tbuckley/cabot-search huggingface dataset:
Abstract 41: Different MicroRNA Expression Profiles in Murine Aorta and Carotid Arteries
Authors: Ernesto Curty-Costa, Luísa Hoffmann, Rosane Silva, Turán P Ürményi, Debora S Faffe
Journal: Circulation Research (2015)

Atherosclerosis, a major cause of death, affects vascular walls diffusely. Some vascular beds are, however, preferentially involved. Small noncoding RNAs, microRNAs, have emerged as key regulators of gene expression in either physiological or pathophysiological processes. Here, we investigated whether different vascular beds, commonly affected by atherosclerosis, present specific microRNA expression profiles. To this end, aorta (Ao) and carotid (Ca) arteries from two male Wistar rats (200 g) were dissected, total RNA was extracted with Trizol, and the small RNA fraction was enriched using magnetic beads. Sequencing was performed using RNA-Seq on Ion Torrent PGM platform and data were analyzed using CLC Genomics Workbench software. We identified 372 and 305 microRNAs in Ca and Ao, respectively - the arteries shared 280 microRNAs. The majority of the 20 most expressed microRNAs were similar between the arteries. Of these top 20, 90% in the Ao were also among the most expressed in Ca, and in Ca 65% were also among the most expressed in Ao. Both mechano and platelet-microRNAs were identified in both arteries. Note that overexpression of mechano-miR-21 is reported to attenuate lipid accumulation and to reduce inflammation, preventing atherosclerosis. We detected mechano-miR-21, however, only in the Ao. We also found that murine aorta and carotid arteries express differently 29 microRNAs (p&lt;0.05). Among the 29 microRNAs, 8 (28%) have been related to atherosclerosis. Of these, 6 were more expressed in Ca (miR-181, miR-9a-1, miR-9a-2, miR-511, miR-146, miR-27), and 2 were more expressed in Ao (miR-144 and miR-322). Note that 3 of the 6 more expressed microRNAs in Ca are related to atherosclerosis, that is: miR-181 regulates cell stress and proliferation; miR-511 regulates cholesterol synthesis, and miR-27 is a known marker of the disease. Taken together, our results suggest that specific microRNA expression profiles may play a role in the vascular behavior during the atherosclerotic process.
A snoring child
Authors: Jared Gursanscky, Marnee Boston, Tawakir Kamani
Journal: BMJ (2017)

#### What you need to know

The parents of a 4 year old child complain that he is snoring loudly, is restless during sleep, and is irritable during the day.

Snoring occurs in 8%-15% of children, while obstructive sleep apnoea occurs in 1%-4%.1 2 The spectrum of sleep disordered breathing extends from normal breathing and uncomplicated snoring through to obstructive sleep apnoea, with increasing degrees of airway obstruction (fig 1⇓). Parents are often concerned about snoring because of the disordered breathing and behaviour changes that sometimes accompany it, and the possibility of an underlying medical cause. This first consultation will help to discriminate obstructive sleep apnoea from uncomplicated snoring.



Fig 1  Spectrum of symptoms and signs seen in sleep disordered breathing



Snoring results from turbulent airflow and vibration of soft tissues. In children, the primary cause of airflow turbulence …
RESPONSE 2: A phase 3b study evaluating the efficacy and safety of ruxolitinib in patients with hydroxyurea (HU)-resistant/intolerant polycythemia vera (PV) versus best available therapy (BAT).
Authors: Francesco Passamonti, Guray Saydam, Liberata Lim, Mahmudul H Khan, Nadjat Mounedji, Martin Griesshammer
Journal: Journal of Clinical Oncology (2014)

