tbuckley/cabot-search huggingface dataset:
Abstract P3-10-09: Gene deletion of IRS1 inhibited IGF-I, insulin and estradiol stimulated MCF-7L breast cancer cell growth
Authors: Xihong Zhang, Douglas Yee
Journal: Cancer Research (2020)

Abstract Targeting of the type I insulin-like growth factor receptor (IGF-IR) has not been successful in breast cancer. Data suggest the highly homologous insulin receptor (IR) may be an alternate growth stimulatory pathway used by cancer cells. Since both receptors phosphorylate the insulin receptor substrate-1 (IRS-1) protein as an immediate consequence of ligand binding, disruption of both receptors could be accomplished by suppression of IRS-1. To test this hypothesis, we created a doxycycline-inducible IRS-1 shRNA lentiviral construct to infect hormone dependent MCF-7 breast cancer cells. IRS-1 shRNA downregulation resulted in decreased responses to IGF-I, insulin, and estradiol in monolayer and anchorage independent growth assays. Decreased IRS-1 levels also suppressed estradiol stimulated gene expression and estrogen receptor binding to DNA. Xenograft growth was also inhibited by induction of IRS-1 shRNA. These data show IRS-1 is a critical regulator of endocrine responsive breast cancer. To further study the critical effects of IRS1 in ER positive breast cancer biology, CRISPR technology was used to delete IRS1 from MCF-7L cells. We analyzed 5 CRISPR IRS1 gene edited clones. Two different commercial available IRS1 antibodies were used to examine IRS1 protein expression. Clones #16, #20 did not show any IRS1 expression, while clones #22, #33 and #38 showed truncated IRS1 expression. IGFIRβ and Insulin R levels were comparable to the parent MCF-7L cells in all the clones, while IRS2 and ERα levels were significantly lower in clone #16. IRS phosphorylation, detected by PY20 antibody, was significantly lower in clone #16. The downstream signaling measured by pAKT and pErk1,2 did not change in all clones compared to those in MCF-7L. In all the clones, ERα ser118 phosphorylation by estradiol stimulation (10 nM) and ERα downregulation by fulvestrant treatment (100 nM) were not affected by IRS1 knockout. IGF-I (5 nM), insulin (10 nM) and estradiol (10 nM) stimulated monolayer cell growth in clone #16 was completely inhibited, while other clones were partially inhibited. In contrast, growth in clone #22 was not inhibited due to extremely high IRS2 expression and compensation. In conclusion, when the IRS1 gene was deleted, multiple growth stimulatory ligands (IGF-I, insulin and estradiol) were inhibited in breast cancer cells. However, IRS-2 compensated for IRS-1 gene deletion in one of the clones we studied. Thus, targeting the IRS proteins may inhibit multiple ligands that cause growth stimulation in ER positive breast cancer therapy. Citation Format: Xihong Zhang, Douglas Yee. Gene deletion of IRS1 inhibited IGF-I, insulin and estradiol stimulated MCF-7L breast cancer cell growth [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-09.
Therapy Response in a Pediatric Patient With Extracutaneous Juvenile Xanthogranuloma Monitored by FDG PET/CT
Authors: Zhe Wen, Hongming Zhuang
Journal: Clinical Nuclear Medicine (2020)

Abstract Juvenile xanthogranuloma, a rare type of non-Langerhans cell histiocytosis, generally manifests as widespread skin lesions, which is often self-limited. However, when other organs are involved, its outcome can be unfavorable, and there is no clearly defined consensus regarding what is the best imaging modality in monitoring the therapy. We report here findings of a series of FDG PET/CT scans during the course of clofarabine therapy in a 12-year-old girl with extracutaneous juvenile xanthogranuloma.
Annals Graphic Medicine - Progress Notes: Sweater
Authors: Michael Natter
Journal: Annals of Internal Medicine (2019)

