tbuckley/cabot-search huggingface dataset:
Impact of molecular subtype on presenting characteristics of T1a,b tumors
Authors: L. Wiechmann, L. Jacks, S. Patil, M. Stempel, M. Morrow
Journal: Journal of Clinical Oncology (2009)

11111 Background: Gene expression profiling of breast cancers has identified molecular subtypes (Lum A and B, basal, HER2) which impact upon the risk of both local and distant recurrence. There is interest in the impact of molecular subtype on outcome in T1a,bN0M0 tumors, a group thought to have good prognosis and to be amenable to breast conservation. The purpose of this study was to determine if presenting features of T1a,b tumors differ among molecular subtypes. Methods: Subtypes were classified using IHC as Lum A (ER±PR pos, HER2 neg); Lum B: (ER±PR pos, HER2 pos); HER2: (ER+PR neg, HER2 pos); or Basal: ER, PR, and HER2 neg. Data was obtained from a registered database which included patients treated in our institution between 1/98 and 6/07. Of 7906 eligible patients, 6016 were classifiable into molecular subtypes and 1974 tumors (32.8%) measured 10 mm or less. The Chi square test and ANOVA were used for statistical analysis. Results: Data are shown in Table 1 . Patients overexpressing HER2 were significantly younger, had more nodal involvement, multicentric/multifocal (Multi) disease, extensive intraductal component (EIC), and lymphovascular invasion (LVI) (all p&lt;0.0001). On multivariate analysis the HER2 subtype had an odds ratio of 2.5 for Multi versus Lum A/B, but HER 2 was not predictive of nodal status. Conclusions: Even in small breast cancers, presenting features vary with molecular subtype. Unlike Multi, the higher incidence of positive nodes in HER2 patients is explained by traditional prognostic features such as grade, age, and size rather than subtype, suggesting that evaluation of traditional prognostic factors remains valuable in the molecular era. [Table: see text] No significant financial relationships to disclose.
Reward Processing in Children With Disruptive Behavior Disorders and Callous-Unemotional Traits in the ABCD Study
Authors: Samuel W. Hawes, Rebecca Waller, Amy L. Byrd, James M. Bjork, Anthony S. Dick, Matthew T. Sutherland, Michael C. Riedel, Michael J. Tobia, Nicholas Thomson, Angela R. Laird, Raul Gonzalez
Journal: American Journal of Psychiatry (2020)

Objective: Disrupted reward processing is implicated in the etiology of disruptive behavior disorders (DBDs) and callous-unemotional traits. However, neuroimaging investigations of reward processing underlying these phenotypes remain sparse. The authors examined neural sensitivity in response to reward anticipation and receipt among youths with DBDs, with and without callous-unemotional traits. Methods: Data were obtained from the Adolescent Brain and Cognitive Development Study (mean age=9.51 years [SD=0.50]; 49% female). Reward-related activation during the monetary incentive delay task was examined across 16 brain regions, including the amygdala, anterior cingulate cortex (ACC), nucleus accumbens (NAcc), and orbitofrontal cortex (OFC). Latent variable modeling was used to examine network-level coactivation. The following diagnostic groups were compared: typically developing youths (N=693) and youths with DBDs (N=995), subdivided into those with callous-unemotional traits (DBD+CU, N=198) and without callous-unemotional traits (DBD only, N=276). Results: During reward anticipation, youths in the overall DBD group (with and without callous-unemotional traits) showed decreased dorsal ACC activation compared with typically developing youths. The DBD-only group exhibited reduced ventral and dorsal striatal activity compared with the DBD+CU and typically developing groups. During reward receipt, youths with DBDs showed increased cortical (e.g., OFC) and subcortical (e.g., NAcc) regional activation compared with typically developing youths. The DBD+CU group demonstrated greater activation in several regions compared with those in the typically developing (e.g., amygdala) and DBD-only (e.g., dorsal ACC) groups. At the network level, the DBD-only group showed reduced anticipatory reward activation compared with the typically developing and DBD+CU groups, whereas youths in the DBD+CU group showed increased activation during reward receipt compared with those in the typically developing group. Conclusions: These findings advance our understanding of unique neuroetiologic pathways to DBDs and callous-unemotional traits.
New era of trophoblast research: integrating morphological and molecular approaches
Authors: Shingo Io, Eiji Kondoh, Yoshitsugu Chigusa, Kaoru Kawasaki, Masaki Mandai, and Shigehito Yamada
Journal: Human Reproduction Update (2020)