TPS7128^ Background: PV is a myeloproliferative neoplasm characterized by clonal stem cell proliferation, hyperviscous blood, significant morbidity, and reduced life span. Advanced PV results in splenomegaly, severe constitutional symptoms, and possible evolution to myelofibrosis and acute myeloid leukemia (AML). Nearly all patients (pts) have a mutation in JAK2, and > 95% have the JAK2 V617F allele. HU is the myelosuppressive agent of choice in high-risk pts, but it often loses efficacy over time and may cause unacceptable skin toxicities. Therapeutic options in the case of HU resistance are limited, and survival is significantly reduced. A phase 2 study in HU-resistant/-intolerant PV pts showed that ruxolitinib, a potent and selective JAK1/JAK2 inhibitor, was well tolerated and achieved rapid and durable clinical responses, including hematocrit (Hct) normalization, phlebotomy independence, resolution of splenomegaly, and improvements in symptoms (Verstovsek et al, Cancer, 2013). RESPONSE, a phase 3 trial, was designed to compare the efficacy and safety of ruxolitinib with best available therapy (BAT) in HU-resistant/-intolerant PV pts with splenomegaly. Methods: RESPONSE 2 is an open-label, randomized (1:1), phase 3b study (NCT02038036) designed to compare the efficacy and safety of ruxolitinib with BAT in PV pts (per revised WHO criteria) who require phlebotomy and are HU-resistant/-intolerant. Target enrollment is 104 pts and includes pts without splenomegaly, expanding the RESPONSE patient population. The primary endpoint is the achievement of Hct control, defined as Hct < 45% at week 16 and maintained until week 28, and no phlebotomy from week 4 to week 28, with ≤ 1 phlebotomy postrandomization and prior to week 4. Secondary endpoints include peripheral blood count remission, partial remission (ELN and IWG-MRT criteria), and resolution of symptoms in MPN-SAF TSS at week 28. The BAT group may cross over to ruxolitinib on or after week 28 if they have Hct > 45%, receive phlebotomy, or need to discontinue BAT. Pts will be treated for 52 weeks to assess safety and durability of response. Clinical trial information: NCT02038036.
Pancreatic β-cell regeneration: advances in understanding the genes and signaling pathways involved
Authors: Solomon Afelik, Meritxell Rovira
Journal: Genome Medicine (2017)

Recent advances in β-cell regeneration in vivo are providing insights into the mechanisms involved in the conversion of distinct pancreatic cell lineages into β cells. These mechanisms mostly involve reactivation of the gene encoding the pancreatic endocrine cell-specifying transcription factor neurogenin-3.
18F-FDG PET/CT of Papillary Carcinoma in a Lateral Thyroglossal Duct Cyst
Authors: Christos Sachpekidis, Matthias S. Dettmer, Sabine Weidner, Roland Giger, Jan Wartenberg
Journal: Clinical Nuclear Medicine (2017)

A 69-year-old man presented with bulging of the right oropharyngeal wall, which revealed cytopathologically malignant cells. The man underwent MRI and F-FDG PET/CT, which demonstrated a cystic parapharyngeal lesion with an F-FDG-avid soft tissue component and right cervical lymph node. The patient was operated on and showed thyroid cancer in normal thyroid tissue, compatible with a papillary thyroid carcinoma in a lateral thyroglossal duct cyst and 2 ipsilateral lymph node metastases. Despite its rarity, papillary thyroid carcinoma in a thyroglossal duct cyst should be kept as one of the differential diagnoses in patients presenting with parapharyngeal cystic lesion.
Platelet Function Prior to Ibrutinib Treatment Is More Severely Impaired in Chronic Lymphocytic Leukemia Than in Mantle Cell Lymphoma
Authors: Eugene Nikitin, Anastasia Ignatova, Vladimir Vorobyev, Alexander Poletaev, Dmitrii Polokhov, Anton Fedotov, Elena A. Seregina, Alexey Pshonkin, Mikhail Panteleev, Vadim Ptushkin
Journal: Blood (2016)
Efficacy of sirolimus (rapamycin) administered concomitantly with a subtherapeutic dose of cyclosporin in the treatment of severe psoriasis: a randomized controlled trial
Authors: S. Reitamo, P. Spuls, B. Sassolas, M. Lahfa, A. Claudy, C.E.M. Griffiths
Journal: British Journal of Dermatology (2008)

