tbuckley/cabot-search huggingface dataset:
Adaptor protein APPL1 coordinates HDAC3 to modulate brown adipose tissue thermogenesis in mice
Authors: Linling Fan, Hongying Ye, Yun Wan, Lang Qin, Lu Zhu, Jing Su, Xiaoming Zhu, Lv Zhang, Qing Miao, Qiongyue Zhang, Zhaoyun Zhang, Aimin Xu, Yiming Li, Xi Li, Yi Wang
Journal: Metabolism (2019)

The activation of brown adipose tissue (BAT) is considered as a promising therapeutic target for obesity. APPL1 (Adaptor protein containing the Pleckstrin homology domain, Phosphotyrosine binding domain and Leucine zipper motif) is an intracellular adaptor protein and its genetic variation is correlated with BMI and body fat distribution in diabetic patients. However, little is known about the roles of APPL1 in BAT thermogenesis.In this study, adipose tissue specific knockout (ASKO) mice were generated to evaluate APPL1's role in BAT thermogenesis in vivo, and possible signaling pathways were further explored in cultured brown adipocytes.After high fat diet challenge, APPL1 ASKO mice developed more severe obesity, glucose intolerance and insulin resistance compared with control mice. Metabolic cage study showed that APPL1 deficiency impaired energy expenditure and adaptive thermogenesis in ASKO mice. PET-CT analysis showed decreased standardized uptake value (SUV) in the inter-scapular region which indicated impaired BAT activity in ASKO mice. Further study showed deletion of APPL1 attenuated brown fat specific gene expression, such as UCP1 and PGC1α in both BAT and brown adipocytes. In cultured brown adipocytes, upon cAMP stimulation, APPL1 shuttled from cytosol to nuclei. Co-IP and ChIP study showed that APPL1 could directly interact with histone deacetylase 3 (HDAC3) to mediate chromatin remodeling and UCP1 gene expression.Our data demonstrated the essential role of APPL1 in regulating brown adipocytes thermogenesis via interaction with HDAC3, which may have potential therapeutic implications for treatment of obesity.
Evaluation of potential predictive markers of efficacy of dacomitinib in patients (pts) with recurrent/metastatic SCCHN from a phase II trial.
Authors: Marie-Lise Audet, Ghassan Allo, Xiaoduan Weng, Lucia Kim, Olguta Gologan, Suzanne Kamel-Reid, Lillian Siu, Francois Coutlee, Scott Andrew Laurie, Sebastien J. Hotte, Simron Singh, Eric Winquist, Stephen K. L. Chia, Eric Xueyu Chen, Kelvin K. Chan, Patricia A English, Ian Taylor, Susan Quinn, Christine Mormont, Denis Soulieres
Journal: Journal of Clinical Oncology (2013)

6041 Background: Dacomitinib is an irreversible pan-HER TKI with preclinical (EGFRvIII+ cell lines, SCCHN xenografts) and clinical activity (phase II recurrent/metastatic SCCHN; Razak et al, Ann Oncol 2012). However, little is known about predictive markers of efficacy related to EGFR signalling in this setting. Methods: Of69 pts treated with 1st-line dacomitinib in a phase II trial for recurrent/metastatic SCCHN, 48 pts had archival tumor specimens obtained before treatment and 13 had paired biopsies (days 0 and 7 of therapy, FFPE and snap frozen). EGFRvIII and PTEN (IHC), HPV genotyping and human genomic mutations (Sequenom OncoCarta Panel – 19 genes, 238 mutations) were evaluated on archival tissue. IHC expression of AKT, CC3, EGFR, ERK, HER2, HER3, MET, Ki67, pAKT, pEGFR, pERK, pHER2 and pMET was evaluated in paired specimens. The presence/absence or expression level of these markers was correlated with response (RR)/clinical benefit (CB), PFS and OS. Results: In pts with archival tissue, no statistically significant difference was found in RR/CB or PFS based on HPV, EGFRvIII, PTEN or presence of mutation. There was a trend to increased OS in HPV+ pts (HR 0.47, 95% CI 0.21–1.07, P=0.068). In paired biopsies, some expression variation was seen for cytoplasm AKT, membrane EGFR, nuclear ERK and pAKT. There was no correlation between basal expression of these markers and RR/CB or PFS. Variations in ratio to baseline of EGFR, pAKT, pERK and MET were qualitatively associated with RR/CB. No statistically significant correlations could be established for PFS, but there were interesting qualitative variations in the levels of expression of some molecules, eg, EGFR, pAKT. Conclusions: No predictive efficacy marker was identified. It cannot be determined if increased OS in HPV+ cases is due to prognostic or predictive effects. Paired biopsies demonstrated that dacomitinib was associated with variation in expression of multiple elements in signalling pathways linked to EGFR. Given the small number of paired biopsies, and large amount of data generated, descriptive study of cases is required. Further data will be presented at the meeting. Clinical trial information: 00768664.
Phase I dose-escalation study of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumors.
Authors: Takashi Seto, Taito Esaki, Fumihiko Hirai, Shuji Arita, Kaname Nosaki, Akitaka Makiyama, Takuro Kometani, Chinatsu Fujimoto, Motoharu Hamatake, Hiroaki Takeoka, Felix Agbo, Xiaojin Shi
Journal: Journal of Clinical Oncology (2012)

