tbuckley/cabot-search huggingface dataset:
Inhibition of Cyclin‐Dependent Kinase 5: A Strategy to Improve Sorafenib Response in Hepatocellular Carcinoma Therapy
Authors: Maximilian A. Ardelt, Thomas Fröhlich, Emanuele Martini, Martin Müller, Veronika Kanitz, Carina Atzberger, Petra Cantonati, Martina Meßner, Laura Posselt, Thorsten Lehr, Jan‐Georg Wojtyniak, Melanie Ulrich, Georg J. Arnold, Lars König, Dario Parazzoli, Stefan Zahler, Simon Rothenfußer, Doris Mayr, Alexander Gerbes, Giorgio Scita, Angelika M. Vollmar, Johanna Pachmayr
Journal: Hepatology (2018)

Therapeutic options for patients with advanced-stage hepatocellular carcinoma (HCC) are very limited. The only approved first-line treatment is the multi-tyrosine kinase inhibitor sorafenib, which shows low response rates and severe side effects. In particular, the compensatory activation of growth factor receptors leads to chemoresistance and limits the clinical impact of sorafenib. However, combination approaches to improve sorafenib have failed. Here we investigate the inhibition of cyclin-dependent kinase 5 (Cdk5) as a promising combination strategy to improve sorafenib response in HCC. Combination of sorafenib with Cdk5 inhibition (genetic knockdown by short hairpin RNA or CRISPR/Cas9 and pharmacologic inhibition) synergistically impaired HCC progression in vitro and in vivo by inhibiting both tumor cell proliferation and migration. Importantly, these effects were mediated by a mechanism for Cdk5: A liquid chromatography-tandem mass spectrometry-based proteomic approach revealed that Cdk5 inhibition interferes with intracellular trafficking, a process crucial for cellular homeostasis and growth factor receptor signaling. Cdk5 inhibition resulted in an accumulation of enlarged vesicles and respective cargos in the perinuclear region, considerably impairing the extent and quality of growth factor receptor signaling. Thereby, Cdk5 inhibition offers a comprehensive approach to globally disturb growth factor receptor signaling that is superior to specific inhibition of individual growth factor receptors. Conclusion: Cdk5 inhibition represents an effective approach to improve sorafenib response and to prevent sorafenib treatment escape in HCC. Notably, Cdk5 is an addressable target frequently overexpressed in HCC, and with Dinaciclib, a clinically tested Cdk5 inhibitor is readily available. Thus, our study provides evidence for clinically evaluating the combination of sorafenib and Dinaciclib to improve the therapeutic situation for patients with advanced-stage HCC.
SK3 Gene Polymorphism Is Associated with Taxane Neurotoxicity and Cell Calcium Homeostasis
Authors: Carina Rua, Maxime Guéguinou, Imane Soubai, Erika Viel, Marie Potier-Cartereau, Aurélie Chantome, Catherine Barbe, Philippe Bougnoux, Chantal Barin-Le Guellec, Christophe Vandier
Journal: Clinical Cancer Research (2018)

Purpose: Taxane-induced peripheral neuropathy is a common side effect induced by anticancer agents, and no drug capable of preventing its occurrence or ameliorating its long-term course has been identified. The physiology of taxane neuropathy is not clear, and diverse mechanisms have been suggested, with ion channels regulating Ca2+ homeostasis appearing good candidates. The calcium-activated potassium channel SK3 is encoded by the KCNN3 gene, which is characterized by a length polymorphism due to variable number of CAG repeats.Experimental Design: To study the influence of the polymorphism of CAG motif repeat of KCNN3 on the development of taxane-induced neuropathy, we evaluated 176 patients treated with taxanes for breast cancer. In parallel, we measured Ca2+ entry using Fura2-AM dye in HEK cells expressing short versus long CAG alleles of KCNN3Results: In the current study, we report that in the presence of docetaxel, Ca2+ entry was significantly increased in cells expressing short versus long CAG alleles of SK3 and that a SK3-lipid blocker inhibits this effect. We found that patients carrying a short KCNN3 allele exhibited significantly increased incidence of taxane neuropathy compared with those carrying longer alleles.Conclusions: The clinical implication of these findings is that KCNN3 polymorphism may increase patient susceptibility to taxane neurotoxicity and that the use of SK3 blockers during taxanes' administration may represent an interesting approach for the prevention of this neurotoxicity. Clin Cancer Res; 24(21); 5313-20. ©2018 AACR.
Initial and 6-Month Results of Biodegradable Poly-l-Lactic Acid Coronary Stents in Humans
Authors: HideoTamai, KeijiIgaki, EishoKyo, KunihikoKosuga, AkiyoshiKawashima, ShigeoMatsui, HidenoriKomori, TakafumiTsuji, SeiichiroMotohara, HiromuUehata
Journal: Circulation (2000)

