tbuckley/cabot-search huggingface dataset:
Response to tyrosine kinase inhibitors in myeloid neoplasms associated with <scp><i>PCM1</i>‐<i>JAK2</i></scp>, <scp><i>BCR‐JAK2</i></scp> and <scp><i>ETV6‐ABL1</i></scp> fusion genes
Authors: Juliana Schwaab, Nicole Naumann, Johannes Luebke, Mohamad Jawhar, Tim C.P. Somervaille, Mark S. Williams, Rebecca Frewin, Philipp J. Jost, Felix S. Lichtenegger, Paul La Rosée, Nicola Storch, Torsten Haferlach, Hans‐Peter Horny, Alice Fabarius, Claudia Haferlach, Andreas Burchert, Wolf‐Karsten Hofmann, Nicholas C.P. Cross, Andreas Hochhaus, Andreas Reiter, Georgia Metzgeroth
Journal: American Journal of Hematology (2020)

We report on 18 patients with myeloid neoplasms and associated tyrosine kinase (TK) fusion genes on treatment with the TK inhibitors (TKI) ruxolitinib (PCM1-JAK2, n = 8; BCR-JAK2, n = 1) and imatinib, nilotinib or dasatinib (ETV6-ABL1, n = 9). On ruxolitinib (median 24 months, range 2-36 months), a complete hematologic response (CHR) and complete cytogenetic response (CCR) was achieved by five of nine and two of nine patients, respectively. However, ruxolitinib was stopped in eight of nine patients because of primary resistance (n = 3), progression (n = 3) or planned allogeneic stem cell transplantation (allo SCT, n = 2). At a median of 36 months (range 4-78 months) from diagnosis, five of nine patients are alive: four of six patients after allo SCT and one patient who remains on ruxolitinib. In ETV6-ABL1 positive patients, a durable CHR was achieved by four of nine patients (imatinib with one of five, nilotinib with two of three, dasatinib with one of one). Because of inadequate efficacy (lack of hematological and/or cytogenetic/molecular response), six of nine patients (imatinib, n = 5; nilotinib, n = 1) were switched to nilotinib or dasatinib. At a median of 23 months (range 3-60 months) from diagnosis, five of nine patients are in CCR or complete molecular response (nilotinib, n = 2; dasatinib, n = 2; allo SCT, n = 1) while two of nine patients have died. We conclude that (a) responses on ruxolitinib may only be transient in the majority of JAK2 fusion gene positive patients with allo SCT being an important early treatment option, and (b) nilotinib or dasatinib may be more effective than imatinib to induce durable complete remissions in ETV6-ABL1 positive patients.
Discrete functional and mechanistic roles of chromodomain Y-like 2 (CDYL2) transcript variants in breast cancer growth and metastasis
Authors: Li-Feng Yang, Fan Yang, Fang-Lin Zhang, Yi-Fan Xie, Zhi-Xiang Hu, Sheng-Lin Huang, Zhi-Min Shao, Da-Qiang Li
Journal: Theranostics (2020)

Rationale: Chromodomain Y-like 2 (CDYL2) is a member of the CDY gene family involved in spermatogenesis, but its role in human cancer has not been reported.Analyses of publicly available databases demonstrate that CDYL2 is abundantly expressed in breast tumors.However, whether CDYL2 is involved in breast cancer progression remains unknown.Methods: Quantitative real-time PCR and immunoblotting assays were used to determine the expression levels of CDYL2 transcript variants in breast cancer cell lines and primary breast tumors.The effect of CDYL2 transcript variants on the malignant phenotypes of breast cancer cells was examined through in vitro and in vivo assays.Immunofluorescent staining, RNA-seq, ATAC-seq, and ChIP-qPCR were used to investigate the underlying mechanisms behind the aforementioned observations.Results: Here we show that CDYL2 generated four transcript variants, named CDYL2a-CDYL2d.CDYL2a and CDYL2b were the predominant variants expressed in breast cancer cell lines and breast tumors and exerted strikingly discrete functions in breast cancer growth and metastasis.CDYL2a was upregulated in the majority of the breast cancer cell lines and tumors, and promoted breast cancer cell proliferation, colony formation in vitro, and tumorigenesis in xenografts.In contrast, CDYL2b was mainly expressed in luminal-and HER2-positive types of breast cancer cell lines and tumors, and suppressed the migratory, invasive, and metastatic potential of breast cancer cells in vitro and in vivo.Mechanistically, CDYL2a partially localized to SC35-positive nuclear speckles and promoted alternative splicing of a subset of target genes, including FIP1L1, NKTR, and ADD3 by exon skipping.Elimination of full-length FIP1L1, NKTR, and ADD3 rescued the impaired cell proliferation through CDYL2a depletion.In contrast, CDYL2b localized to heterochromatin and transcriptionally repressed several metastasis-promoting genes, including HPSE, HLA-F, and SELL.Restoration of HPSE, HLA-F, or SELL expression in CDYL2b-overexpressing cells attenuated the ability of CDYL2b to suppress breast cancer cell migration and invasion.Conclusions: Collectively, these findings establish an isoform-specific function of CDYL2 in breast cancer development and progression and highlight that pharmacological inhibition of the CDYL2a, but not the CDYL2b, isoform may be an effective strategy for breast cancer therapy.
“Starry Sky” Appearance from Multiple Biliary Hamartomas
Authors: Takafumi Taguchi, Takuhiro Kohsaki
Journal: New England Journal of Medicine (2020)

