tbuckley/cabot-search huggingface dataset:
Exosomal miR-196a derived from cancer-associated fibroblasts confers cisplatin resistance in head and neck cancer through targeting CDKN1B and ING5
Authors: Xing Qin, Haiyan Guo, Xiaoning Wang, Xueqin Zhu, Ming Yan, Xu Wang, Qin Xu, Jianbo Shi, Eryi Lu, Wantao Chen, Jianjun Zhang
Journal: Genome biology (2019)

Cisplatin resistance is a major challenge for advanced head and neck cancer (HNC). Understanding the underlying mechanisms and developing effective strategies against cisplatin resistance are highly desired in the clinic. However, how tumor stroma modulates HNC growth and chemoresistance is unclear. We show that cancer-associated fibroblasts (CAFs) are intrinsically resistant to cisplatin and have an active role in regulating HNC cell survival and proliferation by delivering functional miR-196a from CAFs to tumor cells via exosomes. Exosomal miR-196a then binds novel targets, CDKN1B and ING5, to endow HNC cells with cisplatin resistance. Exosome or exosomal miR-196a depletion from CAFs functionally restored HNC cisplatin sensitivity. Importantly, we found that miR-196a packaging into CAF-derived exosomes might be mediated by heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1). Moreover, we also found that high levels of plasma exosomal miR-196a are clinically correlated with poor overall survival and chemoresistance. The present study finds that CAF-derived exosomal miR-196a confers cisplatin resistance in HNC by targeting CDKN1B and ING5, indicating miR-196a may serve as a promising predictor of and potential therapeutic target for cisplatin resistance in HNC.
Surveillance for familial melanoma: recommendations from a national centre of expertise
Authors: A.B. Halk, T.P. Potjer, N.A. Kukutsch, H.F.A. Vasen, F.J. Hes, R. Doorn
Journal: British Journal of Dermatology (2019)

decreased detection of the anaphylatoxin C5a (a marker of complement activation located downstream in the complement cascade) in CFT supernatants from the same experiments (Fig. 1b).Our in vitro results suggest that patients with BP may benefit from off-label LMWH use.Inhibiting ongoing complement fixation and C5a liberation by LMWH may improve skin disease, as suggested in part by BP disease models employing C5a receptor-deficient mice. 9Such therapy might also help prevent coagulation-related complications in BP, 2,10 but the risk vs. benefit in this regard would have to be carefully studied.LMWHs are generally considered safe therapeutics, although long-term side-effects do include osteoporosis, which is also a side-effect of standard BP therapy with corticosteroids.One limitation of our in vitro study may be the rather supraphysiological concentrations of TS used, but at the same time, a high-titre pool of BP sera was used for CFT, resulting in strong BMZ autoantibody binding.Given that clinically overt disease is seen at considerably lower titres of circulating autoantibodies in patients with BP and that the in vitro CFT also works with highly diluted BP sera by extending times of incubation with the fresh complement source (data not shown), we find it conceivable that lower, more physiological TS doses may also be effective, as already suggested in patients with complement-mediated renal disease. 7 In addition, there may be LMWHs other than TS that could inhibit complement better at similar or even lower doses.In summary, we suggest that patients with BP with complement deposits at the BMZ may benefit from LMWH administration.Positive effects of LMWH may also be observed in other complement-fixing diseases such as mucous membrane pemphigoid, epidermolysis bullosa acquisita, autoantibodymediated forms of glomerulonephritis and C3 glomerulonephritis.To confirm conclusively the therapeutic potential hypothesized in this report, additional in vivo studies employing animal models and randomized controlled trials in patients are warranted.
Bacterial sexually transmitted infections in France: recent trends and patients’ characteristics in 2016
Authors: Ndeindo Ndeikoundam Ngangro, Delphine Viriot, Nelly Fournet, Corinne Pioche, Bertille De Barbeyrac, Agathe Goubard, Nicolas Dupin, Béatrice Berçot, Sébastien Fouéré, Isabelle Alcaraz, Michel Ohayon, Nathalie Spenatto, Chantal Vernay-Vaisse, Josiane Pillonel, Florence Lot
Journal: Eurosurveillance (2019)