Background—Although metallic stents are effective in preventing acute occlusion and reducing late restenosis after coronary angioplasty, many concerns still remain. Compared with metallic stents, poly-l-lactic acid (PLLA) stents are biodegradable and can deliver drugs locally. The aim of this study was to evaluate the feasibility, safety, and efficacy of the PLLA stent. Methods and Results—Fifteen patients electively underwent PLLA Igaki-Tamai stent implantation for coronary artery stenoses. The Igaki-Tamai stent is made of a PLLA monopolymer, has a thickness of 0.17 mm, and has a zigzag helical coil pattern. A balloon-expandable covered sheath system was used, and the stent expanded by itself to its original size with an adequate temperature. A total of 25 stents were successfully implanted in 19 lesions in 15 patients, and angiographic success was achieved in all procedures. No stent thrombosis and no major cardiac event occurred within 30 days. Coronary angiography and intravascular ultrasound were ser...
EUS-guided treatment of WON using lumen-apposing metal stents: protocol standardisation based on the occurrence of natural healing processes
Authors: Mihai Rimbaş, Margherita Pizzicanella, Alberto Larghi
Journal: Gut (2018)

We read with great interest the paper by Bang et al ,1 which reported the results of a randomised controlled trial comparing endoscopic ultrasound (EUS)-guided placement of lumen-apposing metal stents (LAMS) (Hot Axios) versus plastic stents (PS) for the treatment of patients with walled-off pancreatic necrosis (WON). During the first phase of the study, a very high number of adverse events (AEs) (32.2%) occurred in the LAMS arm, including two patients with a buried stent, three with bleeding pseudoaneurysms that required coil embolisation and other three with stent-induced biliary stricture. All these AEs occurred within 6 weeks from stent placement, which was the time established to assess treatment response by an abdominal CT. Due to this high rate of AEs, the protocol was changed and follow-up CT anticipated at 3 weeks, resulting in a decrease of AEs to 6.5% in the …
Rapid Viral Symbiogenesis via Changes in Parasitoid Wasp Genome Architecture
Authors: Gaelen R Burke, Tyler J Simmonds, Barbara J Sharanowski, Scott M Geib
Journal: Molecular Biology and Evolution (2018)

