tbuckley/cabot-search huggingface dataset:
A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability
Authors: Carolin Temps, Daniel Lietha, Emily R. Webb, Xue-Feng Li, John C. Dawson, Morwenna Muir, Kenneth G. Macleod, Teresa Valero, Alison F. Munro, Rafael Contreras-Montoya, Juan R. Luque-Ortega, Craig Fraser, Henry Beetham, Christina Schoenherr, Maria Lopalco, Mark J. Arends, Margaret C. Frame, Bin-Zhi Qian, Valerie G. Brunton, Neil O. Carragher, Asier Unciti-Broceta
Journal: Cancer Research (2021)

Abstract Despite the approval of several multikinase inhibitors that target SRC and the overwhelming evidence of the role of SRC in the progression and resistance mechanisms of many solid malignancies, inhibition of its kinase activity has thus far failed to improve patient outcomes. Here we report the small molecule eCF506 locks SRC in its native inactive conformation, thereby inhibiting both enzymatic and scaffolding functions that prevent phosphorylation and complex formation with its partner FAK. This mechanism of action resulted in highly potent and selective pathway inhibition in culture and in vivo. Treatment with eCF506 resulted in increased antitumor efficacy and tolerability in syngeneic murine cancer models, demonstrating significant therapeutic advantages over existing SRC/ABL inhibitors. Therefore, this mode of inhibiting SRC could lead to improved treatment of SRC-associated disorders. Significance: Small molecule–mediated inhibition of SRC impairing both catalytic and scaffolding functions confers increased anticancer properties and tolerability compared with other SRC/ABL inhibitors.
Abstract 866: Secreted Frizzled Related Protein 2 Modulates Post Myocardial Infarct Remodeling by Inhibiting Collagen Maturation through the Inhibition of Bone Morphogenetic Protein 1 Activity
Authors: Wei He, Lunan Zhang, Richard E Pratt, Victor J Dzau
Journal: Circulation (2007)

Myocardial infarction and post-infarction remodeling with heart failure are the major cause of mortality and morbidity in the United States. We recently reported that intracardiac implantation of genetically engineered mesenchymal stem cell (MSC) overexpressing the Akt gene dramatically reduced the infarct size and restored cardiac functions in rodent hearts after coronary artery ligation. Further, we identified Secreted Frizzled Related Protein 2 (sfrp2) as a key factor released by Akt-MSC mediating myocardial survival and repair. However, the underlying mechanism remains elusive. Bone Morphogenetic Protein1 (BMP1)/Tolloid (TLD)-like metalloproteinases belong to a subgroup of astacin family and play key roles in the regulation of extracelluar matrix (ECM) formation and cardiac fibrosis. These proteases have procollagen C-proteinase (PCP) activities which are responsible for the cleavage of C-propeptides from procollagen precursors to produce mature collagen fibrils. In this report, we showed that three days following myocardial infarction in rats, both BMP1 protein expression and activity were upregulated in the infarcted left ventricle. Interestingly, we found recombinant sfrp2 could inhibit BMP1 activity in MI tissue samples as measured by an in vitro PCP activity assay. Furthermore, using purified recombinant proteins, we demonstrated that sfrp2, but not sfrp1 or sfrp3, inhibited BMP-1 activity in vitro. Moreover, purified sfrp2 could physically interact with BMP1 protein as shown by the co-immunoprecipitation assay. To provide further evidence that sfrp2 can interfere with collagen processing, we demonstrated that exogenously added sfrp2 interfered with procollagen processing in primary cultures of cardiac fibroblast culture medium. Similar results were obtained when these cells were transiently transfected with sfrp2 expressing plasmids. In summary, our data suggest that one of the molecular mechanisms underlying the cardioprotective and repair effects of sfrp2 protein on myocardial infarction is through the inhibition of BMP-1 activity. Therefore, sfrp2 has the potential clinical application as a novel anti-fibrotic reagent for the modulation of cardiac remodeling after acute myocardial infarction.
The Current State of Efforts to Address Disparities, Racism and Cultural Humility in Medical Education
Authors: Ross E. McKinney, Norma Poll-Hunter, Lisa D. Howley
Journal: The American Journal of Bioethics (2021)

