tbuckley/cabot-search huggingface dataset:
Lymphatic and Hematogenous Dissemination in Patients With Primary Cutaneous Melanoma—Reply
Authors: Eduardo Nagore, Rajiv Kumar
Journal: JAMA Dermatology (2019)

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 Dermatology 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 Dermatology journal
Vein-First Ligation Procedure for Lung Cancer Surgery
Authors: Han-Yu Deng
Journal: JAMA Surgery (2019)

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 Surgery 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 Surgery journal
Beyond the Ligand: Extracellular and Transcellular G Protein–Coupled Receptor Complexes in Physiology and Pharmacology
Authors: Henry A. Dunn, Cesare Orlandi, Kirill A. Martemyanov
Journal: Pharmacological Reviews (2019)

G protein–coupled receptors (GPCRs) remain one of the most successful targets of U.S. Food and Drug Administration–approved drugs. GPCR research has predominantly focused on the characterization of the intracellular interactome's contribution to GPCR function and pharmacology. However, emerging evidence uncovers a new dimension in the biology of GPCRs involving their extracellular and transcellular interactions that critically impact GPCR function and pharmacology. The seminal examples include a variety of adhesion GPCRs, such as ADGRLs/latrophilins, ADGRBs/brain angiogenesis inhibitors, ADGRG1/GPR56, ADGRG6/GPR126, ADGRE5/CD97, and ADGRC3/CELSR3. However, recent advances have indicated that class C GPCRs that contain large extracellular domains, including group III metabotropic glutamate receptors (mGluR4, mGluR6, mGluR7, mGluR8), <i>γ</i>-aminobutyric acid receptors, and orphans GPR158 and GPR179, can also participate in this form of transcellular regulation. In this review, we will focus on a variety of identified extracellular and transcellular GPCR-interacting partners, including teneurins, neurexins, integrins, fibronectin leucine-rich transmembranes, contactin-6, neuroligin, laminins, collagens, major prion protein, amyloid precursor protein, complement C1q-likes, stabilin-2, pikachurin, dystroglycan, complement decay-accelerating factor CD55, cluster of differentiation CD36 and CD90, extracellular leucine-rich repeat and fibronectin type III domain containing 1, and leucine-rich repeat, immunoglobulin-like domain and transmembrane domains. We provide an account on the diversity of extracellular and transcellular GPCR complexes and their contribution to key cellular and physiologic processes, including cell migration, axon guidance, cellular and synaptic adhesion, and synaptogenesis. Furthermore, we discuss models and mechanisms by which extracellular GPCR assemblies may regulate communication at cellular junctions. <h3>SIGNIFICANCE STATEMENT</h3> G protein–coupled receptors (GPCRs) continue to be the prominent focus of pharmacological intervention for a variety of human pathologies. Although the majority of GPCR research has focused on the intracellular interactome, recent advancements have identified an extracellular dimension of GPCR modulation that alters accepted pharmacological principles of GPCRs. Herein, we describe known endogenous allosteric modulators acting on GPCRs both in <i>cis</i> and in <i>trans</i>.
The effect of novel small molecule drugs in human explants across the disease sequence in colorectal cancer.
Authors: Adrian Gerard Murphy, Rory Casey, David William Fennelly, Alison Reynolds, Miriam Tosetto, John Hyland, Kieran Sheahan, Diarmuid O'Donoghue, Hugh Mulcahy, Breandan Kennedy, Jacintha O'Sullivan
Journal: Journal of Clinical Oncology (2012)

