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Article: An electrophysiological approach to the evaluation of regional sympathetic dysfunction: a proposed classification.

Longmire, David R

2006 Volume 9, Issue 1, Page(s) 69–82

Abstract: Background: The importance to physicians of maintaining a level of understanding of illnesses and their treatment continues to reveal itself in a most striking fashion when it comes to the progressive interest recently directed to disorders of the ... ...

Abstract	Background: The importance to physicians of maintaining a level of understanding of illnesses and their treatment continues to reveal itself in a most striking fashion when it comes to the progressive interest recently directed to disorders of the autonomic nervous system (ANS). In particular, the relevance to pain practitioners of disease states which directly involve the sympathetic portion of the ANS has increased markedly following the international renaming of reflex sympathetic dystrophy (RSD) and causalgia to complex regional pain syndrome (CRPS) Type I and Type II respectively, as well as sympathetically maintained pain (SMP). Subsequently it has become better understood that many other forms of neuropathic pain also demonstrate local abnormalities of the sympathetic nervous supply to the skin within the painful territory, thereby increasing the diagnostic value of these (often subtle) cutaneous clinical signs. Objectives: The objectives of this presentation include (a) a concise review of laboratory tests that are currently used in the evaluation of the autonomic nervous system, (b) a discussion of those procedures that were developed for the assessment of sympathetic sudomotor function, (c) a review of the anatomic pathways subserving those electrophysiological methods for sudomotor testing, and (d) the current diagnostic classification for regional abnormalities of sympathetic sudomotor dysfunction. Methods: Methods used in the preparation of this article have included a review of (a) historic clinical and laboratory articles (or translations thereof) regarding the medical importance of disorders of the autonomic nervous system, dating back to more than 155 years ago (b) anatomic and electrophysiological basis for electroneurodiagnostic sudomotor testing, and (c) the author's proposal for a diagnostic classification of regional sympathetic sudomotor dysfunction.
MeSH term(s)	Autonomic Nervous System Diseases/classification ; Autonomic Nervous System Diseases/physiopathology ; Electrophysiology/methods ; Evaluation Studies as Topic ; Humans
Language	English
Publishing date	2006-01
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2146393-1
ISSN	1533-3159
ISSN	1533-3159
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Article: Exploring Patient Experience of Facial Nerve Palsy to Inform the Development of a PROM.

Norris, Jonathan H / Longmire, Natasha M / Kilcoyne, Sarah / Johnson, David / Fitzpatrick, Ray / Klassen, Anne F

Plastic and reconstructive surgery. Global open

2019 Volume 7, Issue 1, Page(s) e2072

Abstract: Background: There is currently a mandate globally to incorporate patient's perceptions of their illness into outcome measures, in order to provide a deeper insight into medical practice. Facial nerve palsy (FNP) is a devastating condition that can ... ...

Abstract	Background: There is currently a mandate globally to incorporate patient's perceptions of their illness into outcome measures, in order to provide a deeper insight into medical practice. Facial nerve palsy (FNP) is a devastating condition that can significantly impact quality of life. However, no measure currently exists that comprehensively assesses outcome in FNP using patient perception. The aim of this study is to explore patients' experiences of FNP with the aim of informing the development of a patient-reported outcome measure. Methods: Presented is a qualitative study, using in-depth semi-structured interviews with FNP patients. An interview guide was developed using expert opinion and a literature review. Interpretative description was used as the qualitative approach. Interviews were audio-recorded, transcribed, and coded line-by-line. Codes were refined using the constant comparison approach. Interviews continued until data saturation was reached. The data were used to develop a conceptual framework of patient perceived issues relating to FNP. Results: The sample included 5 men and 9 women aged 57.7 years (range, 36-78) with a range of causes of FNP, including Bell's palsy (n = 5), acoustic neuroma (n = 3), trauma (n = 2), meningioma (n = 1), muscular dystrophy (n = 1), congenital (n = 1), and Ramsay Hunt syndrome (n = 1). Analysis of the 14 participant interviews led to identification of 5 major domains including "facial function concerns," "appearance concerns," "psychological function," "social function," and "experience of care." Conclusion: This study provides a conceptual framework covering outcomes that matter to patients with FNP, which can be used to inform the development of a new comprehensive FNP-specific patient-reported outcome measure.
Language	English
Publishing date	2019-01-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	2851682-5
ISSN	2169-7574 ; 2169-7574
ISSN (online)	2169-7574
ISSN	2169-7574
DOI	10.1097/GOX.0000000000002072
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Article: Addition of Fluorine and a Late-Stage Functionalization (LSF) of the Oral SERD AZD9833.