A 45-year-old woman presented with an incidental finding of multiple small lesions in the liver. Magnetic resonance imaging with cholangiopancreatography revealed a “starry sky” appearance, consistent with a diagnosis of multiple biliary hamartomas.
DNA Topoisomerase IIα (TOP2A) inhibitors doxorubicin and etopoxide (VP-16) up-regulate Fatty Acid Synthase (FAS) gene expression in SK-Br3 breast cancer cells: In vitro evidence for a “functional amplicon” involving FAS, Her-2/neu and TOP2A genes
Authors: Javier A. Menendez, Luciano Vellon, Eva Horak, Ruth Lupu
Journal: Cancer Research (2005)

3540  Fatty Acid Synthase (FAS), the key metabolic multi-enzyme that is responsible for the terminal catalytic step in the de novo fatty acid biosynthesis, plays an active role in the development, maintenance, and enhancement of the malignant phenotype of breast carcinomas. We recently described that a molecular bi-directional cross-talk between FAS and the Her-2/neu (erbB-2) oncogene is taking place at the level of transcription, translation, and activity in breast cancer cells. Because Her-2/neu has been linked with altered sensitivity to cytotoxic drugs, we envisioned that FAS expression may represent a novel predictive molecular factor for breast cancer response to chemotherapy in a Her-2/neu-related manner. Here, we evaluated whether chemotherapy-induced cell damage may act in an epigenetic fashion by inducing changes in the transcriptional activation of FAS gene in breast carcinoma cells. To evaluate this option, FAS- and Her-2/neu-overexpressing SK-Br3 breast cancer cells were transiently transfected with a FAS promoter-reporter construct (FAS-Luciferase) harboring all the elements necessary for high level expression in cancer cells. Interestingly, SK-Br3 cells cultured in the presence of topoisomerase II-alpha (TOP2A) inhibitors doxorubicin and etopoxide (VP-16) demonstrated a significant 2- to 3-fold increase in FAS promoter activity when compared with control cells grown in drug-free culture conditions. We failed to observe any significant activation of FAS promoter following exposure to 5-fluorouracil (5-FU), cisplatin (CDDP), paclitaxel (PTX) or vincristine (VCR). Moreover, the up-regulatory effects of TOP2A inhibitors on the transcriptional activation of FAS gene expression were not significantly decreased when the FAS promoter was damaged at the SREBP-binding site. Considering that FAS inhibition produces profound inhibition of DNA replication and S-phase progression in cancer cells, we finally asked whether a cross-talk between TOP2A and FAS could exhibit a Her-2/neu-related bi-directional nature. TOP2A protein levels decreased during treatment with the anti-Her-2/neu antibody trastuzumab while, concomitantly, FAS promoter activity and FAS protein levels were significantly reduced. Interestingly, when the expression levels of TOP2A protein were analyzed following exposure of SK-Br3 cells to increasing concentrations of C75, a novel slow-binding inhibitor of FAS activity, a dose-dependent reduction in TOP2A protein expression was observed. Although FAS gene is not physically located in the Her-2/neu-TOP2A amplicon, our present findings strongly suggest that a tight functional association between FAS, Her-2/neu and TOP2A genes is taking place in a subset of breast carcinomas cells.
Enteric involvement in hospitalised patients with COVID-19 outside Wuhan
Authors: Yunle Wan, Jie Li, Lihan Shen, Yifeng Zou, Linlin Hou, Lixin Zhu, Howard S Faden, Zhipeng Tang, Mang Shi, Na Jiao, Yichen Li, Sijing Cheng, Yibo Huang, Dingfeng Wu, Zhifeng Xu, Linnuo Pan, Jun Zhu, Guangjun Yan, Ruixin Zhu, Ping Lan
Journal: The Lancet. Gastroenterology & hepatology (2020)
Results from a Phase 1/2 Study of INCB050465, a Highly Selective and Highly Potent PI3Kδ Inhibitor, in Patients with Relapsed or Refractory B-Cell Malignancies (CITADEL-101)
Authors: Andres Forero-Torres, Rod Ramchandren, Abdulraheem Yacoub, Michael S. Wertheim, William J. Edenfield, Paolo Caimi, Martin Gutierrez, Luke Akard, Carolina Escobar, Justin Call, Daniel Persky, Swami P. Iyer, Douglas J. DeMarini, Li Zhou, Swamy Yeleswaram, Tycel J. Phillips
Journal: Blood (2017)
Human CD8 T cells are susceptible to TNF-mediated activation-induced cell death
Authors: Itziar Otano, Maite Alvarez, Luna Minute, María Carmen Ochoa, Itziar Migueliz, Carmen Molina, Arantza Azpilikueta, Carlos E. de Andrea, Iñaki Etxeberria, Miguel F. Sanmamed, Álvaro Teijeira, Pedro Berraondo, Ignacio Melero
Journal: Theranostics (2020)