Background The identification of a highly potent immunosuppressive/antiproliferative agent with an acceptable toxicity profile has long been a goal for the management of severe plaque psoriasis. Objectives To investigate the efficacy and safety of sirolimus (Rapamune®) for severe psoriasis when given alone or in association with cyclosporin. Methods In a randomized, double-blind, eight parallel group, pilot study in 24 out-patient centres in seven European countries, 150 patients, 18 years and older, with severe chronic plaque psoriasis were given sirolimus 0·5, 1·5 and 3·0 mg m−2 daily for 8 weeks, either alone or in association with a subtherapeutic dose of cyclosporin (1·25 mg kg−1 daily). Cyclosporin 5 mg kg−1 daily was the positive control and cyclosporin 1·25 mg kg−1 daily the negative control. The primary efficacy variable was the mean percentage reduction in Psoriasis Area and Severity Index (PASI). Safety assessments included monitoring of adverse events, clinical laboratory parameters and sirolimus/cyclosporin blood concentrations. Results The greatest mean percentage decreases in PASI were seen with cyclosporin 5·0 mg kg−1 daily (70·5%) and with sirolimus 3·0 mg m−2 daily + cyclosporin 1·25 mg kg−1 daily (63·7%). Both groups demonstrated significantly better results than cyclosporin 1·25 mg kg−1 daily (mean decrease 33·4%). Serum creatinine levels were significantly lower for groups with sirolimus alone and sirolimus plus reduced-dose cyclosporin when compared with cyclosporin 5·0 mg kg−1 daily. Adverse events associated with sirolimus included thrombocytopenia (5%), hyperlipidaemia (9%), aphthous stomatitis (9%) and acne (13%), whereas adverse events associated with cyclosporin included hot flushes (12%), hyperlipidaemia (9%) and increased serum creatinine (9%). Conclusions The concomitant administration of sirolimus with a subtherapeutic dose of cyclosporin in severe psoriasis may permit a reduction in their respective toxicities, notably cyclosporin-induced nephrotoxicity.
Interferon-λ Mediates Non-redundant Front-Line Antiviral Protection against Influenza Virus Infection without Compromising Host Fitness
Authors: Ioanna E. Galani, Vasiliki Triantafyllia, Evridiki-Evangelia Eleminiadou, Ourania Koltsida, Athanasios Stavropoulos, Maria Manioudaki, Dimitris Thanos, Sean E. Doyle, Sergei V. Kotenko, Kalliopi Thanopoulou, Evangelos Andreakos
Journal: Immunity (2017)
Abstract 10931: Serum Mac-2 Binding Protein May be a Potential Biomarker for Diagnosis of Silent Atherosclerosis in Subjects With Cardiovascular Risk Factors
Authors: Tomonori Sugiura, Yasuaki Dohi, Sumiyo Yamashita, Yasuhito Tanaka, Nobuyuki Ohte
Journal: Circulation (2015)

