tbuckley/cabot-search huggingface dataset:
aPKC‐ι/P‐Sp1/Snail signaling induces epithelial–mesenchymal transition and immunosuppression in cholangiocarcinoma
Authors: Yawei Qian, Wei Yao, Tao Yang, Yan Yang, Yan Liu, Qi Shen, Jian Zhang, Weipeng Qi, Jianming Wang
Journal: Hepatology (2017)

Cholangiocarcinoma (CCA) is a highly malignant bile duct cancer that tends to invade and metastasize early. The epithelial–mesenchymal transition (EMT) has been implicated in cancer cell invasion and metastasis, as well as in cancer cell evasion of host immunity. In this study, we investigated the interaction between atypical protein kinase C‐iota (aPKC‐ι) and Snail in the regulation of EMT and its relationship to CCA immunosuppression. Our results demonstrated that aPKC‐ι, Snail, and infiltrated immunosuppressive cells were significantly up‐regulated in CCA tumor tissues and linked to poor prognosis. aPKC‐ι induced EMT and immunosuppression by regulating Snail in vitro and in vivo , although aPKC‐ι did not directly interact with Snail in coimmunoprecipitation experiments. To further clarify the molecular interaction between aPKC‐ι and Snail in relation to EMT, quantitative iTRAQ‐based phosphoproteomic analysis and liquid chromatography–tandem mass spectrometry were conducted to identify the substrates of aPKC‐ι‐dependent phosphorylation. Combined with coimmunoprecipitation, we showed that specificity protein 1 (Sp1) was directly phosphorylated by aPKC‐ι on Ser59 (P‐Sp1). Both Sp1 and P‐Sp1 were up‐regulated in CCA tumor tissues and associated with clinicopathological features and poor prognosis in CCA patients. Moreover, using chromatin immunoprecipitation assays, we found that P‐Sp1 regulated Snail expression by increasing Sp1 binding to the Snail promoter. P‐Sp1 also regulated aPKC‐ι/Snail‐induced EMT‐like changes and immunosuppression in CCA cells. Our findings further indicated that CCA cells with EMT‐like features appear to generate immunosuppressive natural T regulatory–like cluster of differentiation 4–positive (CD4 + )CD25 – cells rather than to increase CD4 + CD25 + natural T regulatory cells, in part by mediating T regulatory–inducible cytokines such as transforming growth factor β1 and interleukin 2. Conclusion: These results demonstrate that aPKC‐ι promotes EMT and induces immunosuppression through the aPKC‐ι/P‐Sp1/Snail signaling pathway and may be a potential therapeutic target for CCA. (H epatology 2017;66:1165‐1182).
Systolic blood pressure targets are too high, meta-analysis suggests
Authors: Zosia Kmietowicz
Journal: BMJ (2017)

Reducing systolic blood pressure (SBP) to levels below currently recommended targets may significantly reduce the risk of cardiovascular disease and all cause death, a meta-analysis has found.1

As the optimal SBP target is still uncertain and recommendations in guidelines around the world vary, many organisations have recently relaxed treatment goals.

In the United States, advice from the National Heart, Lung, and Blood Institute in 2014 raised the recommended SBP treatment goal from below 130 mm Hg to below 140 mm Hg in people with type 2 diabetes or chronic kidney disease and raised it from below 140 mm Hg to below 150 mm Hg in people over 60.2

In the …
Shorter regimens for multidrug-resistant tuberculosis should also be applicable in Europe
Authors: Marieke J. van der Werf, Csaba Ködmön, Mike Catchpole
Journal: European Respiratory Journal (2017)

In response to our manuscript on the eligibility for shorter treatment of multidrug-resistant tuberculosis (MDR-TB) in the European Union (EU) [1], Heldal and co-workers highlight the limitations of the surveillance data that were used to estimate the proportion of MDR-TB cases eligible for the shorter regimen, and they question the criteria that we used to define eligibility. Strict application of criteria shows that 11% of MDR-TB cases are eligible for the shorter MDR-TB regimen in the EU <http://ow.ly/p9aq30bt1AI>
Benefit of cardiopoietic mesenchymal stem cell therapy on left ventricular remodelling: results from the Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART‐1) study
Authors: John R. Teerlink, Marco Metra, Gerasimos S. Filippatos, Beth A. Davison, Jozef Bartunek, Andre Terzic, Bernard J. Gersh, Thomas J. Povsic, Timothy D. Henry, Bertrand Alexandre, Christian Homsy, Christopher Edwards, Aymeric Seron, William Wijns, Gad Cotter
Journal: European Journal of Heart Failure (2017)
MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2− Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy
Authors: George W. Sledge, Masakazu Toi, Patrick Neven, Joohyuk Sohn, Kenichi Inoue, Xavier Pivot, Olga Burdaeva, Meena Okera, Norikazu Masuda, Peter A. Kaufman, Han Koh, Eva-Maria Grischke, Martin Frenzel, Yong Lin, Susana Barriga, Ian C. Smith, Nawel Bourayou, Antonio Llombart-Cussac
Journal: Journal of Clinical Oncology (2017)