Web Exclusives16 July 2019Annals Graphic Medicine - Progress Notes: SweaterFREEMichael Natter, MDMichael Natter, MDNYU School of Medicine, New York, New York (M.N.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G19-0035 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: NYU School of Medicine, New York, New York (M.N.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G19-0002.Author/Illustrator Information: Michael Natter, MD, is a current internal medicine resident at NYU School of Medicine and a graduate of Sidney Kimmel Medical College of Thomas Jefferson University in Philadelphia. His artwork is inspired by his medical training, patient encounters, and the human condition. A type 1 diabetic, Dr. Natter views himself as a patient as well as a doctor and plans to pursue a fellowship in endocrinology to help others who also share his disease. You can find more of his illustrations, stories, and comics on Instagram (www.instagram.com/mike.natter) and Twitter (@mike_natter).About Progress Notes: Progress Notes explores the everyday emotional, clinical, humorous, and ethical challenges of the medical residency training process. As implied by the title of the series, these pieces act as a visual bildungsroman, graphically dissecting the subtext of what it means to be a young doctor in today's medical world. Progress Notes appears monthly in Annals Graphic Medicine at Annals.org. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 16 July 2019Volume 171, Issue 2Page: W3-W4KeywordsConflicts of interestDisclosureEmotionsEndocrinologyFellowshipsGraduate medical educationResidency ePublished: 16 July 2019 Issue Published: 16 July 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Abstract 2938: Transmembrane chloride intracellular channel 1 (tmCLIC1) correlates with metastatic potential of colorectal cancer cells
Authors: Valentina Carlini, Francesca Cianci, Ivan Verduci, Michele Mazzanti
Journal: Cancer Research (2019)

Abstract Colorectal cancer (CRC) is the third most common and lethal tumor worldwide. Although CRC can be efficiently eradicated when diagnosed in the early stage, no effective therapies are currently available for advanced metastatic disease. Therefore, targeting metastasis represents a critical challenge for the successful treatment of CRC. To achieve this purpose, our laboratory has found a promising candidate inthe transmembrane localized Chloride Intracellular Channel 1 (tmCLIC1) protein. Growing scientific evidence have suggested an involvement of tmCLIC1 in different human malignancies, including CRC, with an unknown mechanism. CLIC1 is a metamorphic protein able to shuttle between a soluble cytoplasmic and a membrane integrated form, the latter characterized by ionic channel function. In normal cells, it is mostly cytoplasmic and cooperates to the maintenance of several physiological processes. Otherwise, in cancer cells CLIC1 undergoes to chronic membrane insertion, where contributes to the abnormal cellular hyperproliferative rate.In the present investigation, using CRC human cell lines at different stage of tumor development, we demonstrate that tmCLIC1 functional expression correlates with CRC cells increasing aggressiveness, while it is almost absent in normal colon cells. We also show that CLIC1 enrichment in plasma membrane is involved in promotion of CRC metastasis. CLIC1 inhibition using different pharmacological treatments led to drastic reduction of cell proliferation, migration and invasiveness.tmCLIC1 function permits to discriminate between normal and malignant cells and its downregulation is able to arrest metastatic cells. This is not the case of other upregulated proteins not only involved in tumorigenesis but also in physiological cell functions. Since metastasis are considered the leading cause of treatment failure and tumor relapse, CLIC1 inhibition coupled to conventional therapies can represent a novel strategy to successfully treat CRC with reduced side effects. (This work is supported by a GRANT from AIRC to MM) Citation Format: Valentina Carlini, Francesca Cianci, Ivan Verduci, Michele Mazzanti. Transmembrane chloride intracellular channel 1 (tmCLIC1) correlates with metastatic potential of colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2938.
A novel BCMA PBD-ADC with ATM/ATR/WEE1 inhibitors or bortezomib induce synergistic lethality in multiple myeloma
Authors: Lijie Xing, Liang Lin, Tengteng Yu, Yuyin Li, Shih-Feng Cho, Jiye Liu, Kenneth Wen, Phillip A. Hsieh, Krista Kinneer, Nikhil Munshi, Kenneth C. Anderson, Yu-Tzu Tai
Journal: Leukemia (2020)
First cases of coronavirus disease 2019 (COVID-19) in France: surveillance, investigations and control measures, January 2020
Authors: Sibylle Bernard Stoecklin, Patrick Rolland, Yassoungo Silue, Alexandra Mailles, Christine Campese, Anne Simondon, Matthieu Mechain, Laure Meurice, Mathieu Nguyen, Clément Bassi, Estelle Yamani, Sylvie Behillil, Sophie Ismael, Duc Nguyen, Denis Malvy, François Xavier Lescure, Scarlett Georges, Clément Lazarus, Anouk Tabaï, Morgane Stempfelet, Vincent Enouf, Bruno Coignard, Daniel Levy-Bruhl
Journal: Eurosurveillance (2020)