Introduction: Mac-2 binding protein (M2BP) is secreted from many cell types. Recently, serum M2BP levels were reported to be useful as a glycoprotein biomarker for liver fibrosis and several types of malignant tumors. Hypothesis: We hypothesized that expression of M2BP might change in the process of atherosclerosis. Hence, the present study was designed to investigate a possible association of the serum M2BP level with cardiovascular risk factors and whether M2BP is a candidate for a marker of progression of atherosclerosis. Methods: Outpatients with one or more cardiovascular risk factors (n=156) and healthy controls without cardiovascular risk factors (n=20) were enrolled. Subjects with liver dysfunction, a history of hepatic disease, malignant neoplasm, or cardiovascular events were excluded. Blood was sampled and serum levels of hyperglycosylated-M2BP were measured by glycan-based immunoassay. Vascular function was assessed by pulse wave velocity (PWV) and flow-mediated dilation (FMD). Results: Serum M2BP levels were positively correlated with cardiovascular risk factors (age, BMI, systolic blood pressure, fasting blood sugar, and HbA1c) and inversely correlated with HDL-cholesterol and estimated-GFR. The M2BP levels were also correlated with CRP, urinary albumin to creatinine ratio, and PWV. The M2BP levels in subjects with hypertension, dyslipidemia, or abnormal glucose metabolism were higher than those in subjects without hypertension, dyslipidemia, or abnormal glucose metabolism (P&lt;0.01, respectively). Moreover, the M2BP levels were associated with accumulation of cardiovascular risk factors. Multiple logistic regression analysis with endpoint of high M2BP (above mean value) revealed that hypertension and dyslipidemia were significantly associated with high M2BP. Subjects with high M2BP showed significantly decreased FMD than those with low M2BP (p&lt;0.05). Conclusions: Serum M2BP levels were increased with age and accumulation of cardiovascular risks factors. Although the spectrum was narrow as compared to that in cases of hepatic fibrosis, significant correlations with cardiovascular risk markers suggest that serum M2BP reflects silent atherosclerosis in subjects with cardiovascular risk factors.
2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction
Authors: Elliott M. Antman, Mary Hand, Paul W. Armstrong, Eric R. Bates, Lee A. Green, Lakshmi K. Halasyamani, Judith S. Hochman, Harlan M. Krumholz, Gervasio A. Lamas, Charles J. Mullany, David L. Pearle, Michael A. Sloan, Sidney C. Smith, Elliott M. Antman, Daniel T. Anbe, Paul W. Armstrong, Eric R. Bates, Lee A. Green, Mary Hand, Judith S. Hochman, Harlan M. Krumholz, Frederick G. Kushner, Gervasio A. Lamas, Charles J. Mullany, Joseph P. Ornato, David L. Pearle, Michael A. Sloan, Sidney C. Smith, Sidney C. Smith, Alice K. Jacobs, Cynthia D. Adams, Jeffrey L. Anderson, Christopher E. Buller, Mark A. Creager, Steven M. Ettinger, Jonathan L. Halperin, Sharon A. Hunt, Harlan M. Krumholz, Frederick G. Kushner, Bruce W. Lytle, Rick Nishimura, Richard L. Page, Barbara Riegel, Lynn G. Tarkington, Clyde W. Yancy
Journal: Circulation (2007)
Antitumor effect of IMGN289, an anti-EGFR antibody-drug conjugate (ADC), in preclinical models of head and neck squamous cell carcinomas (HNSCC).
Authors: Hyunseok Kang, Manjusha Thakar, Rupashree Sen, Christine H. Chung
Journal: Journal of Clinical Oncology (2014)

e17046 Background: IMGN289 is a novel ADC consisting of the humanized anti-EGFR antibody, J2898A, covalently linked to the potent cytotoxic maytansinoid, DM1. Methods: Effects of IMGN289 on clonogenicity and proliferation were tested in ten HNSCC cell lines with varying cetuximab and gefitinib sensitivities including 3 HPV-positives (UPCI-SCC90, UMSCC47, 93VU147T) and 7 HPV-negatives (HN5, SCC61, JHU22, and two pairs of isogenic cell lines SCC25/CTX-R11 and UMSCC1/1cc8) using Matrigel colony formation assays. Half maximal inhibitory concentrations (IC50) were calculated using non-linear regression model. Results: IMGN289 exhibited more potent anti-clonogenic and anti-proliferative activities against all HNSCC cell lines tested with median IC50 of 0.25 nM (0.003 nM to 1.74 nM) compared to cetuximab by approximately 2- to 68-fold (median IC50 of 0.6 nM with range of 0.03 nM to > 100 nM) and gefitinib by 30- to 280-fold (median IC50 of 12.8 nM with range of 0.05 nM to > 100 nM). The cetuximab and/or gefitinib resistant cell lines (UPCI-SCC90, SCC61, JHU22, 1cc8 and CTX-R11) were also sensitive to IMGN289. A positive correlation with correlation coefficient of 0.91 (p=0.01) was observed between IC50s to cetuximab and IMGN289 with exceptions of HN5, SCC61 and JHU22 which were relatively resistant to cetuximab but extremely sensitive to IMGN289. IMGN289 demonstrated tumor growth inhibition independent of HPV status in these cell lines. Conclusions: IMGN289 effectively decreases clonogenicity and inhibits proliferation in HNSCC cell lines independent of HPV status. IMGN289 is also active in cetuximab and/or gefitinib-resistant cells. Further investigation is ongoing to elucidate the efficacy of IMGN289 in in vivo HNSCC models and to identify potential biomarkers of response for future clinical translation.
I WAS AN ACROBAT. AM I IN PAIN?
Authors: Úrsula Martins, João Cunha, Lourenço França, João Amaro, Joana Gomes, Catarina Aguiar Branco
Journal: British Journal of Sports Medicine (2017)