Activation-induced cell death (AICD) is a complex immunoregulatory mechanism that causes the demise of a fraction of T-lymphocytes upon antigen-driven activation.In the present study we investigated the direct role of TNF in AICD of CD8 T lymphocytes.Methods: Human peripheral mononuclear cells were isolated from healthy donors and fresh tumor-infiltrating lymphocytes were obtained from cancer patients undergoing surgery.T cells were activated with anti-CD3/CD28 mAbs or with a pool of virus peptides, in combination with clinicalgrade TNF blocking agents.Results: A portion of CD8 T cells undergoes apoptosis upon CD3/CD28 activation in a manner that is partially prevented by the clinically used anti-TNF agents infliximab and etanercept.TNF-mediated AICD was also observed upon activation of virus-specific CD8 T cells and tumor-infiltrating CD8 T lymphocytes.The mechanism of TNF-driven T cell death involves TNFR2 and production of mitochondrial oxygen free radicals which damage DNA. Conclusion:The use of TNF blocking agents reduces oxidative stress, hyperpolarization of mitochondria, and the generation of DNA damage in CD8 T celss undergoing activation.The fact that TNF mediates AICD in human tumor-reactive CD8 T cells suggests that the use of TNF-blocking agents can be exploited in immunotherapy strategies.
The global significance of PRISm: how data from low- and middle-income countries link physiology to inflammation
Authors: Sara R.A. Wijnant, Lies Lahousse, Guy G. Brusselle
Journal: European Respiratory Journal (2020)

<b>Subjects with PRISm represent a heterogeneous population encompassing distinct phenotypes with distinct risk factors. A spectrum of mechanisms and risk factors contribute to varying degrees to the pathogenesis of PRISm in different populations.</b>http://bit.ly/2TkHJjK
Redirecting extracellular proteases to molecularly guide radiosensitizing drugs to tumors
Authors: Dina V. Hingorani, Jessica L. Crisp, Matthew K. Doan, Maria F. Camargo, Maryam A. Quraishi, Joseph Aguilera, Mara Gilardi, Larry A. Gross, Tao Jiang, Wei T. Li, Weg M. Ongkeko, Ezra E.W. Cohen, J. Silvio Gutkind, Stephen R. Adams, Sunil J. Advani
Journal: Biomaterials (2020)

Patients with advanced cancers are treated with combined radiotherapy and chemotherapy, however curability is poor and treatment side effects severe. Drugs sensitizing tumors to radiotherapy have been developed to improve cell kill, but tumor specificity remains challenging. To achieve tumor selectivity of small molecule radiosensitizers, we tested as a strategy active tumor targeting using peptide-based drug conjugates. We attached an inhibitor of the DNA damage response to antibody or cell penetrating peptides. Antibody drug conjugates honed in on tumor overexpressed cell surface receptors with high specificity but lacked efficacy when conjugated to the DNA damage checkpoint kinase inhibitor AZD7762. As an alternative approach, we synthesized activatable cell penetrating peptide scaffolds that accumulated within tumors based on matrix metalloproteinase cleavage. While matrix metalloproteinases are integral to tumor progression, they have proven therapeutically elusive. We harnessed these pro-tumorigenic extracellular proteases to spatially guide radiosensitizer drug delivery using cleavable activatable cell penetrating peptides. Here, we tested the potential of these two drug delivery platforms targeting distinct tumor compartments in combination with radiotherapy and demonstrate the advantages of protease triggered cell penetrating peptide scaffolds over antibody drug conjugates to deliver small molecule amine radiosensitizers.
What kind of rationalization is system justification?
Authors: Kristin Laurin, William M. Jettinghoff
Journal: Behavioral and Brain Sciences (2020)