Diagnoses of bacterial sexually transmitted infections (STI) have been increasing in France since their resurgence in the late 1990s. This article presents recent epidemiological trends until 2016 and the patients' characteristics. STI surveillance relies on sentinel networks: a clinician-based network RésIST (clinical, biological and behavioural data for early syphilis and gonorrhoea), the lymphogranuloma venereum (LGV) network (clinical, biological and behavioural data for rectal LGV, and the laboratory networks Rénachla and Rénago (demographic and biological data for chlamydial infections and gonorrhoea, respectively). Here we describe trends between 2014 and 2016, using data from diagnostic centres which participated regularly during the study period. The number of early syphilis, gonorrhoea and LGV diagnoses increased between 2014 and 2016, particularly in men who have sex with men. An increase in syphilis and gonorrhoea cases was also observed in heterosexuals. Nevertheless, we observed a drop in 2016 for syphilis and chlamydial infections after two decades of increases. Under-reporting and shortage of benzathine penicillin in 2016 may explain this latest evolution. Regular screening of patients and partners, followed by prompt treatment, remains essential to interrupt STI transmission in a context where human immunodeficiency virus (HIV) prevention has expanded towards biomedical prophylaxis.
The Class of Fast-Dissolving Tablets for Sublingual Allergen Immunotherapy Induce Comparable Serological IgE and IgG4 Responses
Authors: Peter Sejer Andersen, Claus Lundegaard, Hans Henrik Ipsen, Katsuyo Ohashi-Doi, Hendrik Nolte, Thomas Stranzl
Journal: Journal of Allergy and Clinical Immunology (2019)
Molecular and Functional Evolution at the Odorant Receptor Or22 Locus in Drosophila melanogaster
Authors: Katherine H Shaw, Travis K Johnson, Alisha Anderson, Marien de Bruyne, Coral G Warr
Journal: Molecular Biology and Evolution (2019)

Insect odorant receptor (Or) genes determine the responses of sensory neurons that mediate critical behaviors. The Drosophila melanogaster Or22 locus represents an interesting example of molecular evolution, with high levels of sequence divergence and copy number variation between D. melanogaster and other Drosophila species, and a corresponding high level of variability in the responses of the neuron it controls, ab3A. However, the link between Or22 molecular and functional diversity has not been established. Here, we show that several naturally occurring Or22 variants generate major shifts in neuronal response properties. We determine the molecular changes that underpin these response shifts, one of which represents a chimeric gene variant previously suggested to be under natural selection. In addition, we show that several alternative molecular genetic mechanisms have evolved for ensuring that where there is more than one gene copy at this locus, only one functional receptor is generated. Our data thus provide a causal link between the striking levels of phenotypic neuronal response variation found in natural populations of D. melanogaster and genetic variation at the Or22 locus. Since neuronal responses govern animal behavior, we predict that Or22 may be a key player in underlying one or more olfactory-driven behaviors of significant adaptive importance.
Pathologic outcomes of systemic therapy followed by stereotactic body radiation therapy (SBRT) for pancreatic cancer (PC) in a novel lateral decubitus treatment position.
Authors: Ethan Song, Jessica Frakes, Kujtim Latifi, Mokenge Peter Malafa, Pamela Joy Hodul, Jose Mario Pimiento, Dae Won Kim, Richard D. Kim, Sarah E. Hoffe
Journal: Journal of Clinical Oncology (2019)

415 Background: Outcomes of multi-fraction stereotactic body radiotherapy (SBRT) for PC report low rates of toxicity and high local control, improving feasibility for combination with more aggressive systemic therapy regimens. However, SBRT in the ablative range poses risk to adjacent normal structures, excluding this option for tumors within 1 cm of a mucosal organ. In this study, we report our initial experience with treatment in the lateral decubitus position. Methods: An IRB retrospective query identified patients with pancreatic body adenocarcinoma treated with systemic chemotherapy followed by SBRT in the lateral decubitis position. SBRT was delivered to the entire gross disease with 30 Gy in 5 fractions with focal dose escalation up to 40 Gy to the tumor/vessel interface (TVI) as long as constraints were met. Patients were explored for resection if no metastasis or progression on restaging scans. The primary endpoints were pathologic response and margin status. Descriptive analysis was performed with SPSS 24. Results: The median age of the cohort was 68.6 (range, 50-83 yrs), with a white (94%) and male (59%) predominance. Initial staging of the 17 patients who met criteria included 10 (59%) patients diagnosed with borderline resectable disease (BRPC) and 7 (41%) with locally advanced disease (LAPC). 7 (41%) patients were treated with FOLFIRINOX, 5 (29%) with gemcitabine/nab-paclitaxel, 4 (24%) with gemcitabine/capecitabine/docetaxel, and 1 (6%) with gemcitabine/paclitaxel preceding SBRT. A median dose of 40 Gy (range, 33-40 Gy) was delivered to the TVI for all patients. 5 BRCP (29%) and 2 LAPC (12%) patients went to surgery, with 6 of these patients undergoing an R0 resection (86%) and 1 BRPC patient with an R1 resection. Pathologic tumor regression grades by the College of American Pathologists guidelines were 14% Grade 1, 71% Grade 2, and 14% Grade 3. Conclusions: Lateral decubitus treatment expands inclusion of pancreatic body patients for SBRT with focal TVI dose escalation leading to margin negative resection and significant partial tumor response, warranting future studies exploring ablative dosing in this position.
Adipocyte Death Preferentially Induces Liver Injury and Inflammation Through the Activation of Chemokine (C‐C Motif) Receptor 2‐Positive Macrophages and Lipolysis
Authors: Seung‐Jin Kim, Dechun Feng, Adrien Guillot, Shen Dai, Fengming Liu, Seonghwan Hwang, Richard Parker, Wonhyo Seo, Yong He, Grzegorz Godlewski, Won‐Il Jeong, Yuhong Lin, Xuebin Qin, George Kunos, Bin Gao
Journal: Hepatology (2019)