Scott, James S / Moss, Thomas A / Barlaam, Bernard / Davey, Paul R J / Fairley, Gary / Gangl, Eric T / Greenwood, Ryan D R / Hatoum-Mokdad, Holia / Lister, Andrew S / Longmire, David / Polanski, Radoslaw / Stokes, Stephen / Tucker, Michael J / Varnes, Jeffrey G / Yang, Bin

ACS medicinal chemistry letters

2020 Volume 11, Issue 12, Page(s) 2519–2525

Abstract: Herein we describe our efforts using a late stage functionalization together with more traditional synthetic approaches to generate fluorinated analogues of the clinical candidate AZD9833. The effects of the addition of fluorine on the lipophilicity, ... ...

Abstract	Herein we describe our efforts using a late stage functionalization together with more traditional synthetic approaches to generate fluorinated analogues of the clinical candidate AZD9833. The effects of the addition of fluorine on the lipophilicity, permeability, and metabolism are discussed. Many of these changes were tolerated in terms of pharmacology and resulted in high quality molecules which reached advanced stages of profiling in the testing cascade.
Language	English
Publishing date	2020-10-28
Publishing country	United States
Document type	Journal Article
ISSN	1948-5875
ISSN	1948-5875
DOI	10.1021/acsmedchemlett.0c00505
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Article ; Online: Discovery of a Potent and Orally Bioavailable Zwitterionic Series of Selective Estrogen Receptor Degrader-Antagonists.

Scott, James S / Stead, Darren / Barlaam, Bernard / Breed, Jason / Carbajo, Rodrigo J / Chiarparin, Elisabetta / Cureton, Natalie / Davey, Paul R J / Fisher, David I / Gangl, Eric T / Grebe, Tyler / Greenwood, Ryan D / Hande, Sudhir / Hatoum-Mokdad, Holia / Hughes, Samantha J / Hunt, Thomas A / Johnson, Tony / Kavanagh, Stefan L / Klinowska, Teresa C M /

Journal of medicinal chemistry

2023 Volume 66, Issue 4, Page(s) 2918–2945

Abstract: Herein, we report the optimization of a meta-substituted series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer. Structure-based design together with the use of modeling and NMR to favor the bioactive ... ...

Abstract	Herein, we report the optimization of a meta-substituted series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer. Structure-based design together with the use of modeling and NMR to favor the bioactive conformation led to a highly potent series of basic SERDs with promising physicochemical properties. Issues with hERG activity resulted in a strategy of zwitterion formation and ultimately in the identification of
MeSH term(s)	Mice ; Humans ; Animals ; Female ; Receptors, Estrogen/metabolism ; Selective Estrogen Receptor Modulators/pharmacology ; Estrogen Antagonists/therapeutic use ; Breast Neoplasms/drug therapy ; Estrogen Receptor alpha/metabolism ; Cell Line
Chemical Substances	Receptors, Estrogen ; Selective Estrogen Receptor Modulators ; Estrogen Antagonists ; Estrogen Receptor alpha
Language	English
Publishing date	2023-02-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.2c01964
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Article ; Online: Inhibition of MDM2 Promotes Antitumor Responses in p53 Wild-Type Cancer Cells through Their Interaction with the Immune and Stromal Microenvironment.

Cancer research

2021 Volume 81, Issue 11, Page(s) 3079–3091

Abstract: p53 is a transcription factor that plays a central role in guarding the genomic stability of cells through cell-cycle arrest or induction of apoptosis. However, the effects of p53 in antitumor immunity are poorly understood. To investigate the role of ... ...