Abstract Cushman uses rationalization to refer to people's explanations for their own actions. In system justification theory, scholars use the same term to refer to people's efforts to cast their current status quo in an exaggeratedly positive light. We try to reconcile these two meanings, positing that system justification could result from people trying to explain their own failure to take action to combat inequality. We highlight two novel and contested predictions emerging from this interpretation.
Adenopathy and extensive skin patch overlying a plasmacytoma ( <scp>AESOP</scp> ) syndrome: erythrocyanotic vascular patches associated with an underlying rib plasmacytoma
Authors: T.P. Afra, R. Namitha, A. Khader, A. Bishnoi, D.K. Shahul Hameed, M. Razmi T
Journal: British Journal of Dermatology (2020)

Journal Article Adenopathy and extensive skin patch overlying a plasmacytoma (AESOP) syndrome: erythrocyanotic vascular patches associated with an underlying rib plasmacytoma Get access T.P. Afra, T.P. Afra Department of Dermatology, IQRAA Aesthetics IQRAA International Hospital and Research Centre Calicut Kerala India https://orcid.org/0000-0002-9024-6842 Search for other works by this author on: Oxford Academic Google Scholar R. Namitha, R. Namitha Department of Pulmonology IQRAA International Hospital and Research Centre Calicut Kerala India Search for other works by this author on: Oxford Academic Google Scholar A. Khader, A. Khader Department of Pathology IQRAA International Hospital and Research Centre Calicut Kerala India Search for other works by this author on: Oxford Academic Google Scholar A. Bishnoi, A. Bishnoi Department of Dermatology, Venereology and Leprology Postgraduate Institute of Medical Education and Research Sector 12 Chandigarh 160012 India https://orcid.org/0000-0002-1165-1103 Search for other works by this author on: Oxford Academic Google Scholar D.K. Shahul Hameed, D.K. Shahul Hameed Department of Radiology IQRAA International Hospital and Research Centre Calicut Kerala India Search for other works by this author on: Oxford Academic Google Scholar M. Razmi T M. Razmi T Department of Dermatology, IQRAA Aesthetics IQRAA International Hospital and Research Centre Calicut Kerala India Correspondence: Muhammed Razmi T. Email: dr.razmi.t@gmail.com https://orcid.org/0000-0002-2532-1076 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 183, Issue 2, 1 August 2020, Page e33, https://doi.org/10.1111/bjd.19037 Published: 01 August 2020
Maintaining the Quality Standards of Care for Inflammatory Bowel Disease Patients During the COVID-19 Pandemic
Authors: Mariangela Allocca, Gionata Fiorino, Federica Furfaro, Daniela Gilardi, Simona Radice, Ferdinando D’Amico, Alessandra Zilli, Silvio Danese
Journal: Clinical Gastroenterology and Hepatology (2020)

Since February 20, 2020, the SARS-COV2 infection has spread in Lombardy, and in the rest of the Italian regions, forcing our government to impose a national lockdown.1 Hospitals have been forced to adapt and to restructure their units to cope with this urgent new critical situation.2 Alternative solutions have been found to manage patients with inflammatory bowel disease (IBD), including remote monitoring, drug home delivery, limitations for infusion units, and patient education on measures to prevent infection,3 to maintain high-quality care.4.
Mechanism of Eccentric Cardiomyocyte Hypertrophy Secondary to Severe Mitral Regurgitation
Authors: Shujuan Li, Ngoc Uyen Nhi Nguyen, Feng Xiao, Ivan Menendez-Montes, Yuji Nakada, Wilson Lek Wen Tan, Chukwuemeka George Anene-Nzelu, Roger S. Foo, Suwannee Thet, Alisson Campos Cardoso, Ping Wang, Waleed M. Elhelaly, Nicholas T. Lam, Ana Helena Macedo Pereira, Joseph A. Hill, Hesham A. Sadek
Journal: Circulation (2020)

