tbuckley/cabot-search huggingface dataset:
Cardiomyogenesis in the Developing Heart Is Regulated by C-Kit–Positive Cardiac Stem Cells
Authors: JoãoFerreira-Martins, BarbaraOgórek, DonatoCappetta, AlexMatsuda, SergioSignore, DomenicoD'Amario, JamesKostyla, ElisabethSteadman, NorikoIde-Iwata, FumihiroSanada, GraziaIaffaldano, SergioOttolenghi, ToruHosoda, AnnarosaLeri, JanKajstura, PieroAnversa, MarcelloRota
Journal: Circulation Research (2012)

Rationale:Embryonic and fetal myocardial growth is characterized by a dramatic increase in myocyte number, but whether the expansion of the myocyte compartment is dictated by activation and commitment of resident cardiac stem cells (CSCs), division of immature myocytes or both is currently unknown. Objective:In this study, we tested whether prenatal cardiac development is controlled by activation and differentiation of CSCs and whether division of c-kit–positive CSCs in the mouse heart is triggered by spontaneous Ca2+ oscillations. Methods and Results:We report that embryonic-fetal c-kit–positive CSCs are self-renewing, clonogenic and multipotent in vitro and in vivo. The growth and commitment of c-kit–positive CSCs is responsible for the generation of the myocyte progeny of the developing heart. The close correspondence between values computed by mathematical modeling and direct measurements of myocyte number at E9, E14, E19 and 1 day after birth strongly suggests that the organogenesis of the embryonic ...
Review: More-intensive vs less-intensive LDL-cholesterol lowering reduces mortality
Authors: Joseph Yeboah
Journal: Annals of Internal Medicine (2018)

Source Citation Navarese EP, Robinson JG, Kowalewski M, et al. Association between baseline LDL-C level and total and cardiovascular mortality after LDL-C lowering: a systematic review and meta-analysis. JAMA. 2018;319:1566-79. 29677301
Abstract 19493: In Type 1 Diabetes Decreased Bone Marrow Neuronal Support Shifts Normal Hematopoiesis Towards the Generation of (C-C Motif) Receptor 2 Monocytes
Authors: Maria B Grant, Ashay D Bhatwadekar, Ping Hu, Sugata Hazra, Sergio Caballero, Susanne Mohr, Steven F Abcouwer, Daniel R Saban, Tailoi Chan-Ling, Julia V Busik, Mohan K Raizada
Journal: Circulation (2012)

We previously showed that in both type 1 (T1D) and type 2 diabetes loss of bone marrow innervation leads to circadian dysregulation of hematopoietic stem cell (HSC) release from bone marrow (BM) into the circulation. In this study, we extended these findings to humans with T1D and used T1D rodents to examine the role of key neurotransmitters/neuropeptides in the differentiation and the fate of HSCs. Diabetic (n=5) and control (n=5) subjects underwent a 2 hr blood sampling for 24 hr. Diabetic patients showed an increase in the amplitude of the peak and a phase shift (6 hrs) of the peak compared to controls (p&lt;0.001). In marked contrast, CD34 + cells release in diabetics showed no circadian pattern while controls did. In the long bones of T1D mice, immunodetection of calcitonin gene related peptide was reduced by 65% (p&lt;0.05), neuropeptide Y by 67% (p&lt;0.05), acetylcholine by 51% (p&lt;0.05), and somatostatin by 50% (p&lt;0.05). BM cells from T1D mice showed depletion of Side Population-HSCs but increased numbers of monocyte/macrophage colony forming units. BM supernatant of T1D mice showed increased levels (2.5-fold, p&lt;0.002) of macrophage-colony stimulating factor (M-CSF/CSF-1, a stimulator of monocyte generation) and increased levels IL-1β (2-fold, p&lt;0.05) and IL-27 (3-fold, p&lt;0.01). Chimeric mice (transplanted with gfp-expressing HSC) were made T1D using streptozotocin (n=12) and compared to controls (n=12). T1D retinas, kidneys and brains (enzymatically-dissociated and analyzed by flow cytometry) showed a 10-fold, 6-fold, and 4-fold increase in CD11b + /CD45hi/ (C-C motif) receptor 2 (CCR2 + ) populations compared to controls. Immunohistochemistry of these tissues showed lba + resident microglia that exhibited a ramified morphology suggesting an inflammatory activation by extravasated BM cells. Our data suggests that in diabetic subjects, circadian dysregulation of monocyte and CD34 + cell release exists. Our rodent studies support that the loss of BM neurotransmitter regulation (bone marrow neuropathy) may shift hematopoietic towards the generation of excessive numbers of CCR2 + monocytes and reduced reparative endothelial progenitors which can contribute towards both the vascular and tissue pathology observed in diabetes.
Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential
Authors: Adam B. Roberts, Xiaodong Gu, Jennifer A. Buffa, Alex G. Hurd, Zeneng Wang, Weifei Zhu, Nilaksh Gupta, Sarah M. Skye, David B. Cody, Bruce S. Levison, William T. Barrington, Matthew W. Russell, Jodie M. Reed, Ashraf Duzan, Jennifer M. Lang, Xiaoming Fu, Lin Li, Alex J. Myers, Suguna Rachakonda, Joseph A. DiDonato, J. Mark Brown, Valentin Gogonea, Aldons J. Lusis, Jose Carlos Garcia-Garcia, Stanley L. Hazen
Journal: Nature Medicine (2018)
Abstract 12669: Identification of Novel Genetic Modifiers of LQT2 by Combining Patient Derived iPS Derived Cardiomyocytes and Exome Sequencing
Authors: Sam Chai, Xiaoping Wan, Eckhard Ficker, Angelina Ramirez-Navarro, Elizabeth S Kaufman, Alfred L George, Isabelle Deschenes
Journal: Circulation (2015)

