tbuckley/cabot-search huggingface dataset:
Abstract 7: S-nitrosylation Affects Differentiation of Mesenchymal Stem Cells
Authors: Yenong Cao, Samirah A Gomes, Erika B Rangel, Ellena C Paulino, Shathiyah Kulandavelu, Wayne Balkan, Joshua M Hare
Journal: Circulation Research (2012)

Introduction: Bone marrow-derived mesenchymal stem cells (BMMSCs) appear to play an important role in the formation of atherosclerotic lesions. Circulating BMMSCs are attracted to arterial wall where they undergo adipogenic or osteogenic differentiation to form ectopic aggregates of fat and bone. The factors that determine the direction of BMMSC differentiation are poorly understood. We assessed the role of nitric oxide (NO), an inhibitor of lipid formation and vascular calcification, in BMMSC differentiation. Hypothesis: S-nitrosylation mediated-NO signaling controls the balance between adipogenic and osteogenic differentiation of BMMSCs. Methods: We isolated BMMSCs from wild type mice (WT) and mice deficient in S-nitrosoglutathione reductase (GSNOR -/- ), an enzyme that governs levels of S-nitrosylation by promoting protein denitrosylation. Cells were cultured in either adipogenic or osteogenic differentiation media followed by functional and gene expression assays. Results: MSCs derived from GSNOR -/- mice had impaired fat droplet formation and lower expression of the adipogenic markers PPARγ (1329±415.3-fold increase in WT vs. 158±65.61-fold in GSNOR -/- , P&lt;0.05) and FABP4 (11.06±3.29-fold in WT vs. 4.06±0.62-fold in GSNOR -/- , P&lt;0.05). Conversely, GSNOR -/- MSCs exhibited enhanced osteogenic differentiation as indicated by greater calcium deposition and higher expression of the osteogenic marker Osteopontin (1.48±0.17-fold in WT vs. 16.18±5.26-fold in GSNOR -/- , P&lt;0.05). Interestingly, GSNOR -/- cells had higher baseline expression of Osteopontin, Osteocalcin and Runx2. Treatment of GSNOR -/- MSCs with L-NAME, a nitric oxide synthase (NOS) inhibitor, resulted in decreased osteogenic differentiation without affecting adipogenic differentiation. Conclusion: Our results indicate that GSNOR enhances adipogenic differentiation and impairs osteogenic differentiation of BMMSCs in vitro and suggest that interaction of GSNOR- and NOS-mediated processes regulates the balance between adipogenic and osteogenic differentiation of BMMSCs.
Medicare Advantage Reimbursement to Physicians
Authors: James C. Robinson
Journal: JAMA Internal Medicine (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Systematic biopsy of the first metastatic event in breast cancer: Results from ESOPE—A prospective multicenter trial.
Authors: Aurelie Comte, Paul H. Cottu, Lisa Belin, Celine Callens, Vincent Servois, Francois-Clement Bidard, Etienne Brain, Anne Vincent- Salomon, Thomas Denis Bachelot, Mahasti Saghatchian, Mario Campone, Sylvie Giacchetti, Jacques Bonneterre, Brigitte Sigal-Zafrani
Journal: Journal of Clinical Oncology (2016)