A novel coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) causing a cluster of respiratory infections (coronavirus disease 2019, COVID-19) in Wuhan, China, was identified on 7 January 2020. The epidemic quickly disseminated from Wuhan and as at 12 February 2020, 45,179 cases have been confirmed in 25 countries, including 1,116 deaths. Strengthened surveillance was implemented in France on 10 January 2020 in order to identify imported cases early and prevent secondary transmission. Three categories of risk exposure and follow-up procedure were defined for contacts. Three cases of COVID-19 were confirmed on 24 January, the first cases in Europe. Contact tracing was immediately initiated. Five contacts were evaluated as at low risk of exposure and 18 at moderate/high risk. As at 12 February 2020, two cases have been discharged and the third one remains symptomatic with a persistent cough, and no secondary transmission has been identified. Effective collaboration between all parties involved in the surveillance and response to emerging threats is required to detect imported cases early and to implement adequate control measures.
Africa prepares for coronavirus
Authors: Munyaradzi Makoni
Journal: The Lancet (2020)

Africa prepares for coronavirusWith cases of novel coronavirus spreading worldwide, governments and institutions are getting ready for the first cases in Africa.Munyaradzi Makoni reports from Cape Town.On Jan 30, WHO DirectorGeneral Dr Tedros Adhanom Ghebreyesus declared that the novel coronavirus (2019nCoV) epidemic, centred in China, was a public health emergency of international concern.A large part of WHO's reasoning was that "a global coordinated effort is needed to enhance preparedness in other regions of the world".As cases continue to rise, and spread worldwide, governments and institutions are taking action to prepare for the first patients in Africa."The risk and likelihood of getting an outbreak is very, very high", said Ambrose Talisuna, the WHO Africa team lead for emergency preparedness.As of Feb 11, Africa does not have any confirmed cases, but suspected patients have been quarantined in Ethiopia, Kenya, Côte d'Ivoire, and Botswana.Dr Tedros announced on Feb 5 that a US$675 million prepared ness and response plan covering February to April, 2020, had been initiated by the international community for China and globally to protect states with weaker health systems.WHO has prioritised support for 13 countries on the basis of their close transport links with China: Algeria, Angola, Côte d'Ivoire, the Democratic Republic of the Congo, Ethiopia, Ghana, Kenya, Mauritius, Nigeria, South Africa, Tanzania, Uganda, and Zambia."We all know how fragile health systems [are] in the African continent, they are already overwhelmed by many outbreaks.For us, it is critical to detect coronavirus earlier [so] that we can prevent spreading within communities that can trigger a number of cases that can overwhelm the treatment capacity", said Michel
Anti-Saccharomyces cerevisiae IgG and IgA antibodies are associated with systemic inflammation and advanced disease in hidradenitis suppurativa
Authors: Florence Assan, Jeremy Gottlieb, Florence Tubach, Said Lebbah, Nicolas Guigue, Geoffroy Hickman, Emeline Pape, Marine Madrange, Emmanuel Delaporte, Boualem Sendid, François Aubin, Francis Derouin, Stéphane Bretagne, Pascal Richette, Asma Smahi, Emilie Sbidian, Hervé Bachelez
Journal: Journal of Allergy and Clinical Immunology (2020)
Reported Heroin Use, Use Disorder, and Injection Among Adults in the United States, 2002-2018
Authors: Beth Han, Nora D. Volkow, Wilson M. Compton, Elinore F. McCance-Katz
Journal: JAMA (2020)

This study uses National Surveys on Drug Use and Health data to characterize trends in heroin use, heroin use disorder, and heroin injection overall and by age, race, and geographic region.
Abstract P1-10-25: The prognostic and predictive roles of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio in HER2-negative metastatic breast cancer patients treated with paclitaxel-bevacizumab
Authors: Tomomi Hayashi, Junichiro Watanabe, Shyogo Nakamoto
Journal: Cancer Research (2020)