Many pregnancy complications are the result of dysfunction in the placenta. The pathogenic mechanisms of placenta-mediated pregnancy complications, however, are unclear. Abnormal placental development in these conditions begins in the first trimester, but no symptoms are observed during this period. To elucidate effective preventative treatments, understanding the differentiation and development of human placenta is crucial. This review elucidates the uniqueness of the human placenta in early development from the aspect of structural characteristics and molecular markers. We summarise the morphogenesis of human placenta based on human specimens and then compile molecular markers that have been clarified by immunostaining and RNA-sequencing data across species. Relevant studies were identified using the PubMed database and Google Scholar search engines up to March 2020. All articles were independently screened for eligibility by the authors based on titles and abstracts. In particular, the authors carefully examined literature on human placentation. This review integrates the development of human placentation from morphological approaches in comparison with other species and provides new insights into trophoblast molecular markers. The morphological features of human early placentation are described in Carnegie stages (CS), from CS3 (floating blastocyst) to CS9 (emerging point of tertiary villi). Molecular markers are described for each type of trophoblast involved in human placental development. We summarise the character of human trophoblast cell lines and explain how long-term culture system of human cytotrophoblast, both monolayer and spheroid, established in recent studies allows for the generation of human trophoblast cell lines. Due to differences in developmental features among species, it is desirable to understand early placentation in humans. In addition, reliable molecular markers that reflect normal human trophoblast are needed to advance trophoblast research. In the clinical setting, these markers can be valuable means for morphologically and functionally assessing placenta-mediated pregnancy complications and provide early prediction and management of these diseases.
Intra-Articular injection of acid-sensitive stearoxyl-ketal-dexamethasone microcrystals for long-acting arthritis therapy
Authors: Yang Xu, Ziqi Chen, Zunkai Xu, Yanyan Du, Jianghao Han, Xiaoyong Yuan, Shubiao Zhang, Shutao Guo
Journal: Asian Journal of Pharmaceutical Sciences (2020)

Despite advances in treatment of chronic arthritis, there is still a strong need for the development of long-acting formulations that can enable local and sustained drug release at the inflamed tissues. In this work, we fabricated microcrystals of an acid-sensitive stearoxyl-ketal-dexamethasone prodrug for treatment of arthritis. Microcrystals of the prodrug with two sizes were successfully engineered and showed pH-dependent hydrolysis kinetics in vitro. In a collagen-induced arthritis rat model, we evaluated the influence of particle size and injection dose on anti-inflammatory effect after intra-articular injection. Such prodrug demonstrated long-acting anti-arthritis effects with good safety. Our results indicate ketal-based prodrugs are promising for the development of long-acting injectables and may stimulate the development of new treatments for chronic diseases.
PTH-080 Steroids at diagnosis but not mesenteric fat index predicts the need for biologic therapy in treatment naÏve crohn’s diseasepatients: a retrospective cohort study
Authors: IW Reilly, Y Prasad, K Drevelegkas, L Ordas, V Chidambaram, S Subramanian
Journal: Gut (2017)