Adipocyte death occurs under various physiopathological conditions, including obesity and alcohol drinking, and can trigger organ damage particularly in the liver, but the underlying mechanisms remain obscure. To explore these mechanisms, we developed a mouse model of inducible adipocyte death by overexpressing the human CD59 (hCD59) on adipocytes (adipocyte‐specific hCD59 transgenic mice). Injection of these mice with intermedilysin (ILY), which rapidly lyses hCD59 expressing cells exclusively by binding to the hCD59 but not mouse CD59, resulted in the acute selective death of adipocytes, adipose macrophage infiltration, and elevation of serum free fatty acid (FFA) levels. ILY injection also resulted in the secondary damage to multiple organs with the strongest injury observed in the liver, with inflammation and hepatic macrophage activation. Mechanistically, acute adipocyte death elevated epinephrine and norepinephrine levels and activated lipolysis pathways in adipose tissue in a chemokine (C‐C motif) receptor 2‐positive (CCR2 + ) macrophage‐dependent manner, which was followed by FFA release and lipotoxicity in the liver. Additionally, acute adipocyte death caused hepatic CCR2 + macrophage activation and infiltration, further exacerbating liver injury. Conclusion: Adipocyte death predominantly induces liver injury and inflammation, which is probably due to the superior sensitivity of hepatocytes to lipotoxicity and the abundance of macrophages in the liver.
Profile of Mutations Identified in the 3WINTERS-IPS Project on European &amp; Iranian Patients with Previously Diagnosed Type 3 Von Willebrand Disease.
Authors: Luciano Baronciani, Flora Peyvandi, Anne Goodeve, Reinhard Schneppenheim, Zahra Badiee, Mohammad-Reza Baghaipour, Javier Battle, Erik Berntorp, Imre Bodó, Ulrich Budde, Andrea Cairo, Giancarlo Castaman, Laura Crookes, Jeroen C.J. Eikenboom, Peyman Eshghi, Cosimo Ettorre, Jenny Goudemand, Wolf Hassenpflug, Charles Richard Morris Hay, Hamid Hoorfar, Mehran Karimi, Bijan Keikhaei, Riitta Lassila, Frank W.G. Leebeek, Maria Fernanda Lopez Fernandez, Pier Mannuccio Mannucci, Maria Gabriella Mazzucconi, Massimo Morfini, Nikolas Nikšić, Johannes Oldenburg, Florian Oyen, Rafael Parra Lòpez, Ian Peake, Gholamreza Toogeh, Alberto Tosetto, Marc Trossaert, Sayed Omid Reza Zekavat, Eva M.K. Zetterberg, Augusto B Federici
Journal: Blood (2018)
Abstract 12007: Cardiac Th1/Th2 Cytokine Imbalance Was Closely Associated With the Transition From Left Ventricular Hypertrophy to Diastolic Heart Failure in Salt-Sensitive Hypertensive Rats
Authors: Eiichiro Yamamoto, Hiroaki Kusaka, Yasuhiro Hirata, Takanori Tokitsu, Koichi Sugamura, Osamu Yasuda, Seigo Sugiyama, Shokei K Mitsuyama, Hisao Ogawa
Journal: Circulation (2014)

Background: Although cardiac inflammation and fibrosis are closely associated with the progression of cardiac remodeling, little is known about the relative role of inflammation- and fibrosis-relat...
Construct validity and responsiveness of the Colombian version of Skindex‐29
Authors: D. Vasquez, D.‐C. Aguirre, G. Sanclemente
Journal: British Journal of Dermatology (2019)