e13570 Background: The treatment of metastatic colorectal cancer has been improved by combining cytotoxic chemotherapy with bevacizumab. Newer anti-angiogenic agents are required to improve survival rates as response rates with the current therapies are modest. The preclinical development of such drugs is time-consuming and new methods are required to test the efficacy of lead drugs which represent the entire tumor micro-environment. Methods: Chemical screens were performed in zebrafish larvae to identify hits that affected intersegmental angiogenesis. Five lead drugs were then tested for cytotoxicity using the crystal violet assay. These drugs were tested using ex vivo colorectal tumor explants to determine their effect on secretion of IL-1β, TNF, IL-6 and VEGF. Human explants from 20 patients (Dukes A-D) were cultured for 72 hours and the levels of the above factors measured by ELISA. Comparisons were made between early (Dukes A&amp;B) and late stages (Dukes C&amp;D). Results: One thousand drugs were screened and 5 were found to reduce intersegmental angiogenesis in zebrafish larvae: AM1, AM2, AM3, AM4 and AM5. The drugs did not affect cell growth levels at 10 µM concentration. From the explant studies: AM1 decreased secretion of VEGF in late stages (p=0.005) and IL-6 in early stages (p=0.009). AM2 decreased VEGF in early (p=0.004) and late stages (p=0.02). AM3 decreased TNF secretion in late stages (p=0.02) and IL-6 secretion in early (p=0.009) and late stages (p&lt;0.0001). AM4 decreased VEGF secretion in early stages (p=0.001), IL-6 in early stages (p&lt;0.001) and late stages (p=0.03) and IL-1β in early stages (p=0.002). AM5 decreased IL-6 secretion in the early stages (p=0.03) and IL-1β in the early stages (p=0.001).Overall, IL-1β secretion was reduced by AM4, AM3 and AM5 (p&lt;0.05). IL-6 secretion was reduced by AM1, AM3 and AM4 (p=0.001). TNF secretion was reduced by AM3 (p=0.02) and VEGF secretion was reduced by AM1, AM2 and AM4 (p&lt;0.005). Conclusions: These studies show these drugs have stage-specific effects in colorectal tumor explants and may have the potential as new anti-angiogenic agents in colorectal cancer.
Moral judgment as reasoning by constraint satisfaction
Authors: Keith J Holyoak, Derek Powell
Journal: Behavioral and Brain Sciences (2019)

Abstract May's careful examination of empirical evidence makes a compelling case against the primacy of emotion in driving moral judgments. At the same time, emotion certainly is involved in moral judgments. We argue that emotion interacts with beliefs, values, and moral principles through a process of coherence-based reasoning (operating at least partially below the level of conscious awareness) in generating moral judgments and decisions.
Immune overdrive signature in colorectal tumor subset predicts poor clinical outcome
Authors: Marwan Fakih, Ching Ouyang, Chongkai Wang, Travis Yiwey Tu, Maricel C. Gozo, May Cho, Marvin Sy, Jeffrey A. Longmate, Peter P. Lee
Journal: Journal of Clinical Investigation (2019)

The prognostic value of immune cell infiltration within the tumor microenvironment (TME) has been extensively investigated via histological and genomic approaches. Based on the positive prognostic value of T cell infiltration, Immunoscore has been developed and validated for predicting risk of recurrence for colorectal cancer (CRC). Also, association between a consensus T helper 1 (Th-1) immune response and favorable clinical outcomes has been observed across multiple cancer types. Here, we reanalyzed public genomic data sets from The Cancer Genome Atlas (TCGA) and NCBI Gene Expression Omnibus (NCBI-GEO) and performed multispectral immunohistochemistry (IHC) on a cohort of colorectal tumors. We identified and characterized a risk group, representing approximately 10% of CRC patients, with high intratumoral CD8+ T cell infiltration, but poor prognosis. These tumors included both microsatellite instable (MSI) and stable (MSS) phenotypes and had a high density of tumor-associated macrophages (TAMs) that expressed CD274 (programmed death-ligand 1 [PD-L1]), TGF-β activation, and an immune overdrive signature characterized by the overexpression of immune response and checkpoint genes. Our findings illustrate that CRC patients may have poor prognosis despite high CD8+ T cell infiltration and provide CD274 as a simple biomarker for identifying these patients.
Relationship of the p75 neurotrophin receptor (p75NTR) and hypoxic response and treatment resistance in malignant gliomas.
Authors: Rajappa Kenchappa, Peter A. J. Forsyth
Journal: Journal of Clinical Oncology (2013)