Introduction  Identification of Crohn’s disease (CD) patients who require early biological and immunosuppressive therapy is essential to target therapy appropriately (1). Clinical predictors of disabling behaviour may point towards early aggressive medical therapy but some of these may not be apparent at diagnosis. Mesenteric fat index (MFI) has been previously shown to predict a complicated disease course in CD (2). In this study, we examined the utility of MFI and other clinical factors in predicting the need for biological and immunosuppressive therapy in CD.  Method  In this retrospective single centre study, we identified therapy naive CD patients who underwent cross sectional imaging at diagnosis at the Royal Liverpool University Hospital between 2005 and 2015. MFI was calculated using previously described methods. Clinical details and need for biological, immunosuppressive and combination therapy was abstracted from the case notes. A logistic regression model was used to examine the utility of clinical factors including MFI in predicting the need for immunosuppressive, biological and combination therapy.  Results  A total of 81 patients were included in the study. In a multivariate model, steroids at diagnosis was associated with the need for subsequent immunosuppressive (Odds ratio, OR, 8.0, 95% CI 1.3–51, p=0.027), anti-TNF (OR 4.3, 95% CI, 1.2–16.5, p=0.029) and combination therapy (OR 3.8, 95% CI, 1.1–13.9, p=0.041). Deep ulcers on colonoscopy was associated with the need for subsequent anti-TNF therapy (OR 14.9, 95% CI, 1.1–209.2, p=0.045) but not immunosuppressive or combination therapy. MFI was not significantly associated with the need for subsequent immunosupression, biological or combination therapy.  Conclusion  Steroids at diagnosis but not MFI predicted the need for subsequent immunosupressive, anti-TNF and combination therapy. Presence of deep ulceration at index colonoscopy was associated with the need for subsequent anti-TNF therapy. Clinicians should consider patients with these characteristics for early aggressive medical therapy.  References  . D’Haens G, Baert F, van Assche G, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet Lond Engl. 2008Feb 23;371(9613):660–7. doi: 10.1016/S0140-6736(08)60304-9  . Erhayiem B, Dhingsa R, Hawkey CJ, Subramanian V. Ratio of Visceral to Subcutaneous Fat Area Is a Biomarker of Complicated Crohn’s Disease. Clin Gastroenterol Hepatol. 2011Aug;9(8):684–7.e1. doi: 10.1016/j.cgh.2011.05.005  Disclosure of Interest  None Declared
Treatment impact on COVID-19 evolution in hemodialysis patients
Authors: Sylvain Chawki, Albert Buchard, Hamza Sakhi, Karim Dardim, Karim El Sakhawi, Mokhtar Chawki, Henri Boulanger, Tomek Kofman, Djamal Dahmane, Philippe Rieu, David Attaf, Salima Ahriz-Saksi, Frederic Besson, Remy Boula, Ali Hafi, Afshin Massoumi, Ali Zineddine Diddaoui, Luc Fromentin, Patrick Michaut, Rachida Nebbad, Jean-François Desassis, Laurence Nicolet, Abderrahmane Ghazali, Julie Sohier-Attias, Larbi Lamriben, Arezki Adem, Emmanuel Dupuis, Mohamad-Khair Rifard, Dominique Joly, Khalil El Karoui, Philippe Attias
Journal: Kidney International (2020)
ANXA1 Binds and Stabilizes EphA2 to Promote Nasopharyngeal Carcinoma Growth and Metastasis
Authors: Juan Feng, Shan-Shan Lu, Ta Xiao, Wei Huang, Hong Yi, Wei Zhu, Songqing Fan, Xue-Ping Feng, Jiao-Yang Li, Zheng-Zheng Yu, Song Gao, Guo-Hui Nie, Yao-Yun Tang, Zhi-Qiang Xiao
Journal: Cancer Research (2020)