In recent years, the need for international, objective, patient‐reported outcomes measures has grown as international collaboration has increased. As most quality‐of‐life scales have been developed in English, there is a growing need to adapt them transculturally to obtain equivalence between the original instrument and the adapted scale. To assess the construct and convergent–discriminant validity and responsiveness of the Colombian version of Skindex‐29. The cross‐sectional and longitudinal validity and responsiveness were tested in both healthy and dermatology patients. Construct validity was tested through a confirmatory factor analysis. The convergent–discriminant validity was assessed by examining the Spearman correlation coefficient. Change sensitivity was tested by means of the standardized response mean. The effect size and the minimum detectable change were also assessed. A total of 265 participants were included; 21·1% were healthy individuals, and 78·9% patients had either inflammatory or noninflammatory skin diseases. Confirmatory factor analysis showed an adequate comparative fit index and Tucker–Lewis index adjustment for the root mean square error of approximation. Convergent validity showed moderate correlations between the emotions, functioning and physical function or physical role domains. Discriminant validity showed low correlations between overall domains for both scales. Sensitivity to change at the first and third month showed effect sizes in global Skindex scores of 0·92 and 0·82, respectively. The Colombian version of Skindex‐29 is a valid and clinically sensitive instrument, which can be used for clinical practice and for research to measure the impact of skin diseases on the quality of life of dermatology patients.
Late Effects of High-Dose Chemotherapy and Autologous Hematopoietic Cell Transplantation (HDT-AHCT) in Elderly Patients with Lymphoma
Authors: Parastoo B. Dahi, Chikaodi Obioha, Sheila Kenny, Patrick Hilden, Molly Maloy, Alexander Geyer, Wendy Schaffer, Roni Tamari, Craig S. Sauter, Ann A. Jakubowski, Sergio Giralt
Journal: Blood (2018)
The Expression of CD83 Would be Increased in CD34-Positive Monocytes Detected in Peripheral Blood Mobilized By G-CSF in Humans
Authors: Hideki Nakasone, Misato Kikuchi, Yu Akahoshi, Koji Kawamura, Miki Sato, Kazuki Yoshimura, Yukiko Misaki, Ayumi Gomyo, Aki Tanihara, Machiko Kusuda, Masaharu Tamaki, Shun-Ichi Kimura, Shinichi Kako, Yoshinobu Kanda
Journal: Blood (2018)
Physiological, hyaluronan-selected intracytoplasmic sperm injection for infertility treatment (HABSelect): a parallel, two-group, randomised trial
Authors: David Miller, Susan Pavitt, Vinay Sharma, Gordon Forbes, Richard Hooper, Siladitya Bhattacharya, Jackson Kirkman-Brown, Arri Coomarasamy, Sheena Lewis, Rachel Cutting, Daniel Brison, Allan Pacey, Robert West, Kate Brian, Darren Griffin, Yakoub Khalaf
Journal: The Lancet (2019)

BackgroundSperm selection strategies aimed at improving success rates of intracytoplasmic sperm injection (ICSI) include binding to hyaluronic acid (herein termed hyaluronan). Hyaluronan-selected sperm have reduced levels of DNA damage and aneuploidy. Use of hyaluronan-based sperm selection for ICSI (so-called physiological ICSI [PICSI]) is reported to reduce the proportion of pregnancies that end in miscarriage. However, the effect of PICSI on livebirth rates is uncertain. We aimed to investigate the efficacy of PICSI versus standard ICSI for improving livebirth rates among couples undergoing fertility treatment.MethodsThis parallel, two-group, randomised trial included couples undergoing an ICSI procedure with fresh embryo transfer at 16 assisted conception units in the UK. Eligible women (aged 18–43 years) had a body-mass index of 19–35 kg/m2 and a follicle-stimulating hormone (FSH) concentration of 3·0–20·0 mIU/mL or, if no FSH measurement was available, an anti-müllerian hormone concentration of at least 1·5 pmol/L. Eligible men (aged 18–55 years) had not had a vasovasostomy or been treated for cancer in the 24 months before recruitment and were able, after at least 3 days of sexual abstinence, to produce freshly ejaculated sperm for the treatment cycle. Couples were randomly assigned (1:1) with an online system to receive either PICSI or a standard ICSI procedure. The primary outcome was full-term (≥37 weeks' gestational age) livebirth, which was assessed in all eligible couples who completed follow-up. This trial is registered, number ISRCTN99214271.FindingsBetween Feb 1, 2014, and Aug 31, 2016, 2772 couples were randomly assigned to receive PICSI (n=1387) or ICSI (n=1385), of whom 2752 (1381 in the PICSI group and 1371 in the ICSI group) were included in the primary analysis. The term livebirth rate did not differ significantly between PICSI (27·4% [379/1381]) and ICSI (25·2% [346/1371]) groups (odds ratio 1·12, 95% CI 0·95–1·34; p=0·18). There were 56 serious adverse events in total, including 31 in the PICSI group and 25 in the ICSI group; most were congenital abnormalities and none were attributed to treatment.InterpretationCompared with ICSI, PICSI does not significantly improve term livebirth rates. The wider use of PICSI, therefore, is not recommended at present.FundingNational Institute for Health Research Efficacy and Mechanism Evaluation Programme.
Modifiable metabolic markers c-peptide (C-PEP), highly sensitive c-reactive protein (hsCRP), leptin (LEP)] and lung cancer (LC) risk: A matched case-control study nested in the prostate, lung, colorectal and ovarian (PLCO) cancer screening study.
Authors: Pamela Jean Goodwin, Martin Tammemagi, Vuk Stambolic, Ryan JO Dowling, Craig Williams, Matt Moore, Ana Elisa Lohmann, Frances A. Shepherd
Journal: Journal of Clinical Oncology (2015)