3045 Background: AZD7762, a potent Chk1/Chk2 inhibitor, has been shown to enhance the antitumor activity of gemcitabine in xenograft models (Zabludoff SD et al. Mol Cancer Ther 2008;7:2955–66). Methods: This open-label dose-escalation study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy (RECIST) of AZD7762 alone and in combination with gemcitabine in Japanese patients (pts) with advanced solid tumors (NCT00937664). Pts received AZD7762 iv alone on days 1 and 8 of a 14-day cycle (Cycle 0), followed by AZD7762 plus gemcitabine 1000 mg/m 2 on days 1 and 8 of 21-day cycles, in sequential ascending AZD7762 dose cohorts. Results: 20 pts (mean age 60 years) received AZD7762 at doses of 6 (n=3), 9 (3), 21 (6), and 30 mg (8). The most common primary tumor site was lung (n=14). All pts had received ≥1 prior chemotherapy and 18 had metastatic disease. Dose-limiting toxicities (DLTs) occurred in two of six evaluable pts (both 30 mg cohort): one, grade 3 (CTCAE, v3.0) elevated troponin T (Cycle 0; AZD7762 monotherapy); one, neutropenia, thrombocytopenia, and elevated AST and ALT (Cycle 1; combination therapy). Thus, the 30 mg dose was regarded as non-tolerable. DLTs resolved following treatment discontinuation. The most frequently reported adverse events (AEs) in Cycle 0 (AZD7762 monotherapy) were bradycardia (50%), hypertension (25%) and fatigue (15%). Overall, the most common AEs were bradycardia (55%), neutropenia (45%), and hypertension, fatigue, and rash (30% each). AEs grade ≥3 were reported in 11 pts, the most common being neutropenia (45%) and leukopenia (25%). No pt died due to an AE. AZD7762 exposure (C max , AUC) increased in an approximately linear manner. Gemcitabine did not appear to affect AZD7762 PK. Arithmetic mean t ½ and geometric mean CL of AZD7762 across the dose groups were 16.1–19.4 h and 22.0–32.7 L/h, respectively during the monotherapy cycle, and 15.6–18.3 h and 21.1–24.4 L/h, respectively in combination with gemcitabine. There were no objective responses; five pts (all lung cancer) had stable disease. Conclusions: The maximum tolerated dose of AZD7762 in combinationwith gemcitabine 1000 mg/m 2 was determined as 21 mg in Japanese pts.
Cytotoxic activity of semi-synthetic ingenol derived from <i>Euphorbia tirucalli</i> on a large panel of human cancer cell lines.
Authors: Viviane Aline Oliveira Silva, Marcela Nunes Rosa, Aline Tansini, Joao Paulo Da S.N. Lima, Chris Jones, Luiz Francisco Pianowski, Rui Manuel Reis
Journal: Journal of Clinical Oncology (2013)

