prognosis. We also found that high levels of DAG and FFA are present in HCC tissues. Furthermore, the lncRNA-NEAT1 was found to modulate ATGL expression and disrupt lipolysis in HCC cells via ATGL. Notably, ATGL and its products, DAG and FFA, were shown to be responsible for NEAT1-mediated HCC cell growth. NEAT1 regulated ATGL expression by binding miR-124-3p. Additionally, NEAT1 knockdown attenuated HCC cell growth through miR-124-3p/ATGL/DAG+FFA/PPARα signaling. Our results reveal that NEAT1-modulates abnormal lipolysis via ATGL to drive HCC proliferation.
Non-technical skills
Authors: Naomi Engel, Rona E Patey, Sarah Ross, Lucy Wisely
Journal: BMJ (2008)

Developing these skills is good for patients and doctors, say Naomi Engel and colleagues Poor or inadequate use of these skills has been identified as key causes of many industrial disasters, like the Chernobyl nuclear disaster, and were first examined after a series of aircraft crashes in the 1970s Mention of “non-technical skills” is typically met with a blank stare or a dismissive rejection of “soft skills.” Hopefully this article will change your perceptions and inspire you to develop these skills before you graduate. The concept of non-technical skills has only recently been introduced to health care—its origins are non-medical. In the 1970s, after several aeroplane crashes, investigators looked for causes. They found that these weren't related to poor knowledge or technical problems: failure in the pilot and crews' non-technical skills were the key underlying factors.1 Subsequently, poor or inadequate use of these skills has been identified as a key cause of many industrial disasters. Well known examples include the explosion at the Chernobyl nuclear power plant, the explosion on the Piper Alpha oil platform, and the crush at Hillsborough football stadium.2 Non-technical skills are a combination of cognitive (for example, decision making) and social skills (for example, team working), which complement knowledge and technical skills and contribute to safe performance (box).2 ### Tips for good practice #### Situation awareness #### Decision making
<scp>TRE</scp> atment of <scp>AT</scp> opic eczema ( <scp>TREAT</scp> ) Registry Taskforce: an international Delphi exercise to identify a core set of domains and domain items for national atopic eczema photo‐ and systemic therapy registries
Authors: L.A.A. Gerbens, C.J. Apfelbacher, A.D. Irvine, S. Barbarot, R.J. Booij, A.E. Boyce, M. Deleuran, L.F. Eichenfield, M.H. Hof, M.A. Middelkamp‐Hup, A. Roberts, J. Schmitt, C. Vestergaard, D. Wall, S. Weidinger, P.R. Williamson, C. Flohr, P.I. Spuls
Journal: British Journal of Dermatology (2018)

Evidence of immunomodulatory therapies to guide clinical management of atopic eczema (AE) is scarce, despite frequent and often off-label use. Patient registries provide valuable evidence for the effects of treatments under real-world conditions that can inform treatment guidelines, give the opportunity for health economic evaluation and the evaluation of quality of care, as well as pharmacogenetic and dynamic research, which cannot be adequately addressed in clinical trials.The TREatment of ATopic eczema (TREAT) Registry Taskforce aims to seek international consensus on a core set of domains and items ('what to measure') for AE research registries, using a Delphi approach.Participants from six stakeholder groups were included: doctors, nurses, nonclinical researchers, patients, industry and regulatory body representatives. The eDelphi comprised three sequential online rounds, requesting participants to rate the importance of each proposed domain item. Participants could add domain items to the proposed list in round 1. A final consensus meeting was held to ratify the core set.Participants (n = 479) from 36 countries accessed the eDelphi platform, of whom 86%, 79% and 74% completed rounds 1, 2 and 3, respectively. At the face-to-face consensus meeting attended by 42 participants the final core set was established containing 19 domains with 69 domain items (49 baseline and 20 follow-up items).This core set of domains and items to be captured by national AE systemic therapy registries will standardize data collection and thereby allow direct comparability across registries and facilitate data pooling between countries. Ultimately, it will provide greater insight into the effectiveness, safety and cost-effectiveness of photo- and systemic immunomodulatory therapies.
Ready-to-Use Supplementary Food to Prevent Mortality in Severely Immunocompromised Individuals Initiating Antiretroviral Therapy in Africa: An Open-label Randomised Controlled Trial
Authors: J Mallewa, A J Szubert, P Mugyenyi, E Chidziva, M J Thomason, P Chepkorir, G Abongomera, K Baleeta, A Etyang, C Warambwa, B Melly, S Mudzingwa, C Kelly, C Agutu, H C Wilkes, S Nkomani, V Musiime, A Lugemwa, S L Pett, M Bwakura-Dangarembizi, A J Prendergast, D M Gibb, A S Walker, J A Berkley
Journal: The Lancet HIV (2018)
Ivacaftor for cystic fibrosis
Authors: Peter J Barry, Anna L Donaldson, Andrew M Jones
Journal: BMJ (2018)