Background: Long QT Syndrome Type 2 (LQT2) is caused by autosomal dominant loss-of-function in hERG, but often with incomplete penetrance. We investigated the mechanisms underlying genotype-phenotype discordance seen in a large LQT2 family by studying cardiac myocytes derived from induced pluripotent stem cells from affected and unaffected mutation-positive family members. We hypothesize that the presence of disease modifying genes contributes to this phenotype. Methods: Two family pairs displaying this genotype-phenotype discordance were studied. iPS cells were generated from skin biopsies and differentiated into ventricular cardiomyocytes (iPS-CM) that were studied electrophysiologically. Exome sequencing was also performed on the four subjects. Results: hERG R752W mutation-positive cardiomyocytes exhibited reduced I Kr compared to control cells. Further, cardiomyocytes from the affected individuals displayed prolonged action potentials as well as greater L-type calcium current (LTCC) compared to cells from control subjects and an unaffected mutation-positive family member. Whole exome sequencing identified two potential disease-modifying genes. The first is a single nucleotide variant (SNV) in KCNK17 encoding a 2-pore potassium channel. When expressed in Chinese Hamster Ovary cells, this variant potassium channel, which was found only in asymptomatic mutation-positive individuals, leads to increased current density compared to the nonvariant channel. The second SNV was identified in a Ras-like GTPase and was present exclusively in symptomatic mutation-positive individuals. Overexpression of this variant protein in iCells © resulted in a significant increase in LTCC. Conclusion: We have successfully recapitulated the genotype-phenotype discordance seen in a LQT2 family using patient-derived iPS-CMs. We postulate that the difference in the currents conferred by the 2-pore potassium channel variant could partially protect hERG R752W mutation-positive subjects by mitigating the severity of the hERG mutation. However, it appears that ultimately the inheritance of a SNV in a Ras-like GTPase in tandem with the primary mutation in hERG is the permutation that drives the complete disease phenotype.
Laparoscopic vs Open Surgery for Colorectal Liver Metastases
Authors: Francesca Ratti, Guido Fiorentini, Federica Cipriani, Marco Catena, Michele Paganelli, Luca Aldrighetti
Journal: JAMA Surgery (2018)