Abstract Purpose: Many reports have provided real-world evidence that inflammatory response biomarker (IRB) scores may be useful for predicting the therapeutic effect of chemotherapy and the prognosis for various neoplasms. The aim of this retrospective study was to evaluate the clinical roles of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR) as predictive factors of Paclitaxel + Bevacizumab (PB) therapy for patients with HER2-negative metastatic breast cancer (HER2-MBC). Methods: We reviewed the medical records of 123 HER2-MBC patients who underwent PB therapy in our institute. The NLR, PLR, and LMR were calculated from blood cell counts prior to the initiation of PB therapy. The optimal cut-off point of each ratio was determined according to receiver operating characteristic (ROC) curves. The Kaplan-Meier test and Wilcoxon test were used to analyze the progression- free survival (PFS) and overall survival (OS). The differences were considered significant for p &amp;lt; 0.05. Results: The median age at the start of treatment was 53 years old. Of the 123 patients, 98 (80%) were hormone- receptor- positive, and 82 (67%) had multiple (&amp;gt;2) metastatic sites. The median PFS was 7.0 months (95% confidence interval, 5.8-8.4), and the median treatment line before PB therapy was 0 (range: 0-10). The cut-off points of the NLR, PLR, and LMR for the PFS and OS were 2.7, 178, and 3.0, respectively. We found that a high NLR and low LMR were associated with a poor PFS (NLR, median 6.5 vs. 8.4 months, p=0.04: LMR, median 5.6 vs. 8.1 months, p=0.02), and a high LMR was associated with a superior OS (median, not reached vs. 187 months, p=0.02) and 10- year survival rate (76.4% vs. 52.9%, p=0.02). The PLR showed no relationship with the PFS or OS. Conclusion: The NLR and LMR might be independent biomarkers, i.e. predictive factors, for patients with HER2-MBC receiving PB therapy in the real world. A prospective study to confirm the utility of those biomarkers is warranted. Citation Format: Tomomi Hayashi, Junichiro Watanabe, Shyogo Nakamoto. The prognostic and predictive roles of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio in HER2-negative metastatic breast cancer patients treated with paclitaxel-bevacizumab [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-10-25.
PB2271 POMALIDOMIDE‐DEXAMETHASONE IN THE MANAGEMENT OF HEAVILY PRETREATED MULTIPLE MYELOMA
Authors: C. Cerchione, G. Martinelli, D. Nappi, A. E. Pareto, M. Di Perna, K. Ferrara, A. Ferrari, G. Simonetti, F. Pane, L. Catalano
Journal: HemaSphere (2019)

Background: Pomalidomide is a new generation IMID, with a very good compliance, thanks to oral administration, which can be used also in heavily pretreated patients, in a domestic setting. Aims: In this retrospective observational trial, It has been evaluated efficacy and tolerance of pomalidomide plus dexamethasone (PD) as salvage regimen in heavily pretreated patients with relapsed and refractory MM (rrMM), whose prognosis is particularly severe. Methods: 33 patients (19 M/14 F), with rrMM, median age at diagnosis 69 years (r. 52‐84), and median age at start of treatment 76 years (r.56‐89) treated with several lines of treatments (median 7, r. 2‐11), every refractory to all the drugs previously received (also Bortezomib, Thalidomide and Lenalidomide), received Pomalidomide‐Dexamethasone (Pomalidomide 4 mg for 21 days, Dexamethasone 40 mg days 1,8,15,22, pegfilgrastim day +8) every 28 days, until progression. ISS was equally distributed, and cytogenetic at relapse was evaluable in 14 patients. All the patients had previously been treated with schedule containing bortezomib and IMIDs. 60% (20/33) of them had undergone at least to a single ASCT. All patients were relapsed and refractory to last therapies received before PD. Results: Pomalidomide was well tolerated, with grade 3 anemia in 51% (17/33) of patients, 36.3% (12/33) grade 3 neutropenia (pegfilgrastim in primary prophylaxis was given, no hospitalization was required, no septic shocks were observed), 30.3% (10/33) grade 3‐4 thrombocytopenia without hemorrhagic events and transfusion‐dependence. No severe extra‐hematologic toxicity was observed. According to IMWG, ORR1 (≥PR) was 45.4% (15/33: 4 CR, 5 VGPR, 6 PR), but, considering that we are evaluating a cohort of heavily pretreated patients, with poor prognosis, another parameter should be considered, ORR2 (≥SD), considering stable disease as a successful result in progressive MM. ORR2 was 78.7% (26/33: 4 CR, 5 VGPR, 6 PR, 11 SD). These can be considered as impressive result in this subset of patients. Oral treatment gives a really good compliance, in frail and unfit patients, and response, when present, is always really fast (median time to response: 2 months (r.1‐6)), median OS from diagnosis was 92 months (range 21‐234), median OS from start of pomalidomide was 9 months (range 1‐25). Summary/Conclusion: Pomalidomide‐dexamethasone has shown significant efficacy and a very good compliance, thanks to oral administration, in a particularly severe setting of heavily pretreated patients, relapsed and refractory to all available therapeutic resources.
Diagnosis and Treatment of Parkinson Disease
Authors: Melissa J. Armstrong, Michael S. Okun
Journal: JAMA (2020)