Viral genome integration provides a complex route to biological innovation that has rarely but repeatedly occurred in one of the most diverse lineages of organisms on the planet, parasitoid wasps. We describe a novel endogenous virus in braconid wasps derived from pathogenic alphanudiviruses. Limited to a subset of the genus Fopius, this recent acquisition allows an unprecedented opportunity to examine early endogenization events. Massive amounts of virus-like particles (VLPs) are produced in wasp ovaries. Unlike most endogenous viruses of parasitoid wasps, the VLPs do not contain DNA, translating to major differences in parasitism-promoting strategies. Rapid changes include genomic rearrangement, loss of DNA processing proteins, and wasp control of viral gene expression. These events precede the full development of tissue-specific viral gene expression observed in older associations. These data indicate that viral endogenization can rapidly result in functional and evolutionary changes associated with genomic novelty and adaptation in parasitoids.
MAST1 Drives Cisplatin Resistance in Human Cancers by Rewiring cRaf-Independent MEK Activation
Authors: Lingtao Jin, Jaemoo Chun, Chaoyun Pan, Dan Li, Ruiting Lin, Gina N. Alesi, Xu Wang, Hee-Bum Kang, Lina Song, Dongsheng Wang, Guojing Zhang, Jun Fan, Titus J. Boggon, Lu Zhou, Jeanne Kowalski, Cheng-Kui Qu, Conor E. Steuer, Georgia Z. Chen, Nabil F. Saba, Lawrence H. Boise, Taofeek K. Owonikoko, Fadlo R. Khuri, Kelly R. Magliocca, Dong M. Shin, Sagar Lonial, Sumin Kang
Journal: Cancer Cell (2018)
The Urban Exposome during Pregnancy and Its Socioeconomic Determinants
Authors: Oliver Robinson, Ibon Tamayo, Montserrat de Castro, Antonia Valentin, Lise Giorgis-Allemand, Norun Hjertager Krog, Gunn Marit Aasvang, Albert Ambros, Ferran Ballester, Pippa Bird, Leda Chatzi, Marta Cirach, Audrius Dėdelė, David Donaire-Gonzalez, Regina Gražuleviciene, Minas Iakovidis, Jesus Ibarluzea, Mariza Kampouri, Johanna Lepeule, Léa Maitre, Rosie McEachan, Bente Oftedal, Valerie Siroux, Remy Slama, Euripides G. Stephanou, Jordi Sunyer, Jose Urquiza, Kjell Vegard Weyde, John Wright, Martine Vrijheid, Mark Nieuwenhuijsen, Xavier Basagaña
Journal: Environmental Health Perspectives (2018)

Background: The urban exposome is the set of environmental factors that are experienced in the outdoor urban environment and that may influence child development. Objective: The authors’ goal was to describe the urban exposome among European pregnant women and understand its socioeconomic determinants. Methods: Using geographic information systems, remote sensing and spatio-temporal modeling we estimated exposure during pregnancy to 28 environmental indicators in almost 30,000 women from six population-based birth cohorts, in nine urban areas from across Europe. Exposures included meteorological factors, air pollutants, traffic noise, traffic indicators, natural space, the built environment, public transport, facilities, and walkability. Socioeconomic position (SEP), assessed at both the area and individual level, was related to the exposome through an exposome-wide association study and principal component (PC) analysis. Results: Mean±standard deviation (SD) NO2 levels ranged from 13.6±5.1 μg/m3 (in Heraklion, Crete) to 43.2±11 μg/m3 (in Sabadell, Spain), mean±SD walkability score ranged from 0.22±0.04 (Kaunas, Lithuania) to 0.32±0.07 (Valencia, Spain) and mean±SD Normalized Difference Vegetation Index ranged from 0.21±0.05 in Heraklion to 0.51±0.1 in Oslo, Norway. Four PCs explained more than half of variation in the urban exposome. There was considerable heterogeneity in social patterning of the urban exposome across cities. For example, high-SEP (based on family education) women lived in greener, less noisy, and less polluted areas in Bradford, UK (0.39 higher PC1 score, 95% confidence interval (CI): 0.31, 0.47), but the reverse was observed in Oslo (−0.57 PC1 score, 95% CI: −0.73, −0.41). For most cities, effects were stronger when SEP was assessed at the area level: In Bradford, women living in high SEP areas had a 1.34 higher average PC1 score (95% CI: 1.21, 1.48). Conclusions: The urban exposome showed considerable variability across Europe. Pregnant women of low SEP were exposed to higher levels of environmental hazards in some cities, but not others, which may contribute to inequities in child health and development. https://doi.org/10.1289/EHP2862
Phenytoin Could Potentially Increase Hepatic Clearance of 99mTc-Sestamibi in Myocardial Perfusion Imaging
Authors: Anwin Joseph Kavanal, Deepa Singh, Ashwani Sood, Madan Parmar, Bhagwant Rai Mittal
Journal: Clinical Nuclear Medicine (2018)