Racism is a complex problem in the US that is institutionalized, personally mediated, and internalized (Jones 2000). Within medical education the recognition and response to structural racism is be...
Oligodendroglial ring finger protein Rnf43 is an essential injury-specific regulator of oligodendrocyte maturation
Authors: Jianqin Niu, Guangdan Yu, Xiaorui Wang, Wenlong Xia, Yuxin Wang, Kimberly K. Hoi, Feng Mei, Lan Xiao, Jonah R. Chan, Stephen P.J. Fancy
Journal: Neuron (2021)

Oligodendrocyte (OL) maturation arrest in human white matter injury contributes significantly to the failure of endogenous remyelination in multiple sclerosis (MS) and newborn brain injuries such as hypoxic ischemic encephalopathy (HIE) that cause cerebral palsy. In this study, we identify an oligodendroglial-intrinsic factor that controls OL maturation specifically in the setting of injury. We find a requirement for the ring finger protein Rnf43 not in normal development but in neonatal hypoxic injury and remyelination in the adult mammalian CNS. Rnf43, but not the related Znrf3, is potently activated by Wnt signaling in OL progenitor cells (OPCs) and marks activated OPCs in human MS and HIE. Rnf43 is required in an injury-specific context, and it promotes OPC differentiation through negative regulation of Wnt signal strength in OPCs at the level of Fzd1 receptor presentation on the cell surface. Inhibition of Fzd1 using UM206 promotes remyelination following ex vivo and in vivo demyelinating injury.
Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer's disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study
Authors: Elisabeth H Thijssen, Renaud La Joie, Amelia Strom, Corrina Fonseca, Leonardo Iaccarino, Amy Wolf, Salvatore Spina, Isabel E Allen, Yann Cobigo, Hilary Heuer, Lawren VandeVrede, Nicholas K Proctor, Argentina Lario Lago, Suzanne Baker, Rajeev Sivasankaran, Agnieszka Kieloch, Arvind Kinhikar, Lili Yu, Marie-Anne Valentin, Andreas Jeromin, Henrik Zetterberg, Oskar Hansson, Niklas Mattsson-Carlgren, Danielle Graham, Kaj Blennow, Joel H Kramer, Lea T Grinberg, William W Seeley, Howard Rosen, Bradley F Boeve, Bruce L Miller, Charlotte E Teunissen, Gil D Rabinovici, Julio C Rojas, Jeffrey L Dage, Adam L Boxer
Journal: The Lancet Neurology (2021)
Abstract 14120: The Natural Flavone Acacetinslows the Development of Atherosclerosis by Sirt3-Mediated Activation of AMPK Signaling Pathway in Diabetic ApoE Null Mice
Authors: Wei-Min Han, Xu-Chang Chen, Yi-Xiang Hong, Hui-Min Wang, Gui-Rong Li, Yan Wang
Journal: Circulation (2019)

Background: It is well recognized that the risk for atherosclerosis is remarkably increased in diabetes mellitus. The present study investigates whether the natural flavone acacetin can slow the de...
Ischaemic tissue released microvesicles induce monocyte reprogramming and increase tissue repair by a tissue factor-dependent mechanism
Authors: Gemma Arderiu, Esther Peña, Lina Badimon
Journal: Cardiovascular Research (2021)