Background Acrobatic Gymnastics is a competitive discipline where gymnasts work together, perform acrobatic moves, dance and tumbling. Objective Investigate the prevalence of musculoskeletal (MS) disorders in former gymnasts. Design Survey of MS disorders (past and present), sent to former gymnasts. Setting This study included former gymnasts. Participants Retired gymnasts of national teams (n=200) and clubs (n=390) from all over the world (16 countries, 4 continents); 612 responders, 590 included according to the inclusion criteria. Interventions The survey included questions on country, gender, position, years of practice, hours of training/week and competition level, as well as medical information: reason for stopping practice (medical/nonmedical, specify the problem), injuries during practice years, present impact in daily life. Main Outcome Measurements Proportion (%) who stopped practicing as a consequence of a serious MS injury. Proportion (%) having any current MS disorder. Pre-specified analysis of relationship between training hours/week, competition level, position and % with current MS disorders in the present. Results Of 590 gymnasts, 294 (50%) reported having suffered a training injury, while 166 (28%) reported still having current medical problems as result of these. A total of 131 gymnasts (22%) reported having stopped practicing because of a medical problem and 121 (21%) reported having a current MS disorder. The most common injury was a traumatic fracture (n=125), most commonly affecting the knee (n=74) and ankle/foot (n=73). As a consequence of the training period, the most common current problems were spine pathology (n=43) and tendinopathies(n=38). Concerning actual symptoms, 402 (68%) reported low back pain, 320 (54%) knee and 219 (37%) shoulder disorders. Conclusions This is the first study of former gymnasts, allowing us to evaluate the impact of training on the future life quality of the athletes, to identify the most frequent injuries, as well as those with the greatest impact. This may lead to improvements in the treatment of acute injuries, as well as to monitor the level and quality of training, to prevent and also to rehabilitate injuries.
Osteogenesis Imperfecta after the Menopause
Authors: Colin R. Paterson, Susan McAllion, Joan L. Stellman
Journal: New England Journal of Medicine (1984)

We studied the fracture rate as a function of age in 45 women and 20 men with osteogenesis imperfecta. In each variant of the disorder, the fracture rate in women peaked in childhood, declined in adolescence, and rose again after the menopause. In contrast, the fracture rate in men remained low after adolescence. After the menopause women were vulnerable to crush fractures of the spine as well as fractures of the long bones. We conclude that the increased fracture rate after the menopause in women with osteogenesis imperfecta reflects the superimposition of the effects of age-related bone loss on those of the defective collagen structure of osteogenesis imperfecta, and that hormone-replacement therapy may be specifically indicated in this group of patients from the time of the menopause. We also suggest that osteogenesis imperfecta should be included in the differential diagnosis of women presenting with crush fractures of the spine. (N Engl J Med 1984; 310:1694–6.)
Cell-penetrating peptides selectively targeting SMAD3 inhibit profibrotic TGF-β signaling
Authors: Jeong-Han Kang, Mi-Yeon Jung, Xueqian Yin, Mahefatiana Andrianifahanana, Danielle M. Hernandez, Edward B. Leof
Journal: Journal of Clinical Investigation (2017)