Surgery represents the mainstay treatment of colorectal liver metastases. Indications for the laparoscopic approach in this setting have been widened and there is a need to confirm the benefits of minimally invasive liver surgery (MILS) in patients with complex disease states.To compare outcomes of laparoscopic surgery with those of open surgery for liver metastases from colorectal cancer, focusing on the characteristics of modern MILS and therefore overcoming possible selection bias related to different policies for patients' eligibility for MILS over time.A cohort study of 885 resections performed for liver metastases from colorectal cancer between January 1, 2004, and June 30, 2017, at the Hepatobiliary Surgery Unit of San Raffaele Hospital, Milano, Italy, comprising 187 laparoscopic and 698 open resections. Procedures performed using the MILS approach with a ratio of MILS to total resections per year of more than 30% were considered and were matched by propensity scores (ratio of 1:4) to procedures performed using the open approach with a ratio of MILS to total resections per year of less than 30%.The primary end point was short-term outcomes, including morbidity, mortality, functional recovery, and interval between surgery and adjuvant treatments; the secondary end point was long-term outcomes.Among this cohort (104 patients in the MILS group; 46 women and 58 men; median age, 62 years [range, 35-81 years]; and 412 patients in the open group; 181 women and 231 men; median age, 60 years [range, 37-80 years]), primary end-point data showed a significantly higher incidence of postoperative morbidity in patients who underwent open resections compared with those who underwent MILS (94 [22.8%] vs 21 [20.2%]; P = .04). Patients in the MILS group had fewer major complications (Dindo-Clavien grades III-V) compared with patients in the open group (Dindo-Clavien grades III-V; 7 [6.7%] vs 35 [8.5%]; P = .03) as well as shorter lengths of stay (median [range] duration, 3 [2-35] vs 5 [4-37] days; P = .02). Oncologic results were not compromised by the laparoscopic approach.In this study, the results of the propensity score matching analysis between modern laparoscopic surgery and previous open surgery appear to confer more comparable cohorts for complexity, further supporting the advantages of laparoscopy in the surgical treatment of liver metastases from colorectal cancer. The increase in use that laparoscopy has experienced appears to be based on increased feasibility, widening of eligibility criteria for patients, enhanced clinical effectiveness, and oncologic outcomes. All these elements together suggest that up to 70% of patients appear to be candidates for this minimally invasive surgical approach in high-volume centers.
The association of pretreatment neutrophil to lymphocyte ratio with overall survival in patients with glioblastoma multiforme (GBM).
Authors: Richard Martin Bambury, MinYuen Teo, Anny Yusuf, Susan Murray, Jodie E Battley, Catherine Drake, Pauline O'Dea, Niamh Bermingham, Catherine Keohane, Seamus O'Reilly, Derek Gerard Power, Eugene J. Moylan
Journal: Journal of Clinical Oncology (2012)

2062 Background: GBM is the most common and aggressive primary brain tumor. The neutrophil to lymphocyte ratio (NLR) gives a measure of systemic inflammatory response and lymphopenia, both of which are poor prognostic factors in many malignancies. No published study has assessed the prognostic impact of NLR in GBM. Methods: Patients treated for GBM at our regional referral centre with assessable complete blood count at first presentation (prior to corticosteroid therapy or surgery) were identified. Medical notes were reviewed to extract demographic and treatment data. Survival curves were estimated via Kaplan-Meier method and compared via log-rank method. Multivariate analysis was performed via Cox proportional hazards regression modelling. Results: A total of 86 patients were identified, of which 65(76%) were male. Median age at diagnosis was 58 years (range: 18–76). At the time of analysis all patients still alive had ≥ 2 years follow-up. Median overall survival (OS) was 9.3 months (range: 1-82). 57% completed the standard adjuvant Stupp protocol and 43% discontinued early due to disease progression or treatment toxicity. Median OS was 11.2 months in patients with NLR&lt;4 and 7.5 months in patients with NLR&gt;4 (HR 0.59, p=.04). Other significant prognostic factors based on univariate analysis were consistent with published data (Table). After correcting for known prognostic factors NLR remained a significant predictor of survival (Table). Conclusions: Recent advances in immunotherapy have highlighted the importance of the immune system in the treatment and prognosis of cancer patients. Many GBM patients are on corticosteroids for a significant proportion of their disease course which may abrogate the effects of host immunity on outcome. Nevertheless, we have shown that NLR at diagnosis is an independent predictor of survival in GBM patients. Investigation of therapies which harness the immune response are warranted in this disease. [Table: see text]
Functional Shifts in Bat Dim-Light Visual Pigment Are Associated with Differing Echolocation Abilities and Reveal Molecular Adaptation to Photic-Limited Environments
Authors: Eduardo de A Gutierrez, Gianni M Castiglione, James M Morrow, Ryan K Schott, Livia O Loureiro, Burton K Lim, Belinda S W Chang
Journal: Molecular Biology and Evolution (2018)

Bats are excellent models for studying the molecular basis of sensory adaptation. In Chiroptera, a sensory trade-off has been proposed between the visual and auditory systems, though the extent of this association has yet to be fully examined. To investigate whether variation in visual performance is associated with echolocation, we experimentally assayed the dim-light visual pigment rhodopsin from bat species with differing echolocation abilities. While spectral tuning properties were similar among bats, we found that the rate of decay of their light-activated state was significantly slower in a nonecholocating bat relative to species that use distinct echolocation strategies, consistent with a sensory trade-off hypothesis. We also found that these rates of decay were remarkably slower compared with those of other mammals, likely indicating an adaptation to dim light. To examine whether functional changes in rhodopsin are associated with shifts in selection intensity upon bat Rh1 sequences, we implemented selection analyses using codon-based likelihood clade models. While no shifts in selection were identified in response to diverse echolocation abilities of bats, we detected a significant increase in the intensity of evolutionary constraint accompanying the diversification of Chiroptera. Taken together, this suggests that substitutions that modulate the stability of the light-activated rhodopsin state were likely maintained through intensified constraint after bats diversified, being finely tuned in response to novel sensory specializations. Our study demonstrates the power of combining experimental and computational approaches for investigating functional mechanisms underlying the evolution of complex sensory adaptations.
Bioinspired Structural Hierarchy within Macroscopic Volumes of Synthetic Composites
Authors: Anand K. Rajasekharan, Antiope Lotsari, Viviane Lutz‐Bueno, Marianne Liebi, Martin Andersson
Journal: Advanced Healthcare Materials (2018)