Despite increasing evidence that monocytes may acquire endothelial features, it remains unclear how monocytes participate in angiogenesis after ischaemic damage. We investigated whether ischaemic cells can release microvesicles (MVs) and promote neovascularization in a model of peripheral artery disease (PAD).To model PAD, we used an in vivo experimental model of hind-limb ischaemia (HLI) in mice. MVs were isolated from the ischaemic muscle and from peripheral blood at different times after unilateral femoral artery ligation. MVs were phenotypically characterized to identify cell origin. HLI in mice induced the release of MVs with a much higher content of tissue factor (TF) than non-HLI control mice both in the MVs isolated from the affected limb muscle area and from blood. MVs were mainly released from endothelial cells (ECs) and induced Mo differentiation to endothelial cell-like (ECL) cells. Differentiation to ECL cells encompassed highly strict hierarchical transcription factor activation, initiated by ETS1 activation. MVs secreted by microvascular ECs over-expressing TF (upTF-EMVs), were injected in the ischaemic hind-limb in parallel with control EMVs (from random siRNA-treated cells) or EMVs released by silenced TF ECs. In animals treated with upTF-EMVs in the ischaemic zone, there was a highly significant increase in functional new vessels formation (seen by magnetic resonance angiography), a concomitant increase in the pool of circulating Ly6Clow Mo expressing vascular EC markers, and a significantly higher number of Mo/macrophages surrounding and integrating the newly formed collaterals.Ischaemia-activated ECs release EMVs rich in TF that induce monocyte differentiation into ECL cells and the formation of new vessels in the ischaemic zone. TF by this mechanism of formation of new blood microvessels can contribute to ischaemic tissue repair.
Impact of the First Generation of Children’s Oncology Group Clinical Trials on Clinical Practice for Wilms Tumor
Authors: Jeffrey S. Dome, Elizabeth A. Mullen, David B. Dix, Eric J. Gratias, Peter F. Ehrlich, Najat C. Daw, James I. Geller, Murali Chintagumpala, Geetika Khanna, John A. Kalapurakal, Lindsay A. Renfro, Elizabeth J. Perlman, Paul E. Grundy, Conrad V. Fernandez
Journal: Journal of the National Comprehensive Cancer Network (2021)

Refinements in surgery, radiation therapy, and chemotherapy since the mid-20th century have resulted in a survival rate exceeding 90% for patients with Wilms tumor (WT). Although this figure is remarkable, a significant proportion of patients continue to have event-free survival (EFS) estimates of &lt;75%, and nearly 25% of survivors experience severe chronic medical conditions. The first-generation Children’s Oncology Group (COG) renal tumor trials (AREN ‘0’), which opened to enrollment in 2006, focused on augmenting treatment regimens for WT subgroups with predicted EFS &lt;75% to 80%, including those with the adverse prognostic marker of combined loss of heterozygosity (LOH) at chromosomes 1p/16q, pulmonary metastasis with incomplete lung nodule response after 6 weeks of chemotherapy, bilateral disease, and anaplastic histology. Conversely, therapy was reduced for patient subgroups with good outcomes and potential for long-term toxicity, such as those with lung metastasis with complete lung nodule response after 6 weeks of chemotherapy. This article summarizes the key findings of the first-generation COG renal tumor studies and their implications for clinical practice.
A Commentary on “Crisis management for surgical teams and their leaders, lessons from the COVID-19 pandemic; A structured approach to developing resilience or natural organisational responses” (Int J Surg 2021; 91:105987)
Authors: Mario Fernando Cartagena-Gutiérrez, Frank Jaider Pineda-Trujillo, Jhoan Sebastián Robledo-Arias, Ángela María Forero-Hollmann, Maria Paz Bolaño-Romero
Journal: International Journal of Surgery (2021)
Dual targeting of lymphocyte homing and retention through α4β7 and αEβ7 inhibition in inflammatory bowel disease
Authors: Bingbing Dai, Jason A. Hackney, Ryan Ichikawa, Allen Nguyen, Justin Elstrott, Luz D. Orozco, Kai-Hui Sun, Zora Modrusan, Alvin Gogineni, Alexis Scherl, John Gubatan, Aida Habtezion, Monika Deswal, Ma Somsouk, William A. Faubion, Akiko Chai, Zaineb Sharafali, Azra Hassanali, Young S. Oh, Swati Tole, Jacqueline McBride, Mary E. Keir, Tangsheng Yi
Journal: Cell Reports Medicine (2021)
Physical Activity Patterns and Relationships With Cognitive Function in Patients With Breast Cancer Before, During, and After Chemotherapy in a Prospective, Nationwide Study
Authors: Elizabeth A. Salerno, Eva Culakova, Amber S. Kleckner, Charles E. Heckler, Po-Ju Lin, Charles E. Matthews, Alison Conlin, Lora Weiselberg, Jerry Mitchell, Karen M. Mustian, Michelle C. Janelsins
Journal: Journal of Clinical Oncology (2021)