Abstract	p53 is a transcription factor that plays a central role in guarding the genomic stability of cells through cell-cycle arrest or induction of apoptosis. However, the effects of p53 in antitumor immunity are poorly understood. To investigate the role of p53 in controlling tumor-immune cell cross-talk, we studied murine syngeneic models treated with HDM201, a potent and selective second-generation MDM2 inhibitor. In response to HDM201 treatment, the percentage of dendritic cells increased, including the CD103
MeSH term(s)	Animals ; Apoptosis ; CD8-Positive T-Lymphocytes/immunology ; Cell Proliferation ; Colonic Neoplasms/drug therapy ; Colonic Neoplasms/immunology ; Colonic Neoplasms/metabolism ; Colonic Neoplasms/pathology ; Drug Therapy, Combination ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Imidazoles/pharmacology ; Immune Checkpoint Inhibitors/pharmacology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Mice, Nude ; Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors ; Pyrimidines/pharmacology ; Pyrroles/pharmacology ; Stromal Cells/drug effects ; Stromal Cells/immunology ; Tumor Cells, Cultured ; Tumor Microenvironment/drug effects ; Tumor Microenvironment/immunology ; Tumor Suppressor Protein p53/antagonists & inhibitors ; Xenograft Model Antitumor Assays
Chemical Substances	Imidazoles ; Immune Checkpoint Inhibitors ; Pyrimidines ; Pyrroles ; TP53 protein, human ; Tumor Suppressor Protein p53 ; siremadlin (0282IF4JC8) ; MDM2 protein, human (EC 2.3.2.27) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
Language	English
Publishing date	2021-01-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-20-0189
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Article ; Online: Author Correction: Chromatin accessibility landscapes of skin cells in systemic sclerosis nominate dendritic cells in disease pathogenesis.

Liu, Qian / Zaba, Lisa C / Satpathy, Ansuman T / Longmire, Michelle / Zhang, Wen / Li, Kun / Granja, Jeffrey / Guo, Chuang / Lin, Jun / Li, Rui / Tolentino, Karen / Kania, Gabriela / Distler, Oliver / Fiorentino, David / Chung, Lorinda / Qu, Kun / Chang, Howard Y

Nature communications

2020 Volume 11, Issue 1, Page(s) 6416

Language	English
Publishing date	2020-12-14
Publishing country	England
Document type	Published Erratum
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-020-20411-w
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Article ; Online: Chromatin accessibility landscapes of skin cells in systemic sclerosis nominate dendritic cells in disease pathogenesis.

Nature communications

2020 Volume 11, Issue 1, Page(s) 5843

Abstract: Systemic sclerosis (SSc) is a disease at the intersection of autoimmunity and fibrosis. However, the epigenetic regulation and the contributions of diverse cell types to SSc remain unclear. Here we survey, using ATAC-seq, the active DNA regulatory ... ...

Abstract	Systemic sclerosis (SSc) is a disease at the intersection of autoimmunity and fibrosis. However, the epigenetic regulation and the contributions of diverse cell types to SSc remain unclear. Here we survey, using ATAC-seq, the active DNA regulatory elements of eight types of primary cells in normal skin from healthy controls, as well as clinically affected and unaffected skin from SSc patients. We find that accessible DNA elements in skin-resident dendritic cells (DCs) exhibit the highest enrichment of SSc-associated single-nucleotide polymorphisms (SNPs) and predict the degrees of skin fibrosis in patients. DCs also have the greatest disease-associated changes in chromatin accessibility and the strongest alteration of cell-cell interactions in SSc lesions. Lastly, data from an independent cohort of patients with SSc confirm a significant increase of DCs in lesioned skin. Thus, the DCs epigenome links inherited susceptibility and clinically apparent fibrosis in SSc skin, and can be an important driver of SSc pathogenesis.
MeSH term(s)	Case-Control Studies ; Cell Communication ; Chromatin/genetics ; Chromatin/metabolism ; Epigenome ; Fibrosis ; Genetic Predisposition to Disease ; Humans ; Langerhans Cells/pathology ; Polymorphism, Single Nucleotide ; Regulatory Sequences, Nucleic Acid ; Scleroderma, Systemic/pathology ; Skin/cytology ; Skin/pathology ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transcription Initiation Site
Chemical Substances	Chromatin ; Transcription Factors ; Zbtb46 protein, human
Language	English
Publishing date	2020-11-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-020-19702-z
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Article ; Online: Phase I/II study of the LAG-3 inhibitor ieramilimab (LAG525) ± anti-PD-1 spartalizumab (PDR001) in patients with advanced malignancies.