### What you need to know

A 33 year old man with cystic fibrosis has come to discuss a new therapy for which he is eligible because of his genotype Phe508del/Gly551Asp. He has moderate lung function impairment with a forced expiratory volume in one second (FEV1) of 67% of predicted, which has declined from 85% over the preceding five years. During this period, he has noted an increased requirement for intravenous antibiotics (two or three courses a year). In addition, he has pancreatic insufficiency, malnutrition (body mass index 17.5), recurrent constipation, and arthropathy which is disabling and worsens during periods of ill health. The patient is started on ivacaftor. Within a few days of starting therapy, he has noted an improvement in all his symptoms. His sputum has become easier to expectorate and is less in volume. Lung function measured at one month has increased by 15% over his baseline value. 

Cystic fibrosis is an autosomal recessive genetic disorder affecting approximately 10 000 people in the UK and 30 000 in the US.12 Dysfunction or absence of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an anion channel that sits on epithelial cell surfaces, leads to the clinical syndrome of cystic fibrosis. The most common and serious consequences are pulmonary disease, which is almost universal, and exocrine pancreatic insufficiency, which affects approximately 85% of patients).12 There is progressive decline in lung function punctuated by acute episodes with increased cough …
Detection of Urothelial Bladder Carcinoma via Microfluidic Immunoassay and Single-Cell DNA Copy-Number Alteration Analysis of Captured Urinary-Exfoliated Tumor Cells
Authors: Anqi Chen, Guanghou Fu, Zhijie Xu, Yukun Sun, Xiaoyi Chen, Kok Suen Cheng, Kuang Hong Neoh, Zhewen Tang, Shifu Chen, Ming Liu, Tanxiao Huang, Yun Dai, Qibo Wang, Jing Jin, Baiye Jin, Ray P.S. Han
Journal: Cancer Research (2018)

Abstract The increasing incidence of bladder cancer and its high rate of recurrence over a 5-year period necessitate the need for diagnosis and surveillance amelioration. Cystoscopy and urinary cytology are the current tools, and molecular techniques such as BTA stat, NMP22, survivin mRNA, and urovysion FISH have attracted attention; however, they suffer from insufficient sensitivity or specificity. We developed a novel microfluidic approach for harvesting intact urinary-exfoliated tumor cells (UETC), either individually or in clusters, in a clean and segregated environment, which is crucial to minimize cross-contamination and misreads. To reliably and accurately identify UETC, our quantitative immunoassay involved concurrent use of two oncoproteins CK20 and CD44v6 antigen. CK20 is an intermediate filament protein overexpressed in urothelial tumors, and CD44v6 is a membrane adhesion molecule closely associated with cell invasion, tumor progression, and metastatic spread. Single-cell whole-genome sequencing on 12 captured UETCs and copy number alteration analysis showed that 11/12 (91.7%) of the immunofluorescence-identified UETCs possessed genomic instability. A total of 79 patients with bladder cancer and 43 age-matched normal controls (NC) were enrolled in the study. We detected considerably higher UETC counts in patients with bladder cancer versus the NC group [53.3 (10.7–1001.9) vs. 0.0 (0–3.0) UETCs/10 mL; P &amp;lt; 0.0001]. For bladder cancer detection, a stratified 10-fold cross-validation of training data reveals an overall predictive accuracy of 0.84 [95% confidence interval (CI), 0.76–0.93] with an 89.8% (95% CI, 71.5%–86.4%) for sensitivity and 71.5% (95% CI, 59.7%–83.3%) for specificity. Overall, the microfluidic immunoassay demonstrates increased sensitivity and specificity compared with other techniques for the detection of bladder cancer. Significance: A unique and promising diagnostic assay for bladder cancer is proposed with potential clinical utility as a complement for cytology. Cancer Res; 78(14); 4073–85. ©2018 AACR.