Myocardial perfusion imaging (MPI) is one of the most commonly used nuclear medicine imaging modalities for coronary artery disease evaluation and risk stratification. The authors present incidental image findings in a patient who underwent MPI twice because of development of seizures just before the first SPECT-MPI acquisition. The projection images for first MPI done without medication (phenytoin) showed the retention of hepatic tracer activity. After a few days from restarting of phenytoin, the repeat MPI showed complete hepatic clearance of tracer. This case highlights the possible pharmacokinetic interaction between phenytoin intake and Tc-sestamibi, resulting in faster hepatic clearance of the radiotracer.
Mossy Cells Control Adult Neural Stem Cell Quiescence and Maintenance through a Dynamic Balance between Direct and Indirect Pathways
Authors: Chia-Yu Yeh, Brent Asrican, Jonathan Moss, Luis Jhoan Quintanilla, Ting He, Xia Mao, Frederic Cassé, Elias Gebara, Hechen Bao, Wei Lu, Nicolas Toni, Juan Song
Journal: Neuron (2018)
Phospho-ERK is a biomarker of response to a synthetic lethal drug combination of sorafenib and MEK inhibition in liver cancer
Authors: Cun Wang, Haojie Jin, Dongmei Gao, Cor Lieftink, Bastiaan Evers, Guangzhi Jin, Zheng Xue, Liqin Wang, Roderick L. Beijersbergen, Wenxin Qin, René Bernards
Journal: Journal of Hepatology (2018)
Tyrosine Kinase Inhibitors Increase MCL1 Degradation and in Combination with BCLXL/BCL2 Inhibitors Drive Prostate Cancer Apoptosis
Authors: Seiji Arai, Oliver Jonas, Matthew A. Whitman, Eva Corey, Steven P. Balk, Sen Chen
Journal: Clinical Cancer Research (2018)

Clinically available BH3 mimetic drugs targeting BCLXL and/or BCL2 (navitoclax and venetoclax, respectively) are effective in some hematologic malignancies, but have limited efficacy in solid tumors. This study aimed to identify combination therapies that exploit clinical BH3 mimetics for prostate cancer.
Evolutionary Expression of HER2 Conferred by Chromosome Aneuploidy on Circulating Gastric Cancer Cells Contributes to Developing Targeted and Chemotherapeutic Resistance
Authors: Yilin Li, Xiaotian Zhang, Dan Liu, Jifang Gong, Daisy Dandan Wang, Shan Li, Zhi Peng, Yanyan Li, Xiaojuan Wang, Peter Ping Lin, Min Li, Lin Shen
Journal: Clinical Cancer Research (2018)

Purpose: Previous human epidermal growth factor receptor-2 (HER2)-derived resistance studies were based on ex vivo models, which could not mirror evolutionary expression of HER2 during therapy. To investigate dynamic expression of HER2 and its contribution to developing therapeutic resistance conferred by chromosome aneuploidy, both the HER2 phenotype and chromosome 8 (Chr 8) aneuploidy on circulating tumor cells (CTC) were coexamined in advanced gastric cancer (AGC) patients.Experimental Design: A total of 115 AGC patients, including 56 of histopathologic HER2+ (hHER2+) subjects who received first-line HER2-targeted therapy plus chemotherapy, and 59 of hHER2- patients who received chemotherapy alone, were prospectively enrolled. Both HER2 phenotype and Chr8 aneuploidy of CTCs in patients were coexamined by HER2-iFISH during therapy.Results: A fluctuated positive HER2 phenotype on CTCs (cHER2+) was revealed, showing cHER2+ at different time intervals during treatment. Acquisition of the cHER2+ phenotype in 91.0% of hHER2+ and 76.2% hHER2- patients was demonstrated to correlate with development of resistance to trastuzumab-targeted therapy for hHER2+ patients and chemotherapy alone for hHER2- patients. Aneuploid Chr8 was demonstrated to participate in the acquisition of the cHER2+ phenotype, which provides a growth advantage to HER2+ CTCs against therapeutic pressure, leading to the development of therapeutic resistance.Conclusions: Compared with low positivity of conventional histopathologic hHER2 examination routinely performed once, significant higher positivity of cHER2+ on CTCs was observed. Continuously examining cHER2 shows unique advantages with respect to monitoring therapeutic resistance in real time in carcinoma patients. Moreover, contribution of chromosome aneuploidy to the phenotypic evolution of HER2 expression on CTCs may help elucidate underlying mechanisms of developing therapeutic resistance. Clin Cancer Res; 24(21); 5261-71. ©2018 AACR.
Checking our blind spots: current status of research evidence summaries in ME/CFS
Authors: Todd E Davenport, Staci R Stevens, J Mark VanNess, Jared Stevens, Christopher R Snell
Journal: British Journal of Sports Medicine (2018)