550 Background: Tumoral heterogeneity and systemic therapies may induce marked biological differences between the primary tumor (PT) and metastatic (M) tissue in breast cancer (BC). Clinical utility of m biopsy has not been demonstrated. We conducted a prospective study comparing the subtype and the molecular profile of PT and the matched first m event. Methods: ESOPE (NCT 01956552) is a prospective, multicenter trial conducted between 11/2010 and 09/2013. Main inclusion criteria were: patients with available formalin-fixed paraffin-embedded (FFPE) PT sample, and presenting with a first m event accessible to sampling. No previous therapy for m disease was allowed. FFPE tissue samples from PT and m were locally and centrally analyzed for ER, PgR, Ki67 and HER2. Impact on therapeutic decision and clinical outcome were recorded. Comparative genomic analyses including targeted sequencing, exome sequencing and RNAseq were preplanned on FFPE and frozen samples. Results: Overall, 130 pts were included. Median age was 57y (28-81). Median delay to m was 42 m (0-270), 75 pts (61%) had 2+ m sites. Most frequent sites were liver (60%), lymph nodes (44%), bone (43%) and lung/pleura (34%). A biopsy was feasible and performed in 117 pts (90%). After a median delay of 20.7 days, most frequently biopsied sites were liver (45%), lymph node (13%), bone (11%) and lung (10%). A second non BC cancer or benign disease was observed in 5 and 1 pt. Ultimately, 84 matched PT/M pairs were centrally reviewed. PT/M subtype concordance was 100% for triple negative (n = 16) tumors. HER2 (n = 16), lum B PT (n = 29) and lum A PT (n = 23) changed of phenotype in 4%, 20% and 52% of cases, respectively. Treatment allocation was determined according to results of the biopsy in 26.2% of patients with matched PT/M. Overall survival was highly correlated with the m subtype: median OS was 15m (triple negative), 34m (Lum B), 41m (HER2) and not reached (Lum A) (p = 0.0002). Conclusions: Metastatic subtype differs from the PT in BC mostly in Lum A tumors. Systematic m biopsy at the first event yields a treatment change in almost 25% of the patients, underlining its clinical utility. Ongoing in depth genomic analyses will illustrate specific biological changes in m tissue. Clinical trial information: NCT01956552.
Abstract 253: The Tyrosine Kinase ErbB2 Inhibitor Lapatinib and the Anti-ErbB2 Antibody Trastuzumab Depress Cardiac Function Without Inducing Left Ventricular Dilation in Mice
Authors: Carlo G Tocchetti, Carmela Coppola, Domenica Rea, Antonio Barbieri, Giuseppe Palma, Giovanna Piscopo, Marianna Gala, Antonio Luciano, Aldo Giudice, Clemente Cipresso, Rosario V Iaffaioli, Stefania Scala, Claudia De Lorenzo, Claudio Arra, Nicola Maurea
Journal: Circulation Research (2012)

Background: ErbB2, tyrosine kinase receptor of the EGFR family, overexpressed in about 25% of breast cancers, modulates development and function in the myocardium. Lapatinib (LAP) is a small molecule that inhibits ErbB2-tyrosine kinase domain. The few existing trials report it to be associated with a low risk of LV dysfunction (2%), while the prototypical antibody Trastuzumab (TRAS) increases the frequency of asymptomatic ejection fraction decrease by 3-18%, and the risk of heart failure by 2-4%. Here, we characterize our LAP murine cardiotoxicity model in vivo by echocardiography, comparing it to TRAS and doxorubicin (DOX) cardiotoxicities. Methods: LV end-diastolic and end-systolic diameters (LVEDD and LVESD) were assessed. LV function was measured with fractional shortening (FS) by M-mode echo, and with radial myocardial strain (%) with speckle tracking (ST) in sedated C57BL6 mice (2-4 mo. old) at day 0, and after 2 and 7 days of daily administration of LAP (100mg/kg/day orally), and in control mice. For comparison we used our well-established models with TRAS (2.25 mg/kg/day, ip), and DOX (2.17 mg/kg/day ip) as positive control. Results: FS was already reduced with DOX at 2 days: 52±.2%, p&lt;.001 vs 60±.4% (sham), while LAP and TRAS decreased FS only at 7 days (56±2 and 49±1.5%, respectively, both p&lt;.05 vs 60±.5% for sham). Interestingly, FS reduction with LAP was milder than with TRAS (p=.01). At 7 days, both LAP and TRAS only increased LVESD: 1.23±.07 and 1.49±.07mm, respectively, both p&lt;.05 vs 1.1±.03mm (sham). On the other hand, at 7 days DOX induced LV dilation, with significant enlargement of both LVESD (1.55±.08mm) and LVEDD (3.04±.06mm; sham=2.81±.03mm), both p&lt;.005. Importantly, from a diagnostic point of view, myocardial strain was reduced early at 2 days with LAP and TRAS, predicting cardiotoxicity: 34±7% for LAP, 44±7% for TRAS, both p&lt;.05 vs sham (66±.6%). Conclusions: Differently from DOX, ErbB2 inhibition in mice does not produce LV dilation, but only decreases LV function. In particular, specifically targeting ErbB2-tyrosine kinase domain with LAP confers less cardiotoxicity than TRAS. Myocardial strain identifies LV systolic dysfunction earlier than conventional echo and can be a useful tool to predict ErbB2 inhibitors cardiotoxicity.
Tamoxifen in pluronic lecithin organogel: A novel topical approach for cancer treatment.
Authors: Amit Bhatia, Bhupinder Bhoop, Om Katare
Journal: Clinical Cancer Research (2007)