Abstract A key challenge in developing bioinspired composites is the fabrication of well‐defined 3D hierarchical structures ranging from nano to the macroscale. Herein, the development of a synthetic polymer–apatite composite realized by integrating bottom‐up self‐assembly and additive manufacturing (AM) is described. The resulting composite exhibits a bioinspired hierarchical structure over its 3D macroscopic volume. The composite is assembled in a bottom‐up manner, where periodic nanoscale assemblies of organic micellar fibrils and inorganic apatite nanocrystals are organized as bundles of mineralized microstructures. These microstructural bundles are preferentially oriented throughout the macroscopic volume of the material via extrusion based AM. The obtained structural hierarchy is investigated in 3D using electron microscopy and small angle X‐ray scattering tensor tomography and correlated to the structural hierarchy and anisotropy observed in biological tissues such as bone and the bone–cartilage interface. This work demonstrates the possibility to form polymer–apatite composites with a well‐defined hierarchical structure throughout its macroscopic volume, which is crucial for the development of mechanically optimized materials for applications such as bone and osteochondral implants.
Selective neuronal silencing using synthetic botulinum molecules alleviates chronic pain in mice
Authors: Maria Maiarù, Charlotte Leese, Michelangelo Certo, Irene Echeverria-Altuna, Antonina S. Mangione, Jason Arsenault, Bazbek Davletov, Stephen P. Hunt
Journal: Science Translational Medicine (2018)

Silencing key neurons with botulinum toxin conjugates exerts long-lasting pain relief in mouse models of chronic pain.
Increased Sympathetic Nerve Activity in Renovascular Hypertension
Authors: MatsJohansson, MikaelElam, BengtRundqvist, GraemeEisenhofer, HansHerlitz, GavinLambert, PeterFriberg
Journal: Circulation (1999)

Background—Increased sympathetic nerve activity may contribute to the progression of renovascular hypertension. Because previous results have been inconclusive, we investigated whether renovascular hypertensives show increased total and regional sympathetic nerve activity. Methods and Results—Sixty-five patients underwent renal angiography and measurements of plasma renin activity and angiotensin II in conjunction with estimation of sympathetic nerve activity by means of radiotracer dilution and intraneural recordings of muscle sympathetic nerve activity (MSNA). Age-matched healthy subjects (n=15) were examined for comparison. Total body norepinephrine (NE) spillover, an index of overall sympathetic nerve activity, was increased by 100% and MSNA by 60% in the hypertensive patients compared with healthy subjects (P<0.01 for both). A subgroup of 24 patients with well-defined renovascular hypertension (cured or improved hypertension after renal angioplasty) showed similar increases in total body NE spillover...
Abstract 19966: Supervised Aerobic Exercise After Hospital Discharge Improves Pulmonary and Respiratory Muscle Function in Patients With Chronic Heart Failure
Authors: Nobuaki Hamazaki, Takashi Masuda, Kentaro Kamiya, Ryota Matsuzawa, Kohei Nozaki, Shinya Tanaka, Kanae Yabu, Takeshi Nokamura, Minoru Tabata, Emi Maekawa, Chiharu Noda, Minako Yamaoka-Tojo, Junya Ako
Journal: Circulation (2016)