e13026 Background: Malignant gliomas (MGs) are resistant to Radiotherapy (RT). The molecular pathways that produce resistance to therapy and ability to tolerate hypoxia are poorly understood. We previously found that the p75NTR causes invasion &amp; proliferation of MGs/Brain Tumor Initiating Cells (BTICs). We think MGs use the neurotrophin-rich brain environment as a survival advantage to resist treatment by expressing the p75NTR. We hypothesize that hypoxia cause p75NTR proteolysis which produces HIF-1α stabilization and activation of hypoxic responses. This repertoire of hypoxic responses leads to resistance to both hypoxia &amp; radiotherapy (RT) and account for MG recurrence. Methods: We used glioma cells and BTICs they express very low or and high levels of p75NTR and manipulated the expression of p75NTR by shRNAs and activation by mutant receptors and pharmacological inhibitors. We exposed these cells to hypoxia and radiation treatment and performed biochemical and functional assays. We have also used paired pre and post-RT frozen patient specimens. Gene expression profiles were analyzed for patients using microarray expression data for 516 primary GBM patients from the TCGA and 239 patients from Moffitt’s Total Cancer Care (TCC) project. Results: We found that inhibiting p75NTR pharmacologically significantly reduced invasion/proliferation of MGs/BTICs in vitro &amp; in vivo. We have also found that p75NTR is required for HIF-1α stabilization and VEGF expression in MGs/BTICs in vitro &amp; in vivo, that p75NTR expressing MGs/BTICs are very resistant to hypoxia &amp; RT in vitro, and these effects are reversed with inhibition of p75NTR signaling. In addition, p75NTR expression and its cleavage are associated with treatment resistance in patient specimens. We also found using TCGA and Moffitt patient specimen data that the p75NTR/Siah2/PHD axis is expressed in MG patients and associated with RT resistance/poor prognosis. Conclusions: These results suggest that p75NTR expression/cleavage are required for HIF-1α pathway activation and hence the phenotype of MGs/BTICs and their treatment resistance. Targeting the p75NTR signaling axis therefore will provide novel therapeutic approaches.
Equal or not? Women hold less prestigious roles at respiratory medicine conferences than men
Authors: Mayurapriya Raviskanthan, Megan Rees, Jo Douglass, Katherine Sleeman, Irene Higginson, Natasha Smallwood
Journal: European Respiratory Journal (2019)

<b>Analysis of the sex distribution of presenters in national and international conferences in 2017 demonstrates a significantly lower proportion of women in more prominent roles compared with men</b>http://bit.ly/2lGJz02
Abstract 427: Alterations in the Mitochondrial Supercomplex in Pediatric Dilated Cardiomyopathy
Authors: Kathryn C Chatfield, Genevieve C Sparagna, Sarah Chau, Michael J Bennett, Adam J Chicco, Johan L Van Hove, Shelley D Miyamoto, Brian L Stauffer
Journal: Circulation Research (2017)