e13559 Background: The latex from Euphorbia tirucalli is used in Brazil as anticancer and other disease as folk treatment; however, little is known about its anticancer proprieties. We report in vitro activity of 3 semi-synthetic ingenol compounds derived from E. tirucalli, ingenol A (ingenol-3-trans-cinnamate), ingenol B (3-caproyl-ingenol) and ingenol C (ingenol-3-dodecanoate), against a large panel of human cancer cell lines. Methods: Anti-tumor effects of the 3 semi-synthetic compounds were assessed using MTS assays on 77 cancer lines from 13 tumor models, such as breast, colon, bladder, prostate, lung, pancreas, esophagus, glioblastoma, melanoma, head and neck and cervical cancer. Additionally, we evaluate the its potential combinatorial value with temozolomide (TMZ) in gliomas. Ongoing experiments will identify potential drug target(s) by assessing changes in global protein expression. Results: Ingenol A, B and C exhibited dose-dependent and time-dependent cytotoxic effects. Amongst the derived tested, ingenol C displayed the best activity across the tumor cell lines. In comparison with TMZ, ingenol C showed a median of 136 fold higher efficacy, range 15-511 fold, in the glioma cell lines analyzed. Conclusions: The semi-synthetic ingenol compounds, in particular the ingenol C, demonstrated a potent anti-tumor activity on all cancer cell lines evaluated. Our findings may provide insight into designing ingenol-based therapies for cancer patients. [Table: see text]
Effectiveness of Stress-Reducing Interventions on the Response to Challenges to the Immune System: A Meta-Analytic Review
Authors: Lemmy Schakel, Dieuwke S. Veldhuijzen, Paige I. Crompvoets, Jos A. Bosch, Sheldon Cohen, Henriët van Middendorp, Simone A. Joosten, Tom H.M. Ottenhoff, Leo G. Visser, Andrea W.M. Evers
Journal: Psychotherapy and Psychosomatics (2019)

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; There is consistent evidence showing an interplay between psychological processes and immune function in health and disease processes. &lt;b&gt;&lt;i&gt;Objectives:&lt;/i&gt;&lt;/b&gt; The present systematic review and meta-analysis aims to provide a concise overview of the effectiveness of stress-reducing psychological interventions on the activation of immune responses in both healthy subjects and patients. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Included are 3 types of challenges: in vivo, in vitro, and psychophysiological. Such challenges are designed to mimic naturally occurring immune-related threats. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; A systematic literature search was conducted using PubMed, EMBASE, and PsychInfo, resulting in 75 eligible studies. The risk of bias was assessed with the Cochrane risk-of-bias tool. Across all studies, a small-to-medium effect size was found for the effects of psychological interventions on optimization of the immune function (&lt;i&gt;g&lt;/i&gt; = 0.33; 95% CI 0.22–0.43). While the largest effects were found for in vivo immune-related challenges (&lt;i&gt;g&lt;/i&gt; = 0.61; 95% CI 0.34–0.88; especially on studies that incorporated skin tests and wound healing), studies incorporating psychophysiological challenges and in vitro immune-related stimulations similarly suggest more optimal immune responses among those receiving stress-reducing interventions (&lt;i&gt;g&lt;/i&gt; = 0.28; 95% CI 0.15–0.42). &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; These findings showed substantial heterogeneity depending on the type of challenge, the study populations, and the intervention types. These data demonstrate support for the effectiveness of stress-reducing psychological interventions in improving immunity in studies that tested immune function by means of incorporating an in vivo&lt;i&gt;,&lt;/i&gt;in vitro, or psychophysiological challenge. Future research should more consistently incorporate challenges into the study design to gather more insights in the mechanisms underlying the optimized immune function following a psychological intervention. This is also relevant for clinical practice, as psychological interventions can possibly supplement, or at least partially replace, current drug treatments in various somatic conditions to reduce side effects.
Benign cystic ovarian neoplasms and procoagulant potential.
Authors: Omer M. Iqbal, Cagatay Ersahin, Zhihong Hu, Xiuzhen Duan, Debra Hoppensteadt
Journal: Journal of Clinical Oncology (2012)