Primary valvular heart disease is a prevalent cause of morbidity and mortality in both industrialized and developing countries. Although the primary consequence of valvular heart disease is myocardial dysfunction, treatment of valvular heart diseases centers around valve repair or replacement rather than prevention or reversal of myocardial dysfunction. This is particularly evident in primary mitral regurgitation (MR), which invariably results in eccentric hypertrophy and left ventricular (LV) failure in the absence of timely valve repair or replacement. The mechanism of LV dysfunction in primary severe MR is entirely unknown.Here, we developed the first mouse model of severe MR. Valvular damage was achieved by severing the mitral valve leaflets and chords with iridectomy scissors, and MR was confirmed by echocardiography. Serial echocardiography was performed to follow up LV morphology and systolic function. Analysis of cardiac tissues was subsequently performed to evaluate valve deformation, cardiomyocyte morphology, LV fibrosis, and cell death. Finally, dysregulated pathways were assessed by RNA-sequencing analysis and immunofluorescence.In the ensuing 15 weeks after the induction of MR, gradual LV dilatation and dysfunction occurred, resulting in severe systolic dysfunction. Further analysis revealed that severe MR resulted in a marked increase in cardiac mass and increased cardiomyocyte length but not width, with electron microscopic evidence of sarcomere disarray and the development of sarcomere disruption. From a mechanistic standpoint, severe MR resulted in activation of multiple components of both the mammalian target of rapamycin and calcineurin pathways. Inhibition of mammalian target of rapamycin signaling preserved sarcomeric structure and prevented LV remodeling and systolic dysfunction. Immunohistochemical analysis uncovered a differential pattern of expression of the cell polarity regulator Crb2 (crumbs homolog 2) along the longitudinal axis of cardiomyocytes and close to the intercalated disks in the MR hearts. Electron microscopy images demonstrated a significant increase in polysome localization in close proximity to the intercalated disks and some areas along the longitudinal axis in the MR hearts.These results indicate that LV dysfunction in response to severe MR is a form of maladaptive eccentric cardiomyocyte hypertrophy and outline the link between cell polarity regulation and spatial localization protein synthesis as a pathway for directional cardiomyocyte growth.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is likely to be androgen mediated
Authors: Carlos Gustavo Wambier, Andy Goren
Journal: Journal of the American Academy of Dermatology (2020)

Coronavirus disease 2019 (COVID-19) pandemic fatalities are rare before adrenarche/puberty (<10 years of age), and the vulnerability of males to severe disease1Shi Y. Yu X. Zhao H. Wang H. Zhao R. Sheng J. Host susceptibility to severe COVID-19 and establishment of a host risk score: findings of 487 cases outside Wuhan.Crit Care. 2020; 24: 108Crossref PubMed Scopus (344) Google Scholar has been constantly reported over the past months of pandemic. The first biologic step required for potential infectivity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the priming of the spike proteins by transmembrane protease, serine 2 (TMPRSS2). Although other proteases have been described to activate the spikes in vitro, only TMPRSS2 activity is regarded as essential for viral spread and pathogenesis in the infected hosts.2Hoffmann M. Kleine-Weber H. Schroeder S. et al.SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; : 1-10Google Scholar TMPRSS2 may also cleave angiotensin converting enzyme 2 (ACE2) for augmented viral entry.3Heurich A. Hofmann-Winkler H. Gierer S. Liepold T. Jahn O. Pohlmann S. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein.J Virol. 2014; 88: 1293-1307Crossref PubMed Scopus (650) Google Scholar Androgen receptor activity has been considered a requirement for the transcription of the TMPRSS2 gene because no other known TMPRSS2 gene promoter has been described in humans to date.4Lucas J.M. Heinlein C. Kim T. et al.The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis.Cancer Discov. 2014; 4: 1310-1325Crossref PubMed Scopus (349) Google Scholar,5National Institutes of HealthTMPRSS2 transmembrane serine protease 2 [Homo sapiens (human)] Gene ID: 7113.https://www.ncbi.nlm.nih.gov/gene/7113Date accessed: April 2, 2020Google Scholar Male vulnerability may be further enhanced by X-linked inheritance of genetic polymorphisms (androgen receptor and ACE2 genes loci are in chromosome X). Obvious dermatologic signs of hyperactivation of androgen receptors are pattern reduction of density of scalp hair, increased density of facial and chest hair, acne, and oily skin. Theoretically, the hyperandrogenic phenotype might correlate with COVID-19 increased viral load, increased viral dissemination, and severity of lung involvement (Infographic 1). Studies are still required for epidemiologic conclusions. Acknowledging the importance of androgens during the COVID-19 pandemic may offer another targeted therapy for trials, with androgen suppression to reduce host vulnerability when infection risk is high.
Locoregional Therapy Plus Systemic Chemotherapy in Unresectable Intrahepatic Cholangiocarcinoma
Authors: Xu Yang, Jie Pan, Haitao Zhao
Journal: JAMA Oncology (2020)

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