Organization of the mitochondrial electron transport chain (ETC) into a protein “supercomplex” has been shown to be critical for optimal mitochondrial respiration, and is dependent on the phospholipid composition of the inner mitochondrial membrane. A close physical interaction between the ETC supercomplex and the fatty acid beta-oxidation system (FAO, which provides necessary reducing equivalents for ETC) has also been proposed. We have previously demonstrated that content of the primary mitochondrial phospholipid, cardiolipin, is altered in pediatric dilated cardiomyopathy (DCM), with evidence for its dysregulated biosynthesis. We hypothesized that altered cardiolipin content in pediatric DCM is correlated with altered supercomplex-associated ETC activity and mitochondrial fatty acid β-oxidation. A cross-sectional investigation was performed using myocardium from 16 children with DCM and 15 non-failing (NF) controls from the University of Colorado Heart Tissue Bank. Using blue native (BN) -PAGE with in-gel activity staining we demonstrated lower activity of supercomplex-associated complexes I (DCM 80% of NF, P&lt;0.05) and IV (DCM 72% of NF, P&lt;0.05) in pediatric DCM compared with NF controls. Using BN-PAGE and Western blot, as well as proteomic analysis of isolated supercomplex bands, we demonstrated interaction of the ETC supercomplex with FAO enzymes. Quantification of fatty acyl-CoAs was also performed in tissue from pediatric patients with DCM which demonstrated altered content of a subset of acyl-CoAs when compared to NF controls. We detected higher content of some C8, C10 and C12 CoAs in DCM compared with NF (P&lt;0.05), with depletion of C18:1, C18:2, and C16 species (P&lt;0.05). There was no difference between groups in free CoA or Acetyl-CoA. Taken together, these data suggest a potentially important interaction between the ETC supercomplex and long-chain β-oxidation enzymes, which may be altered on heart failure. We provide preliminary evidence for disrupted energy utilization in the failing pediatric heart.
Fatigue resistance of ProTaper gold exposed to high-concentration sodium hypochlorite in double curvature artificial canal
Authors: Fahda Algahtani, Xiangya Huang, Markus Haapasalo, Zhejun Wang, Ahmed Hieawy, Duo Zhang, Jolanta Aleksejuniene, Ya Shen
Journal: Bioactive Materials (2019)

This study aimed to evaluate and compare the fatigue resistance of ProTaper Gold (PTG) and ProTaper Universal (PTU) in artificial single and double curvature canals in 5% sodium hypochlorite (NaOCl) at body temperature (37 °C). PTG and PTU files (size F1) were subjected to fatigue tests in two different artificial ceramic canals. The single curvature model had a 60° curvature angle with a 5 mm radius. The double curvature model had a 60° curvature angle with a 5 mm radius and a second 30° curvature with a 2 mm radius. A file segment was introduced into the artificial canal and immersed in water or 5% NaOCl at 37 °C. The total number of cycles to fracture (NCF) was recorded. Data were analyzed using t-test and linear regression analysis. The NCF of all files was significantly influenced by the type of NiTi metal alloy (P < .01), canal curvatures (P < .01), and the environmental conditions (P < .05). PTG had higher fatigue resistance than PTU files in both single and double curvature canals (P < .05). The NCF of PTU files in 5% NaOCl was shorter than that in water (P < .05). The mean length of broken PTG was significantly shorter than those of PTU files in both single and double curvature canals (P < .01). The fatigue performance of PTG is better than that of PTU in both single and double curvature. Environmental conditions may affect the fatigue behavior of PTU files with single curvature.
Glyco-Dendrimers as Intradermal Anti-Tumor Vaccine Targeting Multiple Skin DC Subsets
Authors: Sanne Duinkerken, Sophie K. Horrevorts, Hakan Kalay, Martino Ambrosini, Lisa Rutte, Tanja D. de Gruijl, Juan J. Garcia-Vallejo, Yvette van Kooyk
Journal: Theranostics (2019)