e15538 Background: Ovarian cancer is one of the leading causes of increased morbidity and mortality worldwide. The fluid content of the cystic ovarian tumors has never been thoroughly analyzed. It is hypothesized that the fluid contents of the ovarian cystic tumors have procoagulant effects. Methods: Under an institutionally approved protocol, cystic fluids from ovarian neoplasms were collected (n=28) and analyzed to determine their procoagulant potential. Assays such as Thrombelastography (TEG, Helige, Germany), Platelet aggregometry (BioData, Horsham, PA), Fibrinopeptide A (FPA, Dade Behring, Marburg, Germany), Thrombin Antithrombin Complex (TAT, Dade Behring), and Zymuphen Platelet Microparticle Activity Assay (Hyphen BioMed, Neuville-Sur-Oise, France). Cerebral Array II (Randox, Crumlin, CO) was used to determine the levels of C-reactive protein (CRP), D-Dimer, Neuron Specific Enolase (NSE), Neutrophil Gelatinase-Associated Lipocalin (NGAL), soluble Tumor Necrosis Factor Receptor I (TNFRI) and Thrombomodulin. Results: The TEG parameters such as r- time, rk-time, k-time, MA, and angle were measured to be 17 , 22 , 5 , 54 mm, 55° with clear cell carcinoma, 18 , 24 , 6 , 58 , 54° with benign serous cyst compared to saline control values of 23 , 30 , 7 , 41 mm and 48° respectively. Platelet aggregometry showed increased aggregations when cystic fluids were supplemented in donor platelet rich plasma. The levels of Fibrinopeptide A were in the range of 24.1 and 56.6 ng/ml compared to a control value of 1.8 ng/ml. The TAT complexes were in the range of 6.7- 175 µg/ml compared to a control value of 0.7 ug/ml. The platelet microparticle measurements were markedly increased and were in the range of 10-45 nM for benign and malignant cystic fluids, compared to control values in the range of 2.3-6.6 nM. The results of CRP, D-Dimer, NSE, NGAL, TNFRI and TM were 9.28 mg/m (Normal=5.03) , &gt;2000 ng/ml (N=227.34) , &gt;120 ng/ml (N=10.50), &gt;1229 ng/ml (N=228.16), 3.98 ng/ml (5.91) and 13.55 ng/ml (N=13.55) respectively. Conclusions: Benign ovarian tumors have prothrombogenic activity as much as the malignant tumors. Early surgical evaluation of clinically silent benign ovarian tumors should be considered.
A three-dimensional immunocompetent intestine-on-chip model as in vitro platform for functional and microbial interaction studies
Authors: Michelle Maurer, Mark S. Gresnigt, Antonia Last, Tony Wollny, Florian Berlinghof, Rebecca Pospich, Zoltan Cseresnyes, Anna Medyukhina, Katja Graf, Marko Gröger, Martin Raasch, Fatina Siwczak, Sandor Nietzsche, Ilse D. Jacobsen, Marc Thilo Figge, Bernhard Hube, Otmar Huber, Alexander S. Mosig
Journal: Biomaterials (2019)
Evaluation of a non-peptidic mimic of host defense proteins, PMX30063, in an animal model of oral mucositis.
Authors: Richard W Scott, Bozena Korczak, Brynmor A Watkins, Stephen T. Sonis
Journal: Journal of Clinical Oncology (2012)