The evidence-based practice (EBP) model hierarchically organises scientific information by level, from lowly case studies to lofty systematic reviews and clinical trials. Clinical trials best influence recommendations because they putatively have the greatest internal validity.1 This assumption is based on sound research ethics, such as scientific competence and good faith actors, as well as observed differences in outcomes. An EBP blind spot emerges when fundamental assumptions are unmet. Based on findings of a 2018 PEDro evidence summary in BJSM 2 and elsewhere,3 it now seems clear that scientific research in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) resides in a blind spot.

ME/CFS is estimated to affect 836 000 to 2.5 million people in the USA.4 Ninety per cent of cases are thought to go undiagnosed,4 suggesting that people with ME/CFS are substantially undercounted, underdiagnosed and undertreated. Substantial literature exists to support that ME/CFS is a multisystem condition that appears associated with a combination of genetic, cellular and systemic metabolic deficits in …
Abstract 18305: Right Ventricular Stemi as a Cause of Death in Idiopathic Pulmonary Arterial Hypertension
Authors: Yang Zhan, Barry Burstein, Ali Abualsaud, Mohamed Nosair, David Langleben
Journal: Circulation (2016)

Introduction: The cause of death in advanced idiopathic pulmonary arterial hypertension (IPAH) is commonly cardiogenic shock or arrhythmia. We describe a 33 year old female with advanced IPAH on IV...
The impact of endoscopic ultrasound-guided fine-needle aspiration of lymph nodes on subsequent positron emission tomography/computed tomography imaging: a prospective study
Authors: Ole Bjerring, Søren Hess, Claus Fristrup, Poul Høilund-Carlsen, Michael Mortensen
Journal: Endoscopy (2018)

Modern cancer diagnostic work-up is based on multiple modalities within a short time period. The interplay between these modalities is complex and not well known. Performing biopsy procedures prior to (18)F-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) is considered to pose a risk of false-positive imaging results; however, this is not based on solid scientific evidence. The use of endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) is commonly used in upper gastrointestinal malignancies, is proven safe, and has very little risk of complications. This study aimed to assess whether EUS-FNA induces inflammation that would increase FDG uptake on subsequent PET/CT.27 patients who were referred for upper gastrointestinal EUS for different reasons initially underwent FDG-PET/CT to detect biopsy-eligible lymph nodes with no FDG uptake. Patients then underwent EUS-FNA of the benign lymph nodes, with a minimum of three passes. Patients were re-evaluated with FDG-PET/CT 1 week later, with specific emphasis on the biopsied lymph nodes.None of the biopsied lymph nodes showed increased FDG uptake on follow-up FDG-PET/CT. No adverse events occurred.EUS-FNA prior to FDG-PET/CT did not lead to false-positive FDG uptake. The interpretive impact of minor procedures prior to FDG-PET/CT needs to be re-evaluated.
Augmented Sympathetic Activation During Short-Term Hypoxia and High-Altitude Exposure in Subjects Susceptible to High-Altitude Pulmonary Edema
Authors: HervéDuplain, LaurentVollenweider, AlainDelabays, PascalNicod, PeterBärtsch, UrsScherrer
Journal: Circulation (1999)