Background:  Impaired pulmonary and respiratory muscle function is known to deteriorate the clinical outcome in patients with chronic heart failure (CHF). Exercise training was documented to improve exercise capacity, quality of life and prognosis in these patients. However, the effects of exercise training on pulmonary and respiratory muscle function are still controversial. We investigated the influence of supervised aerobic exercise on pulmonary and respiratory muscle function in CHF patients.   Methods:  We followed up 494 patients with compensated CHF (64.3±0.6 years, 337 males) for 5 months. All patients received cardiac rehabilitation consisted of supervised aerobic exercise during hospitalization. We measured forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV 1 ) to evaluate pulmonary function. We also measured maximal inspiratory pressure (PI max ) as respiratory muscle strength. All parameters were measured before and after the 5-month observation period. Patients were divided into three groups based on the frequency of supervised aerobic exercise sessions after hospital discharge: group A (no sessions), group B (1-3 sessions per month) and group C (4 sessions per month or more). We examined the percentage change in the respiratory parameters from baseline to those after the observation period and compared these variables among the three groups using ANCOVA with adjustment for potential confounding factors.   Results:  In all the patients, FVC, FEV 1  and PI max  increased significantly after the observation period as compared with each baseline (P max  as compared with group A (Figure). The %change FEV 1  of group C was significantly higher than that of the other two groups (P=0.008 vs group A and P=0.047 vs group B).   Conclusion:  Supervised aerobic exercise after hospital discharge improved pulmonary and respiratory muscle function in patients with CHF.
The Cytochrome P450 Slow Metabolizers CYP2C9*2 and CYP2C9*3 Directly Regulate Tumorigenesis via Reduced Epoxyeicosatrienoic Acid Production
Authors: Lindsay N. Sausville, Mahesha H. Gangadhariah, Manuel Chiusa, Shaojun Mei, Shouzuo Wei, Roy Zent, James M. Luther, Megan M. Shuey, Jorge H. Capdevila, John R. Falck, F. Peter Guengerich, Scott M. Williams, Ambra Pozzi
Journal: Cancer Research (2018)

Increased expression of cytochrome P450 CYP2C9, together with elevated levels of its products epoxyeicosatrienoic acids (EET), is associated with aggressiveness in cancer. Cytochrome P450 variants
Cartilage Oligomeric Matrix Protein Maintains the Contractile Phenotype of Vascular Smooth Muscle Cells by Interacting With α7β1 Integrin
Authors: LiWang, JingangZheng, YaoyaoDu, YaqianHuang, JingLi, BoLiu, Chuan-juLiu, YiZhu, YuanshengGao, QingboXu, WeiKong, XianWang
Journal: Circulation Research (2010)

Rational: Vascular smooth muscle cells (VSMCs) switching from a contractile/differentiated to a synthetic/dedifferentiated phenotype has an essential role in atherosclerosis, postangioplastic restenosis and hypertension. However, how normal VSMCs maintain the differentiated state is less understood. Objective: We aimed to indentify the effect of cartilage oligomeric matrix protein (COMP), a normal vascular extracellular matrix, on modulation of VSMCs phenotype. Methods and Results: We demonstrated that COMP was associated positively with the expression of VSMC differentiation marker genes during phenotype transition. Knockdown of COMP by small interfering (si)RNA favored dedifferentiation. Conversely, adenoviral overexpression of COMP markedly suppressed platelet-derived growth factor-BB-elicited VSMC dedifferentiation, characterized by altered VSMC morphology, actin fiber organization, focal adhesion assembly, and the expression of phenotype-dependent markers. Whereas α7 integrin coimmunoprecipitated wit...
Exon-Capture-Based Phylogeny and Diversification of the Venomous Gastropods (Neogastropoda, Conoidea)
Authors: Jawad Abdelkrim, Laetitia Aznar-Cormano, Alexander E Fedosov, Yuri I Kantor, Pierre Lozouet, Mark A Phuong, Paul Zaharias, Nicolas Puillandre
Journal: Molecular Biology and Evolution (2018)

Transcriptome-based exon capture methods provide an approach to recover several hundred markers from genomic DNA, allowing for robust phylogenetic estimation at deep timescales. We applied this method to a highly diverse group of venomous marine snails, Conoidea, for which published phylogenetic trees remain mostly unresolved for the deeper nodes. We targeted 850 protein coding genes (678,322 bp) in ca. 120 samples, spanning all (except one) known families of Conoidea and a broad selection of non-Conoidea neogastropods. The capture was successful for most samples, although capture efficiency decreased when DNA libraries were of insufficient quality and/or quantity (dried samples or low starting DNA concentration) and when targeting the most divergent lineages. An average of 75.4% of proteins was recovered, and the resulting tree, reconstructed using both supermatrix (IQ-tree) and supertree (Astral-II, combined with the Weighted Statistical Binning method) approaches, are almost fully supported. A reconstructed fossil-calibrated tree dates the origin of Conoidea to the Lower Cretaceous. We provide descriptions for two new families. The phylogeny revealed in this study provides a robust framework to reinterpret changes in Conoidea anatomy through time. Finally, we used the phylogeny to test the impact of the venom gland and radular type on diversification rates. Our analyses revealed that repeated losses of the venom gland had no effect on diversification rates, while families with a breadth of radula types showed increases in diversification rates, thus suggesting that trophic ecology may have an impact on the evolution of Conoidea.