<h3>Importance</h3> Parkinson disease is the most common form of parkinsonism, a group of neurological disorders with Parkinson disease–like movement problems such as rigidity, slowness, and tremor. More than 6 million individuals worldwide have Parkinson disease. <h3>Observations</h3> Diagnosis of Parkinson disease is based on history and examination. History can include prodromal features (eg, rapid eye movement sleep behavior disorder, hyposmia, constipation), characteristic movement difficulty (eg, tremor, stiffness, slowness), and psychological or cognitive problems (eg, cognitive decline, depression, anxiety). Examination typically demonstrates bradykinesia with tremor, rigidity, or both. Dopamine transporter single-photon emission computed tomography can improve the accuracy of diagnosis when the presence of parkinsonism is uncertain. Parkinson disease has multiple disease variants with different prognoses. Individuals with a diffuse malignant subtype (9%-16% of individuals with Parkinson disease) have prominent early motor and nonmotor symptoms, poor response to medication, and faster disease progression. Individuals with mild motor-predominant Parkinson disease (49%-53% of individuals with Parkinson disease) have mild symptoms, a good response to dopaminergic medications (eg, carbidopa-levodopa, dopamine agonists), and slower disease progression. Other individuals have an intermediate subtype. For all patients with Parkinson disease, treatment is symptomatic, focused on improvement in motor (eg, tremor, rigidity, bradykinesia) and nonmotor (eg, constipation, cognition, mood, sleep) signs and symptoms. No disease-modifying pharmacologic treatments are available. Dopamine-based therapies typically help initial motor symptoms. Nonmotor symptoms require nondopaminergic approaches (eg, selective serotonin reuptake inhibitors for psychiatric symptoms, cholinesterase inhibitors for cognition). Rehabilitative therapy and exercise complement pharmacologic treatments. Individuals experiencing complications, such as worsening symptoms and functional impairment when a medication dose wears off ("off periods"), medication-resistant tremor, and dyskinesias, benefit from advanced treatments such as therapy with levodopa-carbidopa enteral suspension or deep brain stimulation. Palliative care is part of Parkinson disease management. <h3>Conclusions and Relevance</h3> Parkinson disease is a heterogeneous disease with rapidly and slowly progressive forms. Treatment involves pharmacologic approaches (typically with levodopa preparations prescribed with or without other medications) and nonpharmacologic approaches (such as exercise and physical, occupational, and speech therapies). Approaches such as deep brain stimulation and treatment with levodopa-carbidopa enteral suspension can help individuals with medication-resistant tremor, worsening symptoms when the medication wears off, and dyskinesias.
The surprising complexity of KATP channel biology and of genetic diseases
Authors: Guiling Zhao, Aaron Kaplan, Maura Greiser, W. Jonathan Lederer
Journal: Journal of Clinical Investigation (2020)

The ATP-sensitive K+ channel (KATP) is formed by the association of four inwardly rectifying K+ channel (Kir6.x) pore subunits with four sulphonylurea receptor (SUR) regulatory subunits. Kir6.x or SUR mutations result in KATP channelopathies, which reflect the physiological roles of these channels, including but not limited to insulin secretion, cardiac protection, and blood flow regulation. In this issue of the JCI, McClenaghan et al. explored one of the channelopathies, namely Cantu syndrome (CS), which is a result of one kind of KATP channel mutation. Using a knockin mouse model, the authors demonstrated that gain-of-function KATP mutations in vascular smooth muscle resulted in cardiac remodeling. Moreover, they were able to reverse the cardiovascular phenotypes by administering the KATP channel blocker glibenclamide. These results exemplify how genetic mutations can have an impact on developmental trajectories, and provide a therapeutic approach to mitigate cardiac hypertrophy in cases of CS.