Purpose MONARCH 2 ( ClinicalTrials.gov identifier: NCT02107703) compared the efficacy and safety of abemaciclib, a selective cyclin-dependent kinase 4 and 6 inhibitor, plus fulvestrant with fulvestrant alone in patients with advanced breast cancer (ABC). Patients and Methods MONARCH 2 was a global, double-blind, phase III study of women with hormone receptor-positive and human epidermal growth factor receptor 2-negative ABC who had progressed while receiving neoadjuvant or adjuvant endocrine therapy (ET), ≤ 12 months from the end of adjuvant ET, or while receiving first-line ET for metastatic disease. Patients were randomly assigned 2:1 to receive abemaciclib or placebo (150 mg twice daily) on a continuous schedule and fulvestrant (500 mg, per label). The primary end point was investigator-assessed progression-free survival (PFS), and key secondary end points included overall survival, objective response rate (ORR), duration of response, clinical benefit rate, quality of life, and safety. Results Between August 2014 and December 2015, 669 patients were randomly assigned to receive abemaciclib plus fulvestrant (n = 446) or placebo plus fulvestrant (n = 223). Abemaciclib plus fulvestrant significantly extended PFS versus fulvestrant alone (median, 16.4 v 9.3 months; hazard ratio, 0.553; 95% CI, 0.449 to 0.681; P < .001). In patients with measurable disease, abemaciclib plus fulvestrant achieved an ORR of 48.1% (95% CI, 42.6% to 53.6%) compared with 21.3% (95% CI, 15.1% to 27.6%) in the control arm. The most common adverse events in the abemaciclib versus placebo arms were diarrhea (86.4% v 24.7%), neutropenia (46.0% v 4.0%), nausea (45.1% v 22.9%), and fatigue (39.9% v 26.9%). Conclusions Abemaciclib at 150 mg twice daily plus fulvestrant was effective, significantly improving PFS and ORR and demonstrating a tolerable safety profile in women with hormone receptor-positive and human epidermal growth factor receptor 2-negative ABC who progressed while receiving ET.
Alabama “pill mill” doctors get 20 year prison sentence
Authors: Owen Dyer
Journal: BMJ (2017)

Two Alabama pain specialists who took kickbacks from an opioid manufacturer to prescribe immense quantities of fentanyl have been sentenced to 20 and 21 years’ imprisonment.

John Patrick Couch received a 20 year sentence and his business partner Xiulu Ruan 21 years after both were convicted of a slew of federal charges, including mail and wire fraud, conspiracy to receive illegal kickbacks, conspiracy to prescribe controlled substances including fentanyl, and racketeering charges.

Couch and Ruan ran two clinics as part of their company Physicians’ Pain Specialists of Alabama.1 They also owned a pharmacy attached to one of their clinics that processed most of the opioid prescriptions. Both were heavy prescribers of fentanyl, a drug heavily implicated in the epidemic of …
Abstract 044: Transient Receptor Potential Channel 6 (TRPC6) Is An Important Mediator Of Mechanical Stretch Responses In The Atrial Endocardial Endothelium.
Authors: Vesna Nikolova-Krstevski, Soeren Wagner, Oliver Friedrich, Diane Fatkin
Journal: Circulation Research (2013)