TGF-β is considered a master switch in the pathogenesis of organ fibrosis. The primary mediators of this activity are the SMAD proteins, particularly SMAD3. In the current study, we have developed a cell-penetrating peptide (CPP) conjugate of the HIV TAT protein that is fused to an aminoterminal sequence of sorting nexin 9 (SNX9), which was previously shown to bind phosphorylated SMAD3 (pSMAD3). We determined that specifically preventing the nuclear import of pSMAD3 using the TAT-SNX9 peptide inhibited profibrotic TGF-β activity in murine cells and human lung fibroblasts as well as in vivo with no demonstrable toxicity. TGF-β signaling mediated by pSMAD2, bone morphogenetic protein 4 (BMP4), EGF, or PDGF was unaffected by the TAT-SNX9 peptide. Furthermore, while the TAT-SNX9 peptide prevented TGF-β's profibrotic activity in vitro as well as in 2 murine treatment models of pulmonary fibrosis, a 3-amino acid point mutant that was unable to bind pSMAD3 proved ineffective. These findings indicate that specifically targeting pSMAD3 can ameliorate both the direct and indirect fibroproliferative actions of TGF-β.
Hypoxia-inducible factor-1α (HIF-1α) modulation in combination with anti-angiogenic therapy
Authors: G. S. Falchook, J. J. Wheler, N. M. Tannir, A. Naing, E. Jackson, D. Hong, K. N. Lawhorn, C. Ng, H. Amin, R. Kurzrock
Journal: Journal of Clinical Oncology (2009)

3555 Background: HIF-1α mediates adaptive responses to hypoxic conditions induced by anti-angiogenic therapy. Bortezomib has demonstrated the ability to inhibit transcriptional activity of HIF-1α. We hypothesized that the addition of bortezomib to bevacizumab would augment response, and we performed this phase I trial to assess safety, MTD, and correlative studies of anti-angiogenic activity. Methods: Patients with advanced malignancy refractory to standard therapy were eligible. Cohorts of 6 patients received bevacizumab and bortezomib on a 3-week cycle, with a stair-step dose escalation design. Pharmacodynamic assessment included plasma VEGF, VEGFR2, 20S proteasome inhibition, DCE-MRI, and tumor expression of HIF-1α, VEGF, VEGFR2, and polymorphisms of VEGF and VEGFR2. Results: 71 patients were treated, and the MTD was identified at the highest dose level (bevacizumab 15 mg/kg, bortezomib 1.3 mg/m 2 ). Two partial responses were observed in patients with renal cell carcinoma (RCC) (Total patients with RCC = 6). Minor responses or stable disease lasting ≥4 months was achieved in 8 patients, including RCC (1), breast (1), leiomyosarcoma (1), nasopharyngeal (2), hepatocellular (1), neuroendocrine (1), lacrimal gland adenocystic carcinoma (1). The most common drug-related toxicities observed included hypertension (36%), fatigue (34%), thrombocytopenia (29%), and myalgia (19%). 22 patients (31%) experienced no drug-related toxicities greater than grade 1. 56 patients (79%) experienced no drug-related toxicities greater than grade 2. One DLT (G5 bleeding) was observed at the MTD. Plasma VEGF levels demonstrated decreases at 1 and 4 hours post-infusion, followed by increases to levels above baseline on days 2, 3, and at the end of cycle 1. DCE-MRI analysis demonstrated decreases in K trans on days 2 and 3. Analysis of HIF-1α expression in biopsies is underway. Conclusions: Combination bevacizumab and bortezomib is well-tolerated and has demonstrated clinical activity in patients with previously treated, advanced malignancy. Pharmacodynamic assessment with biomarkers and DCE-MRI suggests that inhibition of angiogenic activity was achieved. Updated clinical and biomarker data will be presented. No significant financial relationships to disclose.