Physical activity (PA) is a promising intervention for cancer-related cognitive decline, yet research assessing its use during chemotherapy is limited. This study evaluated patterns of PA before, during, and after chemotherapy in patients with breast cancer and the association between PA and cognitive function.
Abstract 14955: The Cost Effectiveness of Mobile Stroke Unit Compared to the Standard Care Ambulance in the United States
Authors: Salin Sriudomporn, Ryan R Nugraha, Nishtha Ahuja, Emmanuel Drabo
Journal: Circulation (2019)

Introduction: Stroke is a leading cause of mortality and the number one cause of morbidity in the United States. Timely administration of thrombolysis, followed by proper supportive care, is critic...
Effect of Training on Peak Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction
Authors: Peter H. Brubaker, Steven J. Keteyian, Wesley J. Tucker
Journal: JAMA (2021)

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 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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
27346 Efficacy and safety from a phase II study of AUR101, a RORγ inhibitor in moderate-to-severe psoriasis (INDUS-2)
Authors: Divyesh Mandavia, Sushil Pande, Suneel Vartak, Shyamal Balki, Shilendra Pandey, Sanjeev Giri, Murali Ramachandra
Journal: Journal of the American Academy of Dermatology (2021)
Changes in Hemodynamic Parameters in Various Morphological Changes in the Kidney Transplant in Children
Authors: M. I. Pykov, D. B. Ektov
Journal: Radiology - Practice (2021)

Ultrasound scanning is one of the main methods of instrumental examination of patients after allogenic transplantation of kidney. The main reasons of dysfunction of the kidney transplant in long posttransplantation term are acute or chronic rejection, as well as acute and chronic nephrotoxicity of calcineurin inhibitors. The study includes an analysis of the medical history of 130 children with end-stage chronic renal failure who underwent 130 allogeneic kidney transplants from a posthumous donor. There were analyzed the results of 231 percutaneous puncture biopsies and ultrasound studies of renal transplants. The analyzed data of morphological studies are divided into 4 groups: 1st group — there are no morphological changes affecting graft function; 2nd group — morphological signs of calcineurin toxicity; 3rd group — borderline damage of the graft; 4th group — acute and chronic graft rejection; 5th group — non-specific tubulointerstitial sclerosis and tubular atrophy. Indices of resistance and pulsation measured at the level of the renal artery and interlobular arteries tended to decrease in the kidneys with immunological influence and remained stable in other morphological groups. This means that, the higher the degree of hyalinosis of the arteries, the lower the indices of resistance and pulsation indices measured at the level of the common renal artery and interlobular arteries. The revealed tendency of a decrease in the values of the resistance index and the pulsation index at the level of the common renal artery of the interlobular arteries can be considered as one of the initial ultrasound signs that allow to speak of a decrease in the elasticity of the vascular wall. Normal indices of renal hemodynamics do not exclude the presence of pathological processes leading to graft dysfunction.
Genome-Wide miRNA Expression Profiling of Molecular Subgroups of Peripheral T-cell Lymphoma
Authors: Waseem Lone, Alyssa Bouska, Sunandini Sharma, Catalina Amador, Mallick Saumyaranjan, Tyler A. Herek, Tayla B. Heavican, Jiayu Yu, Soon Thye Lim, Choon Kiat Ong, Graham W. Slack, Kerry J. Savage, Andreas Rosenwald, German Ott, James R. Cook, Andrew L. Feldman, Lisa M. Rimsza, Timothy W. McKeithan, Timothy C. Greiner, Dennis D. Weisenburger, Federica Melle, Giovanna Motta, Stefano Pileri, Julie M. Vose, Wing C. Chan, Javeed Iqbal
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non–Hodgkin lymphomas with aggressive clinical behavior. We performed comprehensive miRNA profiling in PTCLs and corresponding normal CD4+ Th1/2 and TFH-like polarized subsets to elucidate the role of miRNAs in T-cell lymphomagenesis. Experimental Design: We used nCounter (NanoString Inc) for miRNA profiling and validated using Taqman qRT-PCR (Applied Biosystems, Inc). Normal CD4+ T cells were polarized into effector Th subsets using signature cytokines, and miRNA significance was revealed using functional experiments. Results: Effector Th subsets showed distinct miRNA expression with corresponding transcription factor expression (e.g., BCL6/miR-19b, -106, -30d, -26b, in IL21-polarized; GATA3/miR-155, miR-337 in Th2-polarized; and TBX21/miR-181a, -331-3p in Th1-polarized cells). Integration of miRNA signatures suggested activation of TCR and PI3K signaling in IL21-polarized cells, ERK signaling in Th1-polarized cells, and AKT–mTOR signaling in Th2-polarized cells, validated at protein level. In neoplastic counterparts, distinctive miRNAs were identified and confirmed in an independent cohort. Integrative miRNA–mRNA analysis identified a decrease in target transcript abundance leading to deregulation of sphingolipid and Wnt signaling and epigenetic dysregulation in angioimmunoblastic T-cell lymphoma (AITL), while ERK, MAPK, and cell cycle were identified in PTCL subsets, and decreased target transcript abundance was validated in an independent cohort. Elevated expression of miRNAs (miR-126-3p, miR-145-5p) in AITL was associated with poor clinical outcome. In silico and experimental validation suggest two targets (miR-126→ SIPR2 and miR-145 → ROCK1) resulting in reduced RhoA-GTPase activity and T–B-cell interaction. Conclusions: Unique miRNAs and deregulated oncogenic pathways are associated with PTCL subtypes. Upregulated miRNA-126-3p and miR-145-5p expression regulate RhoA-GTPase and inhibit T-cell migration, crucial for AITL pathobiology.
Early life gut microbiota is associated with rapid infant growth in Hispanics from Southern California
Authors: Tanya L. Alderete, Roshonda B. Jones, Justin P. Shaffer, Elizabeth A. Holzhausen, William B. Patterson, Elham Kazemian, Lida Chatzi, Rob Knight, Jasmine F. Plows, Paige K. Berger, Michael I. Goran
Journal: Gut Microbes (2021)