1520 Background: LC is not associated with obesity; however, metabolic factors have been inconsistently associated with LC risk or death in previous small studies (involving < 100 LC cases). We investigated pre-diagnosis C-PEP, hsCRP and LEP and LC risk in EVER and NEVER smoking PLCO participants. Methods: 986 LC cases and 2054 controls [matched for age, gender, race/ethnicity, study center, duration in study, smoking status (never, former and current smoker)] provided non-fasting blood ≥ 2 years pre-diagnosis ( ≥ 3 yrs in 75%). After storage at -80°C, C-PEP, hsCRP and LEP were assayed using Luminex xMAP Multiplex immunoassays. Log transformed continuous blood markers were analyzed using multivariable conditional logistic regression [that included family history LC (FH), COPD, and smoking intensity, duration and quit-time]. 2-tail P ≤ 0.05 was considered significant. Results: Cases [854 NSCLC, 132 SCLC] and controls had similar age (64 yr) and ethnicity (90% white); cases had more smoking pack years (57.4 vs 39.6, p < 0.001). In EVER smokers (89.2% of total), LC cases (vs controls) had higher mean C-PEP (976.9 vs 939.4 pmol/L, ptrend = 0.02), hsCRP (22.6 vs 18.3 mg/L, ptrend < 0.001) and lower LEP (7.7 vs 8.1 ng/ml, ptrend < 0.001). Multivariably, higher C-PEP (p = 0.049) and hsCRP (p = 0.001) but lower LEP (p = 0.001) were associated with LC [Odds Ratios (OR) for upper vs lower quartiles 1.23, 1.54, 0.60 respectively]. FH (OR 1.75, p < 0.001), COPD (OR 1.38, p = 0.04), and extent of smoking were also associated with LC. When BMI was added to the model, it was inversely associated with LC (p = 0.003); C-PEP (p = 0.025) and hsCRP (p < 0.001) remained significant but LEP become non-significant. Metabolic markers were not associated with LC in NEVER smokers. Conclusions: In EVER smokers, higher pre-diagnosis C-PEP and hsCRP were associated with higher LC risk; inverse associations were seen for LEP and BMI. Future research should replicate our findings and investigate biologic mechanisms. Because these factors are potentially modifiable, intervention studies may be warranted.
Neonatologist is struck off for forging emails over specialist registration
Authors: Clare Dyer
Journal: BMJ (2019)

A doctor who worked as a consultant neonatologist for NHS Grampian from 2009 has been struck off after a medical practitioners tribunal found that she forged emails about her application for specialist registration and told her employers that the emails came from the General Medical Council (GMC).

Annie Kirk Robertson forwarded two emails purporting to be from the GMC to her employers in 2017, and she relayed accounts of phone calls she claimed to have made to the regulator to hurry along the processing of her application for specialist registration.

She had in fact created the emails herself, the tribunal found, and her account of being …
Safety, pharmacokinetics, and pharmacodynamics of lumacaftor and ivacaftor combination therapy in children aged 2–5 years with cystic fibrosis homozygous for F508del-CFTR: an open-label phase 3 study
Authors: John J McNamara, Susanna A McColley, Gautham Marigowda, Fang Liu, Simon Tian, Caroline A Owen, David Stiles, Chonghua Li, David Waltz, Linda T Wang, Gregory S Sawicki
Journal: The Lancet Respiratory Medicine (2019)
Scientists on the Spot: advances in cardiac surgery
Authors: Albano C Meli, Ottavio Alfieri
Journal: Cardiovascular Research (2019)

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