Background—Pulmonary hypertension is a hallmark of high-altitude pulmonary edema and may contribute to its pathogenesis. Cardiovascular adjustments to hypoxia are mediated, at least in part, by the sympathetic nervous system, and sympathetic activation promotes pulmonary vasoconstriction and alveolar fluid flooding in experimental animals. Methods and Results—We measured sympathetic nerve activity (using intraneural microelectrodes) in 8 mountaineers susceptible to high-altitude pulmonary edema and 7 mountaineers resistant to this condition during short-term hypoxic breathing at low altitude and at rest at a high-altitude laboratory (4559 m). We also measured systolic pulmonary artery pressure to examine the relationship between sympathetic activation and pulmonary vasoconstriction. In subjects prone to pulmonary edema, short-term hypoxic breathing at low altitude evoked comparable hypoxemia but a 2- to 3-times-larger increase in the rate of the sympathetic nerve discharge than in subjects resistant to ed...
Abstract 15847: Inhibition of Drp1-mediated Mitochondrial Fission Improves Diastolic Function in Right Ventricular Ischemia-reperfusion Injury
Authors: Lian Tian, Ming-Guo Feng, Zhigang Hong, Willard W Sharp, Shelby Kutty, Stephen L Archer
Journal: Circulation (2015)

Introduction: Mitochondrial fission, regulated by the GTPase dynamin-related protein 1 (Drp1), contributes to impairment of left ventricular function following ischemia-reperfusion (IR) injury or cardiac arrest. Drp1 inhibition improves LV function in IR. The effects of IR on the right ventricle (RV) and the contribution of mitochondrial fission to impaired RV function following IR are unknown. We hypothesize that: a) IR activates Drp1 in RV myocytes leading to mitochondrial fission and RV dysfunction b) inhibiting Drp1 will improve RV function. Methods: RV-IR was compared in control rats versus rats with monocrotaline-induced pulmonary arterial hypertension (MCT PAH). PAH was confirmed by measuring pulmonary artery acceleration time (PAAT), RV diastolic and systolic thickness (RVFW), and tricuspid annular plane systolic excursion (TAPSE) via ultrasound. IR was created in RV Langendorff preparation using two cycles of 15 min of ischemia followed by 15 min of reperfusion. We investigated the effects of two Drp1 inhibitors on RV function following IR: Mdivi-1, an inhibitor of Drp1’s GTPase activity and P110, a peptide inhibitor of the interaction between Drp1 and its binding partner, fission protein 1 (Fis1). Immunoblotting was performed on mitochondrial and cytosolic protein extracted from RV after Langendorff experiment to measure total and active Drp1 (defined as Drp1 in the mitochondria or phosphorylated at serine 616). Results: Compared to control, MCT produced severe PAH in week 4 as indicated by reduced PAAT and TAPSE and increased RVFW thickness. IR increased RV end diastolic pressure (RVEDP) without impairing developed systolic RV pressure. Both Mdivi-1 and P110 reduced the rise of RVEDP in the PAH RV following IR, with P110 being more effective. At baseline, cytosolic Drp1 expression was lower and mitochondrial Drp1 expression was higher in PAH vs. control RV. With IR, mitochondrial Drp1 expression increased in normal RV. Conclusions: The RV-IR response is characterized by isolated diastolic dysfunction and it results from Drp1 activation. Inhibition of mitochondrial fission, particularly by blocking the Drp1-Fis1 interaction, preserves RV diastolic function and may be a promising therapeutic strategy to improve RV function in PAH.
The Role of SPECT/CT of Foot and Ankle in the Evaluation of Heel Pain
Authors: Minkyung Lee, Bom Soo Kim, Yeoju Kim, In Young Hyun
Journal: Clinical Nuclear Medicine (2018)

Abstract Heel pain is a common symptom in foot and ankle disorders. Typical heel pain can be assessed according to the patient’s history and the location of pain. In some atypical inconclusive cases, bone SPECT/CT is the upcoming imaging modality for the detection of causes of heel pain. We present the case of 57-year-old man with atypical heel pain, plantar and Achilles spurs. SPECT/CT images demonstrated increased bony activity in arthritis of midfoot, not plantar and Achilles spurs. It suggests potential role of SPECT/CT in the evaluation and management of heel pain by showing hidden pathology of foot and ankle.