We aimed to determine if the newborn gut microbiota is an underlying determinant of early life growth trajectories. 132 Hispanic infants were recruited at 1-month postpartum. The infant gut microbiome was characterized using 16S rRNA amplicon sequencing. Rapid infant growth was defined as a weight-for-age z-score (WAZ) change greater than 0.67 between birth and 12-months of age. Measures of infant growth included change in WAZ, weight-for-length z-score (WLZ), and body mass index (BMI) z-scores from birth to 12-months and infant anthropometrics at 12-months (weight, skinfold thickness). Of the 132 infants, 40% had rapid growth in the first year of life. Multiple metrics of alpha-diversity predicted rapid infant growth, including a higher Shannon diversity (OR = 1.83; 95% CI: 1.07–3.29; p = .03), Faith's phylogenic diversity (OR = 1.41, 95% CI: 1.05–1.94; p = .03), and richness (OR = 1.04, 95% CI: 1.01–1.08; p = .02). Many of these alpha-diversity metrics were also positively associated with increases in WAZ, WLZ, and BMI z-scores from birth to 12-months (pall<0.05). Importantly, we identified subsets of microbial consortia whose abundance were correlated with these same measures of infant growth. We also found that rapid growers were enriched in multiple taxa belonging to genera such as Acinetobacter, Collinsella, Enterococcus, Neisseria, and Parabacteroides. Moreover, measures of the newborn gut microbiota explained up to an additional 5% of the variance in rapid growth beyond known clinical predictors (R2 = 0.37 vs. 0.32, p < .01). These findings indicate that a more mature gut microbiota, characterized by increased alpha-diversity, at as early as 1-month of age, may influence infant growth trajectories in the first year of life.
Mast cells in liver disease progression: An update on current studies and implications
Authors: Linh Pham, Lindsey Kennedy, Leonardo Baiocchi, Vik Meadows, Burcin Ekser, Debjyoti Kundu, Tianhao Zhou, Keisaku Sato, Shannon Glaser, Ludovica Ceci, Gianfranco Alpini, Heather Francis
Journal: Hepatology (2021)

Abbreviationsα-SMA = α-smooth muscle actin; ALD = alcoholic liver disease; ALDH1A3 = aldehyde dehydrogenase 1 family, member A3; BDL = bile duct