B24    Purpose:  The present work entails the development and evaluation of pluronic lecithinized organogels of a potent antiestrogen, tamoxifen, drug of choice for treatment of breast cancer. The key objectives of the study include, improvised skin penetration, site specific and prolonged duration of action, with fewer or no side effects as encountered with conventional oral dosage forms of tamoxifen. Means enhancing the overall efficacy of tamoxifen by exploiting novel drug delivery systems/approaches.   Methods:  Organogels of tamoxifen were prepared employing different blends of aqueous & non-aqueous phase in combination with gel former  viz.  surfactant(s) and co-surfactant. Further, the process and composition variables were standardized to stable organogel system.  The Systematic optimization studies were carried out using 3 2  factorial design to obtain the optimized organogel composition with reference to  ex vivo  drug permeation and retention (skin drug deposition) studies employing Franz diffusion cell assembly. The optimized formulation was further characterized for its rheological properties, micromeritics and morphology of gel-structures.  Finally, in order to assess the  in vivo  effects of optimized tamoxifen-loaded organogel on rats, dermal irritation test was conducted as per the OECD guidelines. Furthermore, the skin-histology studies were carried out to establish the safety of the developed topical system.   Results:  The initially selected organogel comprising non-aqueous (isopropyl myristate, lipid & span) and aqueous phases (water & poloxamer) with volume ratio of 1:4 (nonaqueous: aqueous) was selected, as it showed maximum stability.  Based on the preliminary studies, optimization of organogel composition was carried out with two independent variables (lipid & span) at three levels (i.e., 3 2 ) with three replicates each. Optimized organogel formulation demonstrated overall best  ex vivo  results in terms of better drug permeation along with high drug retention within the skin tissue, in comparison to the conventional cream and hydrogel formulations.  The optimized organogel formulation was found to possess all the desired gel-characteristics and uniformity of the microstructures as confirmed from gel texture analysis and polydispersity index in conjunction with microscopy, respectively.  On  in vivo  evaluation employing dermal irritation test, the irritation index value for the developed lecitinized organogel was found to be zero. Moreover the histological studies were found to be in consonance with irritancy test showing bio-friendly characteristic of the selected optimized system.   Conclusions:  The results point towards the possible potential of lecithinized organogel system for the improved localized delivery of tamoxifen. The latter will be a very useful proposition in succeeding to avoid its severe toxicities on account of its oral use, the same can be explored further.
Synergistic cooperation and crosstalk between <i>MYD88L265P</i> and mutations that dysregulate CD79B and surface IgM
Authors: James Q. Wang, Yogesh S. Jeelall, Peter Humburg, Emma L. Batchelor, Sarp M. Kaya, Hee Min Yoo, Christopher C. Goodnow, Keisuke Horikawa
Journal: The Journal of Experimental Medicine (2017)

CD79B and MYD88 mutations are frequently and simultaneously detected in B cell malignancies. It is not known if these mutations cooperate or how crosstalk occurs. Here we analyze the consequences of CD79B and MYD88L265P mutations individually and combined in normal activated mouse B lymphocytes. CD79B mutations alone increased surface IgM but did not enhance B cell survival, proliferation, or altered NF-κB responsive markers. Conversely, B cells expressing MYD88L265P decreased surface IgM coupled with accumulation of endoglycosidase H–sensitive IgM intracellularly, resembling the trafficking block in anergic B cells repeatedly stimulated by self-antigen. Mutation or overexpression of CD79B counteracted the effect of MYD88L265P. In B cells chronically stimulated by self-antigen, CD79B and MYD88L265P mutations in combination, but not individually, blocked peripheral deletion and triggered differentiation into autoantibody secreting plasmablasts. These results reveal that CD79B and surface IgM constitute a rate-limiting checkpoint against B cell dysregulation by MYD88L265P and provide an explanation for the co-occurrence of MYD88 and CD79B mutations in lymphomas.
Drug resistant mechanism for human bladder cell lines to doxorubicin
Authors: Tomoko Furukawa, Yoshiro Saikawa, Yoshihide Otani, Tetsuro Kubota, Masaki Kitajima
Journal: Cancer Research (2005)