Atrial fibrillation (AF) is the most common heart arrhythmia and a major risk factor for thromboembolic stroke and hearth failure. Atrial pressure and/or volume overload that cause increased mechanical stretch in the atrium are the common features of the diseases that cause AF. The latter suggests that mechanical stress has a major role in the pathogenesis of AF. The atrial endocardial endothelium (AE) is the interface between the myocardium and the circulating blood but its role in the mechanotransduction in the atrium is unknown. Endothelial cells (EC) are very sensitive and responsive to external mechanical stimuli and AE dysfunction has been reported in individuals with AF. We therefore hypothesized that the AE is an important mediator of stretch responses in the atrium and that stretch-induced AE dysfunction may be critical for initiation and/or maintenance of AF. We investigated the AE responses to increased mechanical stress by subjecting novel primary AE cells to mechanical stretch. The mechanical stretch conditions included cyclic stretch of 30 cycles/min at 10 percent displacement. The AE cells were stretched for 1-10 min, and 1, 4, 8, and 24h. Changes in the cell shape with elongation, hypertrophy and re-alignment of the cells and their stress fibres in a direction perpendicular to the lines of stretch were first observed after 1h of stretch. TRPC6 is a stretch sensitive ion channel and important regulator of Ca2+-signalling in the EC cells. Immunostaining and Western blot analysis showed redistribution and changed levels of expression of TRPC6 in the stretched AE cells, respectively. The latter suggested changed TRPC6 activity which was evaluated by measuring extracellular Ca2+ influx through the TRPC6 channels in the AE cells under baseline and stretch conditions. We found that short-stretch (1-10min) increased TRPC6 activity, while the long stretch (1-24h) silenced it. Based on these findings it could be concluded that TRPC6 is an important mediator of the mechanical stretch responses in the AE; the functional consequences of the altered channel activity are predetermined by the duration of the stretch-stimulus; and TRPC6 changes in the stretched AE may cause AE dysfunction through altered Ca2+ signalling that contributes to AF development.
Id2 and Id4 expression and function in glioblastoma multiforme and neural stem cells
Authors: Kyuson Yun, Paula Knittle, Akio Mantani, Mark A. Israel
Journal: Cancer Research (2005)

1065  Helix-loop-helix (HLH) proteins regulate proliferation and differentiation in both developing mouse embryos and in human tumor-derived cell lines. We found that Id4 and Id2 are highly expressed in high-grade brain tumor tissues and some brain tumor-derived cell lines, but only at very low levels in normal mature brain tissue. As a prelude to studying the role of these important genes in the biology of brain tumors, we examined their function in vivo, analyzing the brains of Id4-/-; Id2-/-,Id4-/-; and Nestin-Id2 transgenic animals. Consistent with the known role of Id genes to inhibit differentiation and promote proliferation, Id4 -/- embryos have smaller brains and this phenotype arises from both premature differentiation and defective G1-S transition in early neural stem cells. Importantly, this phenotype is more severe in the dorsal medial cortex and hippocampus suggesting either that other Id genes compensate for Id4 in the lateral cortex or that in different regions of the brain, there are environmental influences that can modify the effect of genetic alterations that regulate brain maturation. The Id2 single null animal does not show an obvious brain phenotype, and the Id2/4 double null brain phenotype is similar to that of the Id4 single null animal, indicating that Id2 is not compensating for Id4 in the lateral cortex. Surprisingly, in contrast to in vitro studies showing that ectopic expression of Id2 inhibits differentiation and promotes proliferation, ectopic expression of Id2 from the Nestin promoter in neural stem cells leads to a smaller, rather than a larger, brain phenotype in vivo. This phenotype results from both reduced lateral expansion of the neuroepithelium (approximately 30% at E12.5) and increased apoptosis (greater than 10 fold at E12.5), providing in vivo evidence for the role of Id2 in inducing apoptosis and implicating Id2 in regulating neural stem cell maintenance, proliferation, and maturation. Furthermore, while both mutant brains show compromised lateral expansion of the neuroepithelium, there is no increased apoptosis in Id4-/- animals. Together, the similarities and differences between Id4-/- and Nestin-Id2 transgenic animals suggest that Id2 and Id4 affect both overlapping and unique pathways in neural stem cells. We are currently testing the effects of Id2 and Id4 expression in brain tumor derived cell lines by both gain- and loss-of-function approaches. In addition, we are examining the molecular mechanisms underlying the apparently opposing functions of Id2 and Id4 by identifying downstream target genes of Id4 and analyzing the pathways that Id4 and its target genes regulate in human brain tumor-derived cells.
Airway Hyperresponsiveness Does Not Predict Morbidity in Children with Sickle Cell Anemia
Authors: Shaina M. Willen, Mark Rodeghier, Robert C. Strunk, Carol L. Rosen, Fenella J. Kirkham, Joshua J. Field, Michael R. DeBaun, Robyn T. Cohen
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Photopharmacological control of bipolar cells restores visual function in blind mice
Authors: Laura Laprell, Ivan Tochitsky, Kuldeep Kaur, Michael B. Manookin, Marco Stein, David M. Barber, Christian Schön, Stylianos Michalakis, Martin Biel, Richard H. Kramer, Martin P. Sumser, Dirk Trauner, Russell N. Van Gelder
Journal: Journal of Clinical Investigation (2017)