9119 Background: Oral ulcerative mucositis (OM) is a common, painful, dose-limiting toxicity of cancer therapy. The care for OM is largely palliative and there is an urgent need for new and effective therapies. Host defense proteins (HDPs) are amphiphilic components of the innate immune system that serve as a primary response to infection. Exclusive of their direct antimicrobial activity, HDPs have been shown to possess immune modulatory and anti-inflammatory activities. We are developing non-peptidic mimics of HDPs, capturing the structural and biological properties of HDPs within a framework of smaller fully synthetic oligomers. The lead compound, PMX30063, is in Phase 2 clinical trials for iv treatment of systemic staphylococcal infections. Recently, we observed that HDP mimics attenuate anti-inflammatory pathways and reasoned that these activities could be leveraged into a mucositis intervention. Methods: In an acute radiation hamster model, PMX30063 was applied as a topical rinse, 3 times daily at 1, 3 or 10 mg/ml over a 28 day treatment regimen ( n = 10), following a single radiation dose to the buccal cheek pouch (40 Gy). In a fractionated radiation model, radiation (7.5 Gy/dose) was administered on days 0, 1, 2, 3, 6, 7, 8 and 9, targeting the left buccal pouch mucosa. PMX30063 was given topically 3 times daily at 3 mg/ml over a 35 day regimen beginning on day 0 (n = 10). OM was scored using an established blinded method. Results: In the acute model, PMX30063 reduced the number of animal days with ulceration from 43% in vehicle-treated hamsters to &lt; 5% in all 3 PMX30063 dose groups (χ 2 test; p&lt;0.001). In the fractionated model, PMX30063 significantly reduced the daily mucositis scores prior to peak mucositis and throughout the remaining course of treatment (Mann-Whitney Rank-sum analysis; p&lt;0.001). PMX30063 reduced the number of animal days with ulceration from 55% in vehicle-treated hamsters to 3.3% (χ 2 test; p&lt;0.001). The time courses of efficacy argue that direct antimicrobial action is not the primary driver of efficacy. Conclusions: The safe and highly efficacious activity of PMX30063 in animals supports its further development as a topical therapeutic to prevent OM in cancer patients.
Immunomodulatory effects of a dipeptidyl peptidase inhibitor, ARI-4175, and NK cell activation in a colon cancer model.
Authors: Alexander Macfarlane, Tetyana V Bagnyukova, Kerry Campbell, Barry Jones, William Bachovchin, Hossein Borghaei
Journal: Journal of Clinical Oncology (2013)

3058 Background: A possible mechanism of the antitumor effect of therapeutic antibodies is antibody-dependent cellular cytotoxicity (ADCC). We reported that an inhibitor of dipeptidyl peptidase (DPP)4-like serine proteases, Ari-4175, significantly slowed the growth of KRAS-mutated HCT-116 xenografts in nude mice, either as a single agent or with cetuximab (Ctx). Ari-4175 is not cytotoxic in vitro, and since it was able to overcome the resistance to Ctx due to the KRAS mutation in the HCT-116 line, we hypothesized that the antitumor activity involves the activation of NK cells and enhancement of ADCC. Methods: Ari-4175 was administered orally to nude mice at 200 µg q.d. x5 days/week. Peripheral blood or spleens were assayed for immune parameters, ex vivo, at various time points. Expression of surface markers on myeloid and NK cells were monitored by flow. Natural cytotoxicity and ADCC were assayed using HCT116 cells and Ctx using a flow based assay. Cytokines were measured using Luminex assays. Results: Ari-4175 induced upregulation of CD69 on NK cells on day 2, followed by upregulation of CD16 on day 7. Coordinate with these changes in peripheral blood, splenocytes from treated mice exhibited significantly increased in vitro cytotoxicity toward the HCT116 cells. Increased serum levels of inflammatory cytokines, including IL-1b, IL-6, MCP-1, GCSF, and IL-2 were seen. A significant expansion of a distinct CD45 + CD14 + Gr-1 + MHC-II - CDllb + CD11c variable myeloid cell population in both peripheral blood and spleens of mice was also seen after one week of treatment. Conclusions: Ari-4175 showed dramatic anti-tumor effect in KRAS-mutant CRC xengrafts when given alone or in combination with Ctx. In vitro data suggest that the therapeutic effect of 4175 might partially be due to the augmentation of ADCC through elevated expression of CD16 on NK cells. In addition, Ari-4175 appears, in vivo, to expand a unique myeloid cell population, which may be responsible for an inflammatory cytokine response and subsequent activation of NK cells. Our study provides a mechanistic rationale for testing Ari-4175 in a clinical trial and possible biomarker endpoints for evaluation in peripheral blood samples.
IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes
Authors: Rudragouda Channappanavar, Anthony R. Fehr, Jian Zheng, Christine Wohlford-Lenane, Juan E. Abrahante, Matthias Mack, Ramakrishna Sompallae, Paul B. McCray, David K. Meyerholz, Stanley Perlman
Journal: Journal of Clinical Investigation (2019)