519  Background and Objects: Doxorubicin (DXR) is one of the key drugs for the patients with bladder cancer. The main resistant mechanism of doxorubicin is known to be ABC-transporters, including multidrug resistance gene (MDR-1)/P-glycoprotein, and multidrug resistance-associated protein (MRP-1), which is regulated by cyclooxygenase-2 (COX-2), and eliminates DXR from cancer cells under the presence of glutathione. We previously reported that the main resistant mechanism for two resistant sublines (T-24/DXR, T-24/VCR) of T-24, a human bladder cancer cell line were different to each other, i.e., the resistance of T-24/DXR and T-24/VCR is mainly regulated by MRP-1 and MDR-1, respectively by the experiments using indomethacin, which is known as MRP-1 and COX inhibitor. In the present study, we have investigated the expression MRP-1 regulated by COX-2, the intracellular glutathione concentration, and the inhibitory mechanism of MRP-1 by indomethacin. Method: T-24, and its resistant sublines, T-24/DXR (resistant to DXR) and T-24/VCR (resistant to vincristine) were used for the experiments. The expression of MDR-1 and MRP-1 mRNA were measured by real-time RT-PCR, and their proteins were detected by Western Blotting analysis. The sensitivity of these cell lines to DXR was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl 2H-tetrazolium bromide (MTT) assay, and indomethacin was used as MRP-1 inhibitor. The intracellular glutathione concentration was measured using Glutathione assay kit (Cayman). Result: Two resistant sublines of T-24 were less sensitive to DXR than parental cell line, and the resistance of T-24/DXR to DXR was higher than that of T-24/VCR. The expression of MRP-1 protein was correlated to that of MRP-1 mRNA, and was not affected by pretreatment of DXR or indomethacin. The expression of COX-2 protein in T-24/DXR was lower than that of T-24 and T-24/VCR, and COX-2-expressions in these cell lines were not altered by the treatment of DXR or indomethacin. The intracellular glutathione concentration of untreated T-24 was similar to its sublines, although the concentration in T-24/DXR over-expressing MRP-1, was 10-fold higher when it was pretreated with indomethacin. Conclusion: The T-24/DXR over-expressing MRP-1 had lower COX-2 protein level and its MRP-1 level did not decrease by the pretreatment of indomethacin, suggesting that indomethacin may down-regulate MRP-1 directly, without affecting COX-2. In addition, the decreased intracellular glutathione might be one of the resistant mechanisms by inhibiting MRP-1.
GWAS Meta-Analysis of Glomerular Filtration Rate in Three Cohorts of Sickle Cell Disease Patients and In Vivo Functional Analysis Reveals Potential Nephropathy Candidate Genes
Authors: Blair R. Anderson, Melanie E. Garrett, Karen L. Soldano, Eugene P. Orringer, James R. Eckman, Ludmila Francescatto, Erica E. Davis, Mark T. Gladwin, Victor R. Gordeuk, Marilyn J. Telen, Allison E. Ashley-Koch
Journal: Blood (2016)
Pilot Programs Seek to Integrate Genomic Data Into Practice
Authors: Bridget M. Kuehn
Journal: JAMA (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Circulating Tumor Cells: Moving Biological Insights into Detection
Authors: Lichan Chen, Ann M Bode, Zigang Dong
Journal: Theranostics (2017)

Circulating tumor cells (CTCs) have shown promising potential as liquid biopsies that facilitate early detection, prognosis, therapeutic target selection and monitoring treatment response. CTCs in most cancer patients are low in abundance and heterogeneous in morphological and phenotypic profiles, which complicate their enrichment and subsequent characterization. Several methodologies for CTC enrichment and characterization have been developed over the past few years. However, integrating recent advances in CTC biology into these methodologies and the selection of appropriate enrichment and characterization methods for specific applications are needed to improve the reliability of CTC biopsies. In this review, we summarize recent advances in the studies of CTC biology, including the mechanisms of their generation and their potential forms of existence in blood, as well as the current CTC enrichment technologies. We then critically examine the selection of methods for appropriately enriching CTCs for further investigation of their clinical applications.
Urinary Matrix Metalloproteinase-7 Predicts Severe AKI and Poor Outcomes after Cardiac Surgery
Authors: Xiaobing Yang, Chunbo Chen, Siyuan Teng, Xiaorui Fu, Yan Zha, Huafeng Liu, Li Wang, Jianwei Tian, Xiangyan Zhang, Youhua Liu, Jing Nie, Fan Fan Hou
Journal: Journal of the American Society of Nephrology (2017)