Photopharmacological control of neuronal activity using synthetic photochromic ligands, or photoswitches, is a promising approach for restoring visual function in patients suffering from degenerative retinal diseases. Azobenzene photoswitches, such as AAQ and DENAQ, have been shown to restore the responses of retinal ganglion cells to light in mouse models of retinal degeneration but do not recapitulate native retinal signal processing. Here, we describe diethylamino-azo-diethylamino (DAD), a third-generation photoswitch that is capable of restoring retinal ganglion cell light responses to blue or white light. In acute brain slices of murine layer 2/3 cortical neurons, we determined that the photoswitch quickly relaxes to its inactive form in the dark. DAD is not permanently charged, and the uncharged form enables the photoswitch to rapidly and effectively cross biological barriers and thereby access and photosensitize retinal neurons. Intravitreal injection of DAD restored retinal light responses and light-driven behavior to blind mice. Unlike DENAQ, DAD acts upstream of retinal ganglion cells, primarily conferring light sensitivity to bipolar cells. Moreover, DAD was capable of generating ON and OFF visual responses in the blind retina by utilizing intrinsic retinal circuitry, which may be advantageous for restoring visual function.
Early Evaluation of Circulating Tumor DNA as Marker of Therapeutic Efficacy in Metastatic Colorectal Cancer Patients (PLACOL Study)
Authors: Fanny Garlan, Pierre Laurent-Puig, David Sefrioui, Nathalie Siauve, Audrey Didelot, Nasrin Sarafan-Vasseur, Pierre Michel, Geraldine Perkins, Claire Mulot, Hélène Blons, Julien Taieb, Frederic Di Fiore, Valerie Taly, Aziz Zaanan
Journal: Clinical Cancer Research (2017)

Purpose: Markers of chemotherapy efficacy in metastatic colorectal cancer (mCRC) are essential for optimization of treatment strategies. We evaluated the applicability of early changes in circulating tumor DNA (ctDNA) as a marker of therapeutic efficacy.Experimental Design: This prospective study enrolled consecutive patients with mCRC receiving a first- or second-line chemotherapy. CtDNA was assessed in plasma collected before the first (C0), second (C1) and/or third (C2) chemotherapy cycle, using picodroplet-digital PCR assays based either on detection of gene mutation (KRAS, BRAF, TP53) or hypermethylation (WIF1, NPY). CT scans were centrally assessed using RECIST v1.1 criteria. Multivariate analyses were adjusted on age, gender, ECOG performance status (PS), metastatic synchronicity, and treatment line.Results: Eighty-two patients with mCRC treated in first- (82.9%) or second- (17.1%) line chemotherapy were included. Patients with a high (>10 ng/mL) versus low (≤0.1 ng/mL) ctDNA concentration at C0 had a shorter overall survival (OS; 6.8 vs. 33.4 months: adjusted HR, 5.64; 95% CI, 2.5-12.6; P < 0.0001). By analyzing the evolution of the ctDNA concentration between C0 and C2 or C1 (C2or1), we classified the patients in two groups (named "good" or "bad ctDNA responders"). In multivariate analysis, patients belonging to the group called "good ctDNA responder" (n = 58) versus "bad ctDNA responder" (n = 15) had a better objective response rate (P < 0.001), and a longer median progression-free survival (8.5 vs. 2.4 months: HR, 0.19; 95% CI, 0.09-0.40; P < 0.0001) and OS (27.1 vs. 11.2 months: HR, 0.25; 95% CI, 0.11-0.57; P < 0.001).Conclusions: This study suggests that early change in ctDNA concentration is a marker of therapeutic efficacy in patients with mCRC. Clin Cancer Res; 23(18); 5416-25. ©2017 AACR.
Flow cytometric enrichment of tumor cells from frozen clinical samples of low tumor content to facilitate cancer genome analysis
Authors: Zachary Boyd, Raji Bains, Stephanie Johnson, Robert Soriano, Michael Hamilton, Mark Lackner, David Eberhard, Paul Waring, Lukas Amler
Journal: Clinical Cancer Research (2007)