Abstract Overexpression of ANXA1 and EphA2 has been linked to various cancers and both proteins have attracted considerable attention for the development of new anticancer drugs. Here we report that ANXA1 competes with Cbl for binding EphA2 and increases its stability by inhibiting Cbl-mediated EphA2 ubiquitination and degradation in nasopharyngeal carcinoma (NPC). Binding of ANXA1 to EphA2 promoted NPC cell growth and metastasis in vitro and in vivo by elevating EphA2 levels and increasing activity of EphA2 oncogenic signaling (pS897-EphA2). Expression of ANXA1 and EphA2 was positively correlated and both were significantly higher in NPC tissues than in the normal nasopharyngeal epithelial tissues. Patients with high expression of both proteins presented poorer disease-free survival and overall survival relative to patients with high expression of one protein alone. Furthermore, amino acid residues 20-30aa and 28-30aa of the ANXA1 N-terminus bound EphA2. An 11 amino acid–long ANXA1-derived peptide (EYVQTVKSSKG) was developed on the basis of this N-terminal region, which disrupted the connection of ANXA1 with EphA2, successfully downregulating EphA2 expression and dramatically suppressing NPC cell oncogenicity in vitro and in mice. These findings suggest that ANXA1 promotes NPC growth and metastasis via binding and stabilization of EphA2 and present a strategy for targeting EphA2 degradation and treating NPC with a peptide. This therapeutic strategy may also be extended to other cancers with high expression of both proteins. Significance: These findings show that EphA2 is a potential target for NPC therapeutics and an ANXA1-derived peptide suppresses NPC growth and metastasis.
Dysbiosis in a canine model of human fistulizing Crohn’s disease
Authors: Ana Maldonado-Contreras, Lluís Ferrer, Caitlin Cawley, Sarah Crain, Shakti Bhattarai, Juan Toscano, Doyle V. Ward, Andrew Hoffman
Journal: Gut Microbes (2020)

Crohn's disease (CD) is a chronic immune-mediated inflammatory condition caused by the loss of mucosal tolerance toward the commensal microbiota. On average, 29.5% and 42.7% CD patients experience perianal complications at 10 and 20 y after diagnosis, respectively. Perianal CD (pCD) result in high disease burden, diminished quality of life, and elevated health-care costs. Overall pCD are predictors of poor long-term outcomes. Animal models of gut inflammation have failed to fully recapitulate the human manifestations of fistulizing CD. Here, we evaluated dogs with spontaneous canine anal furunculosis (CAF), a disease with clinical similarities to pCD, as a surrogate model for understanding the microbial contribution of human pCD pathophysiology.By comparing the gut microbiomes between dogs suffering from CAF (CAF dogs) and healthy dogs, we show CAF-dog microbiomes are either very dissimilar (dysbiotic) or similar (healthy-like), yet unique, to healthy dog's microbiomes. Compared to healthy or healthy-like CAF microbiomes, dysbiotic CAF microbiomes showed an increased abundance of Bacteroides vulgatus and Escherichia coli and a decreased abundance of Megamonas species and Prevotella copri.Our results mirror what have been reported in previous microbiome studies of patients with CD; particularly, CAF dogs exhibited two distinct microbiome composition: dysbiotic and healthy-like, with determinant bacterial taxa such as E. coli and P. copri that overlap what it has been found on their human counterpart. Thus, our results support the use of CAF dogs as a surrogate model to advance our understanding of microbial dynamics in pCD.
An international cohort study of autosomal dominant tubulointerstitial kidney disease due to mutations identifies distinct clinical subtypes
Authors: Martina Živná, Kendrah Kidd, Mohamad Zaidan, Petr Vyleťal, Veronika Barešová, Kateřina Hodaňová, Jana Sovová, Hana Hartmannová, Miroslav Votruba, Helena Trešlová, Ivana Jedličková, Jakub Sikora, Helena Hůlková, Victoria Robins, Aleš Hnízda, Jan Živný, Gregory Papagregoriou, Laurent Mesnard, Bodo B. Beck, Andrea Wenzel, Kálmán Tory, Karsten Häeffner, Matthias T.F. Wolf, Michael E. Bleyer, John A. Sayer, Albert C.M. Ong, Lídia Balogh, Anna Jakubowska, Agnieszka Łaszkiewicz, Rhian Clissold, Charles Shaw-Smith, Raj Munshi, Robert M. Haws, Claudia Izzi, Irene Capelli, Marisa Santostefano, Claudio Graziano, Francesco Scolari, Amy Sussman, Howard Trachtman, Stephane Decramer, Marie Matignon, Philippe Grimbert, Lawrence R. Shoemaker, Christoforos Stavrou, Mayssa Abdelwahed, Neila Belghith, Matthew Sinclair, Kathleen Claes, Tal Kopel, Sharon Moe, Constantinos Deltas, Bertrand Knebelmann, Luca Rampoldi, Stanislav Kmoch, Anthony J. Bleyer
Journal: Kidney International (2020)
The Uncertain Role of Corticosteroids in the Treatment of COVID-19
Authors: Grant B. Ellsworth, Marshall J. Glesby, Roy M. Gulick
Journal: JAMA Internal Medicine (2020)