Urinary matrix metalloproteinase-7 (uMMP-7) levels consistently reflect the activity of intrarenal Wnt/β-catenin, which is activated in AKI models. To test the hypothesis that uMMP-7 is a predictor for severe AKI in patients after cardiac surgery, we performed a prospective, multicenter, two-stage cohort study in 721 patients undergoing cardiac surgery. In stage 1, we enrolled 323 children from three academic medical centers. In stage 2, we enrolled 398 adults at six centers. We analyzed levels of uMMP-7 and other injury biomarkers during the perioperative period. Severe AKI was defined as Kidney Disease Improving Global Outcomes stage 2 or 3. uMMP-7 level peaked within 6 hours after surgery in patients who subsequently developed severe AKI. After multivariate adjustment, the highest quintile of postoperative uMMP-7 level, compared with the lowest quintile, associated with 17-fold (in adults) and 36-fold (in children) higher odds of severe AKI. Elevated uMMP-7 level associated with increased risk of composite events (severe AKI, acute dialysis, and in-hospital death) and longer stay in the intensive care unit and hospital. For predicting severe AKI, uMMP-7 had an area under the receiver operating characteristic curve of 0.81 (in children) and 0.76 (in adults), outperforming urinary IL-18, angiotensinogen, neutrophil gelatinase-associated lipocalin, albumin-to-creatinine ratio, and tissue inhibitor of metalloproteinase-2·IGF-binding protein-7 and the clinical model. uMMP-7 significantly improved risk reclassification over the clinical model alone, as measured by net reclassification improvement and integrated discrimination improvement. In conclusion, uMMP-7 is a promising predictor for severe AKI and poor in-hospital outcomes in patients after cardiac surgery.
Correction of Abdominal Distention by Biofeedback-Guided Control of Abdominothoracic Muscular Activity in a Randomized, Placebo-Controlled Trial
Authors: Elizabeth Barba, Anna Accarino, Fernando Azpiroz
Journal: Clinical Gastroenterology and Hepatology (2017)

Background & AimsAbdominal distention is produced by abnormal somatic postural tone. We developed an original biofeedback technique based on electromyography-guided control of abdominothoracic muscular activity. We performed a randomized, placebo-controlled study to demonstrate the superiority of biofeedback to placebo for the treatment of abdominal distention.MethodsAt a referral center in Spain, we enrolled consecutive patients with visible abdominal distention who fulfilled the Rome III criteria for functional intestinal disorders (47 women, 1 man; 21–74 years old); 2 patients assigned to the placebo group withdrew and 2 patients assigned to biofeedback were not valid for analysis. Abdominothoracic muscle activity was recorded by electromyography. The patients in the biofeedback group were shown the signal and instructed to control muscle activity, whereas patients in the placebo received no instructions and were given oral simethicone. Each patient underwent 3 sessions over a 10-day period. The primary outcomes were subjective sensation of abdominal distention, measured by graphic rating scales for 10 consecutive days before and after the intervention.ResultsPatients in the biofeedback group effectively learned to reduce intercostal activity (by a mean 45% ± 3%), but not patients in the placebo group (reduced by a mean 5% ± 2%; P < .001). Patients in the biofeedback group learned to increase anterior wall muscle activity (by a mean 101% ± 10%), but not in the placebo group (decreased by a mean 4% ± 2%; P < .001). Biofeedback resulted in a 56% ± 1% reduction of abdominal distention (from a mean score of 4.6 ± 0.2 to 2.0 ± 0.2), whereas patients in the placebo group had a reduction of only 13% ± 8% (from a mean score of 4.7 ± 0.1 to 4.1 ± 0.4) (P < .001).ConclusionsIn a randomized trial of patients with a functional intestinal disorder, we found that abdominal distention can be effectively corrected by biofeedback-guided control of abdominothoracic muscular activity, compared with placebo. ClincialTrials.gov no: NCT01205100.