A35  The National Cancer Institute’s Cancer Genome Atlas project is attempting to catalogue somatic mutations and copy number changes from a wide spectrum of human cancers. In an effort to limit contamination and influence of stromal DNA in analysis of the cancer genome, > 80% tumor cell content has been set as a threshold for samples to be analyzed. This has made sample acquisition for the project harder than anticipated and is delaying the progress of the project (see Nature (2007) 447:1036-37; Nature Medicine (2007) 13:391). The challenge is further highlighted in certain cancer samples in which the tumor content is generally not high. In a study of pancreatic adenocarcinomas (PA), we found only 13% of our PA samples met the high tumor content requirement. To allow the analysis of samples with lower tumor cell content, a flow cytometric protocol was developed to enrich tumor cells from fresh-frozen, solid tumor samples. Pancreatic adenocarcinoma (PA) tumor cells were separated from stromal cells by mechanical dissociation and subsequent bivariate cytokeratin/DNA fluorescence activated cell sorting (FACS). DNA was extracted from tumor- and stromal-sorted fractions respectively. The relative purity of each fraction was evaluated by screening for the presence of PA-associated mutations (codons 12, 13 and 61 in exons 2 and 3 of K-ras) via Sanger re-sequencing. Copy number changes in respective tumor and stromal fractions were also analyzed using SNP microarrays. K-ras mutations were seen almost exclusively in tumor cell fractions, in which loss of heterozygosity and increased copy number for specific genes were also observed as compared to stromal fractions. These results are interpreted to represent successful enrichment of tumor cells from frozen-archive samples, allowing for further analysis of tumor associated mutations and copy number changes within the cancer genome.
Abstract 310: Inhibition of Class I Histone Deacetylase Activity Improves Left Ventricular Contractile Function and Cardiac Strain in Coronary Artery Occlusion-Induced Myocardial Infarction
Authors: Harinath Kasiganesan, Ludivine Renaud, Santhosh K Mani, Chou C James, Rupak Mukherjee, Donald R Menick
Journal: Circulation Research (2012)

Protection from coronary heart disease-induced damage of the myocardium during myocardial infarction (MI) injury has been a target of investigation for the development of innovative cardioprotective therapies. Histone deacetylases (HDACs) are a class of enzymes that affect the transcriptional regulation of genes during pathological conditions. We observed that class I/IIb HDAC activity was nearly 5 times greater in the 7-day post-MI LV when compared to the sham ventricles. In vitro inhibition studies indicated that the majority of increased activity was due to class I HDACs. Therefore we hypothesized that suppression of class I HDACs would prevent the pathophysiological changes occurring during MI, thus improving LV pump function in post-MI myocardium. CD-1 mice were administered with the a class I HDAC inhibitor pimelic diphenylamide (PD106) or vehicle immediately after induction of MI and the treatment continued every other day for 7 days post MI. LV end-diastolic volumes, expressed as change from pre-MI values, was significantly lower in the PD106 treated mice compared to vehicle treated mice. Further, the post-MI reduction in LV ejection faction was significantly attenuated in the PD106-treated mice compared to the MI alone group. Similarly, echo cardiac strain analysis showed improved LV strain and better coherence in contractile function among infarct and border zones in PD106 MI group compared to MI only. These unique findings demonstrate that class I HDAC inhibitors may provide a novel therapeutic means to attenuate adverse post-MI LV remodeling.
Contents, Vol. 60, 1993
Authors: Ilkka T. Harvima, Heimo Viinamäki, Anita Naukkarinen, Kari Paukkonen, Heikki Neittaanmäki, Rauno J. Harvima, Maija Horsmanheimo, Denise M. Tope, Tim A. Ahles, Peter M. Silberfarb, Andrew B. Littman, M.G. Madianos, D. Madianou-Gefou, C.N. Stefanis, Michael W. Otto, Ronald A. Yeo, Brüt-Maj Wikström, Töres Theorell, Sven Sandström, Graeme J. Taylor, K.M. Bagby, J.D.A. Parker, Paul C. Horton, Herbert Gewirtz, Karole J. Kreutter, P. Bech, Jean Cottraux, Michael Bach, Doris Bach
Journal: Psychotherapy and Psychosomatics (1993)