Chaomin Wu, MD; Xiaoyan Chen, MD; Yanping Cai, MD; Jia'an Xia, MD; Xing Zhou, MD; Sha Xu, MD; Hanping Huang, MD; Li Zhang, MD; Xia Zhou, MD; Chunling Du, MD; Yuye Zhang, BD; Juan Song, BD; Sijiao Wang, BD; Yencheng Chao, MD; Zeyong Yang, MD; Jie Xu, MD; Xin Zhou, MD; Dechang Chen, MD; Weining Xiong, MD; Lei Xu, MD; Feng Zhou, MD; Jinjun Jiang, MD; Chunxue Bai, MD; Junhua Zheng, MD; Yuanlin Song, MD
Dementia prevention, intervention, and care: 2020 report of the Lancet Commission
Authors: Gill Livingston, Jonathan Huntley, Andrew Sommerlad, David Ames, Clive Ballard, Sube Banerjee, Carol Brayne, Alistair Burns, Jiska Cohen-Mansfield, Claudia Cooper, Sergi G Costafreda, Amit Dias, Nick Fox, Laura N Gitlin, Robert Howard, Helen C Kales, Mika Kivimäki, Eric B Larson, Adesola Ogunniyi, Vasiliki Orgeta, Karen Ritchie, Kenneth Rockwood, Elizabeth L Sampson, Quincy Samus, Lon S Schneider, Geir Selbæk, Linda Teri, Naaheed Mukadam
Journal: The Lancet (2020)

should consider dementia in older people without known dementia who have frequent admissions or who develop delirium.Delirium is common in people with dementia and contributes to cognitive decline.In hospital, care including appropriate sensory stimulation, ensuring fluid intake, and avoiding infections might reduce delirium incidence.Acting now on dementia prevention, intervention, and care will vastly improve living and dying for individuals with dementia and their families, and thus society.Research UK, and would like to thank them for financial help.These organisations funded the fares, accommodation, and food for the Commission meeting but had no role
The novel HSP90 inhibitor STA-9090 exhibits activity against Kit dependent and independent malignant mast cell tumors.
Authors: Tzu-Yin Lin, Misty Bear, Kevin Foley, Weiwen Ying, Jim Barsoum, Cheryl London
Journal: Cancer Research (2008)

5638  Mutations that induce ligand-independent activation of the receptor tyrosine kinase Kit are found in several human and canine cancers including gastrointestinal stromal tumors, malignant mast cell disease, and acute myelogenous leukemia. Small molecule Kit inhibitors have been exhibited significant activity in the clinical setting, but they possess variable efficacy against particular forms of mutant Kit, and drug resistance often develops over time. Recently, inhibitors of HSP90, a chaperone for which Kit is a client protein, have demonstrated biologic activity in human cancers and evidence suggests they can efficiently down-regulate several mutated and imatinib-resistant forms of Kit. The purpose of this study was to evaluate a novel HSP90 inhibitor, STA-9090, against wild-type (WT) and mutant Kit in normal canine bone marrow derived cultured mast cells (BMCMCs), malignant canine mast cell lines and fresh malignant canine mast cells cultured ex vivo. Cells were treated with STA-9090, 17-AAG (a geldanamycin analogue), and SU11654 (a small molecule Kit inhibitor) and evaluated for loss of cell viability, cell death, alterations in HSP90 and Kit expression/signaling, and evidence of Kit mutation. STA-9090 activity was also tested in a mastocytoma xenograft model. HSP90 expression levels were found to be similar among the BMCMCs, cell lines and fresh malignant mast cells. Treatment of BMCMCs, cell lines, and fresh malignant cells with STA-9090 induced growth inhibition and apoptosis that was caspase-3 dependent at low nM concentration. STA-9090 down-regulated phospho/total Kit and phospho/total Akt, but not ERK or PI-3 kinase. Loss of Kit cell-surface expression was also observed within 24 hrs of STA-9090 treatment. Furthermore, STA-9090 exhibited superior activity against malignant mast cells compared to 17-AAG or SU11654, and was effective against malignant mast cells expressing either WT or mutant Kit, while SU11654 was effective only against cells expressing mutant Kit. Lastly, STA-9090 inhibited tumor growth in a mastocytoma xenograft model. In summary, STA-9090 exhibits broad activity against mast cells expressing WT or mutant Kit suggesting it may be an effective agent in the clinical setting against Kit-associated malignancies.
How We Manage Patients With Chronic Lymphocytic Leukemia During the SARS‐CoV‐2 Pandemic
Authors: Davide Rossi, Mazyar Shadman, Adalgisa Condoluci, Jennifer R. Brown, John C. Byrd, Gianluca Gaidano, Michael Hallek, Peter Hillmen, Anthony Mato, Emili Montserrat, Paolo Ghia
Journal: HemaSphere (2020)