Type 1 IFNs (IFN-I) generally protect mammalian hosts from virus infections, but in some cases, IFN-I is pathogenic. Because IFN-I is protective, it is commonly used to treat virus infections for which no specific approved drug or vaccine is available. The Middle East respiratory syndrome–coronavirus (MERS-CoV) is such an infection, yet little is known about the role of IFN-I in this setting. Here, we show that IFN-I signaling is protective during MERS-CoV infection. Blocking IFN-I signaling resulted in delayed virus clearance, enhanced neutrophil infiltration, and impaired MERS-CoV–specific T cell responses. Notably, IFN-I administration within 1 day after infection (before virus titers peak) protected mice from lethal infection, despite a decrease in IFN-stimulated gene (ISG) and inflammatory cytokine gene expression. In contrast, delayed IFN-β treatment failed to effectively inhibit virus replication; increased infiltration and activation of monocytes, macrophages, and neutrophils in the lungs; and enhanced proinflammatory cytokine expression, resulting in fatal pneumonia in an otherwise sublethal infection. Together, these results suggest that the relative timing of the IFN-I response and maximal virus replication is key in determining outcomes, at least in infected mice. By extension, IFN-αβ or combination therapy may need to be used cautiously to treat viral infections in clinical settings.
Trainees with previous degree are more likely to progress straight to specialty training after foundation years
Authors: Abi Rimmer
Journal: BMJ (2019)

Over 30% of trainees decide against going straight into specialty training during their second year of foundation training despite having originally intended to do so, a study has found.

Trainees who were graduate entrants to medical school were more likely than non-graduates to move straight into specialty training, the study published in BMJ Open found.1

Researchers looked at 5570 responses to the 2017 UK National Career Destination Survey, a cross sectional study completed by all second year foundation doctors, equivalent to a response rate of 80%. Of …
Campylobacter species prevalence, characterisation of antimicrobial resistance and analysis of whole-genome sequence of isolates from livestock and humans, Latvia, 2008 to 2016
Authors: Irēna Meistere, Juris Ķibilds, Lāsma Eglīte, Laura Alksne, Jeļena Avsejenko, Alla Cibrovska, Svetlana Makarova, Madara Streikiša, Lelde Grantiņa-Ieviņa, Aivars Bērziņš
Journal: Eurosurveillance (2019)

BackgroundCampylobacter is the main cause of bacterial gastroenteritis worldwide. The main transmission route is through consumption of food contaminated with Campylobacter species or contact with infected animals. In Latvia, the prevalence of campylobacteriosis is reported to be low (4.6 cases per 100,000 population in 2016).AimTo determine prevalence, species spectrum and antimicrobial resistance (AMR) of Campylobacter spp. in Latvia, using data from various livestock and human clinical samples.MethodsWe analysed data of Campylobacter microbiological monitoring and AMR (2008 and 2014-16) in Latvia. Data from broilers, poultry, pigs, calves and humans were used to determine prevalence of Campylobacter. Additionally, 45 different origin isolates (22 human) were sequenced on the Illumina MiSeq platform; for each isolate core genome multilocus sequence typing was used and relevant antimicrobial resistance mechanisms were identified.ResultsOverall, Campylobacter prevalence in was 83.3% in pigs, 50.2% in broilers, 16.1% in calves and 5.3% in humans; C. jejuni was the predominant species in all sources except pigs where C. coli was main species. High level of resistance in Campylobacter were observed against fluoroquinolones, tetracycline and streptomycin, in most of sequenced isolates genetic determinants of relevant AMR profiles were identified.ConclusionsIn Latvia, prevalence of Campylobacter in livestock is high, especially in pigs and broilers; prevalence in poultry and humans were lower than in other European countries. AMR analysis reveals increase of streptomycin and tetracycline resistant broiler origin C. jejuni strains. WGS demonstrates a high compliance between resistance phenotype and genotype for quinolones and tetracyclines.