The human skin is an attractive anti-tumor vaccination site due to the vast network of dendritic cell (DC) subsets that carry antigens to the draining lymph nodes and stimulate tumor specific CD4+ and CD8+ T cells in. Specific vaccine delivery to skin DC can be accomplished by targeting glycan coated antigens to C-type lectin receptors (CLRs) such as DC-SIGN expressed by human dermal DCs and Langerin expressed by Langerhans cells (LCs), which facilitate endocytosis and processing for antigen presentation and T cell activation. Although there are multiple human skin DC subsets, targeting individual DC subsets and receptors has been a focus in the past. However, the simultaneous targeting of multiple human skin DC subsets that mobilize the majority of the skin antigen presenting cells (APC) is preferred to accomplish more robust and efficient T cell stimulation. Dual CLR targeting using a single tumor vaccine has been difficult, as we previously showed Langerin to favor binding and uptake of monovalent glyco-peptides whereas DC-SIGN favors binding of larger multivalent glyco-particles such as glyco-liposomes. Methods: We used branched polyamidoamine (PAMAM) dendrimers as scaffold for melanoma specific gp100 synthetic long peptides and the common DC-SIGN and Langerin ligand Lewis Y (LeY), to create multivalent glyco-dendrimers with varying molecular weights for investigating dual DC-SIGN and Langerin targeting. Using DC-SIGN+ monocyte derived DC (moDC) and Langerin+ primary LC we investigated glyco-dendrimer CLR targeting properties and subsequent gp100 specific CD8+ T cell activation in vitro. In situ targeting ability to human dermal DC and LC through intradermal injection in a human skin explant model was elucidated. Results: Dual DC-SIGN and Langerin binding was achieved using glyco-dendrimers of approximately 100kD, thereby fulfilling our criteria to simultaneously target LCs and CD1a+ and CD14+ dermal DC in situ. Both DC-SIGN and Langerin targeting by glyco-dendrimers resulted in enhanced internalization and gp100 specific CD8+ T cell activation. Conclusion: We designed the first glyco-vaccine with dual CLR targeting properties, thereby reaching multiple human skin DC subsets in situ for improved anti-tumor CD8+ T cell responses.
Spontaneous Pulmonary Hypertension Associated With Systemic Sclerosis in P‐Selectin Glycoprotein Ligand 1–Deficient Mice
Authors: Rafael González‐Tajuelo, María de la Fuente‐Fernández, Daniel Morales‐Cano, Antonio Muñoz‐Callejas, Elena González‐Sánchez, Javier Silván, Juan Manuel Serrador, Susana Cadenas, Bianca Barreira, Marina Espartero‐Santos, Carlos Gamallo, Esther F. Vicente‐Rabaneda, Santos Castañeda, Francisco Pérez‐Vizcaíno, Ángel Cogolludo, Luis Jesús Jiménez‐Borreguero, Ana Urzainqui
Journal: Arthritis & Rheumatology (2019)

Objective Pulmonary arterial hypertension (PAH), one of the major complications of systemic sclerosis (SSc), is a rare disease with unknown etiopathogenesis and noncurative treatments. As mice deficient in P‐selectin glycoprotein ligand 1 (PSGL‐1) develop a spontaneous SSc‐like syndrome, we undertook this study to analyze whether they develop PAH and to examine the molecular mechanisms involved. Methods Doppler echocardiography was used to estimate pulmonary pressure, immunohistochemistry was used to assess vascular remodeling, and myography of dissected pulmonary artery rings was used to analyze vascular reactivity. Angiotensin II (Ang II) levels were quantified by enzyme‐linked immunosorbent assay, and Western blotting was used to measure Ang II type 1 receptor (AT 1 R), AT 2 R, endothelial cell nitric oxide synthase (eNOS), and phosphorylated eNOS expression in lung lysates. Flow cytometry allowed us to determine cytokine production by immune cells and NO production by endothelial cells. In all cases, there were 4–8 mice per experimental group. Results PSGL‐1 −/− mice showed lung vessel wall remodeling and a reduced mean ± SD expression of pulmonary AT 2 R (expression ratio [relative to β‐actin] in female mice age &gt;18 months: wild‐type mice 0.799 ± 0.508 versus knockout mice 0.346 ± 0.229). With aging, female PSGL‐1 −/− mice had impaired up‐regulation of estrogen receptor α (ERα) and developed lung vascular endothelial dysfunction coinciding with an increase in mean ± SEM pulmonary Ang II levels (wild‐type 48.70 ± 5.13 pg/gm lung tissue versus knockout 78.02 ± 28.09 pg/gm lung tissue) and a decrease in eNOS phosphorylation, leading to reduced endothelial NO production. These events led to a reduction in the pulmonary artery acceleration time:ejection time ratio in 33% of aged female PSGL‐1 −/− mice, indicating pulmonary hypertension. Importantly, we found expanded populations of interferon‐γ–producing PSGL‐1 −/− T cells and B cells and a reduced presence of regulatory T cells. Conclusion The absence of PSGL‐1 induces a reduction in Treg cells, NO production, and ERα expression and causes an increase in Ang II in the lungs of female mice, favoring the development of PAH.