Abstract Infections are a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). These can be exacerbated by anti‐leukemic treatments. In addition, the typical patients with CLL already have fragilities and background risk factors that apply to the general population for severe COVID‐19. On these bases, patients with CLL may experience COVID‐19 morbidity and mortality. Recurrent seasonal epidemics of SARS‐CoV‐2 are expected, and doctors taking care of patients with CLL must be prepared for the possibility of substantial resurgences of infection and adapt their approach to CLL management accordingly. In this Guideline Article, we aim at providing clinicians with a literature‐informed expert opinion on the management of patients with CLL during SARS‐CoV‐2 epidemic.
Adoptive T Cell Therapy Targeting Different Gene Products Reveals Diverse and Context-Dependent Immune Evasion in Melanoma
Authors: Maike Effern, Nicole Glodde, Matthias Braun, Jana Liebing, Helena N. Boll, Michelle Yong, Emma Bawden, Daniel Hinze, Debby van den Boorn-Konijnenberg, Mila Daoud, Pia Aymans, Jennifer Landsberg, Mark J. Smyth, Lukas Flatz, Thomas Tüting, Tobias Bald, Thomas Gebhardt, Michael Hölzel
Journal: Immunity (2020)
Is multisystem inflammatory syndrome in children on the Kawasaki syndrome spectrum?
Authors: Rae S.M. Yeung, Polly J. Ferguson
Journal: Journal of Clinical Investigation (2020)

An alarming increase in children presenting with fever, hyperinflammation, and multiorgan dysfunction frequently requiring intensive care has been observed after severe acute respiratory syndrome coronavirus 2 infection. The illness resembles Kawasaki disease (KD), with coronary dilatation and aneurysm occurring in some. However, the cardiovascular manifestations were typically on the severe end of the KD spectrum, with cardiogenic shock a common presentation together with other features. This led to defining a unique syndrome named multisystem inflammatory syndrome in children (MIS-C). In this issue of the JCI, Lee and Day-Lewis et al. and Diorio et al. explored the clinical profiles associated with coronavirus disease 2019 in children. We posit that while splitting MIS-C into a separate disease may aid clinical management decisions, lumping it into the KD pot may better serve to understand pathobiology.
Arginine Deprivation Sustains Plasma Cell Fitness Via GCN2: A Novel Immuno-Metabolic Check-Point
Authors: Alessandra Romano, Ugo Orfanelli, Michela Ghizzinardi, Nunziatina Laura Parrinello, Piera La Cava, Todoerti Katia, Laura Oliva, Francesca Paradiso, Floriana Cremasco, Daniele Tibullo, Cesarina Giallongo, Concetta Conticello, Magda Marcatti, Fabio Ciceri, Antonino Neri, Claudio Cerichione, Francesco Di Raimondo, Simone Cenci
Journal: Blood (2017)