Schöffski, Patrick / Tan, Daniel S W / Martín, Miguel / Ochoa-de-Olza, María / Sarantopoulos, John / Carvajal, Richard D / Kyi, Chrisann / Esaki, Taito / Prawira, Amy / Akerley, Wallace / De Braud, Filippo / Hui, Rina / Zhang, Tian / Soo, Ross A / Maur, Michela / Weickhardt, Andrew / Krauss, Jürgen / Deschler-Baier, Barbara / Lau, Allen /

Samant, Tanay S / Longmire, Tyler / Chowdhury, Niladri Roy / Sabatos-Peyton, Catherine A / Patel, Nidhi / Ramesh, Radha / Hu, Tiancen / Carion, Ana / Gusenleitner, Daniel / Yerramilli-Rao, Padmaja / Askoxylakis, Vasileios / Kwak, Eunice L / Hong, David S

Journal for immunotherapy of cancer

2022 Volume 10, Issue 2

Abstract: Background: Lymphocyte-activation gene 3 (LAG-3) is an inhibitory immunoreceptor that negatively regulates T-cell activation. This paper presents preclinical characterization of the LAG-3 inhibitor, ieramilimab (LAG525), and phase I data for the ... ...

Abstract	Background: Lymphocyte-activation gene 3 (LAG-3) is an inhibitory immunoreceptor that negatively regulates T-cell activation. This paper presents preclinical characterization of the LAG-3 inhibitor, ieramilimab (LAG525), and phase I data for the treatment of patients with advanced/metastatic solid tumors with ieramilimab ±the anti-programmed cell death-1 antibody, spartalizumab. Methods: Eligible patients had advanced/metastatic solid tumors and progressed after, or were unsuitable for, standard-of-care therapy, including checkpoint inhibitors in some cases. Patients received ieramilimab ±spartalizumab across various dose-escalation schedules. The primary objective was to assess the maximum tolerated dose (MTD) or recommended phase II dose (RP2D). Results: In total, 255 patients were allocated to single-agent ieramilimab (n=134) and combination (n=121) treatment arms. The majority (98%) had received prior antineoplastic therapy (median, 3). Four patients experienced dose-limiting toxicities in each treatment arm across various dosing cohorts. No MTD was reached. The RP2D on a 3-week schedule was declared as 400 mg ieramilimab plus 300 mg spartalizumab and, on a 4-week schedule (once every 4 weeks; Q4W), as 800 mg ieramilimab plus 400 mg spartalizumab; tumor target (LAG-3) suppression with 600 mg ieramilimab Q4W was predicted to be similar to the Q4W, RP2D schedule. Treatment-related adverse events (TRAEs) occurred in 75 (56%) and 84 (69%) patients in the single-agent and combination arms, respectively. Most common TRAEs were fatigue, gastrointestinal, and skin disorders, and were of mild severity; seven patients experienced at least one treatment-related serious adverse event in the single-agent (5%) and combination group (5.8%). Antitumor activity was observed in the combination arm, with 3 (2%) complete responses and 10 (8%) partial responses in a mixed population of tumor types. In the combination arm, eight patients (6.6%) experienced stable disease for 6 months or longer versus six patients (4.5%) in the single-agent arm. Responding patients trended towards having higher levels of immune gene expression, including Conclusions: Ieramilimab was well tolerated as monotherapy and in combination with spartalizumab. The toxicity profile of ieramilimab in combination with spartalizumab was comparable to that of spartalizumab alone. Modest antitumor activity was seen with combination treatment. Trial registration number: NCT02460224.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal, Humanized/pharmacology ; Antibodies, Monoclonal, Humanized/therapeutic use ; Humans ; Immune Checkpoint Inhibitors/pharmacology ; Immune Checkpoint Inhibitors/therapeutic use ; Immunotherapy/methods ; Middle Aged ; Neoplasms/drug therapy ; Young Adult
Chemical Substances	Antibodies, Monoclonal, Humanized ; Immune Checkpoint Inhibitors ; spartalizumab (QOG25L6Z8Z)
Language	English
Publishing date	2022-02-25
Publishing country	England
Document type	Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2021-003776
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Article ; Online: GHOST: global hepatitis outbreak and surveillance technology.

BMC genomics

2017 Volume 18, Issue Suppl 10, Page(s) 916

Abstract: Background: Hepatitis C is a major public health problem in the United States and worldwide. Outbreaks of hepatitis C virus (HCV) infections associated with unsafe injection practices, drug diversion, and other exposures to blood are difficult to detect ...

Abstract	Background: Hepatitis C is a major public health problem in the United States and worldwide. Outbreaks of hepatitis C virus (HCV) infections associated with unsafe injection practices, drug diversion, and other exposures to blood are difficult to detect and investigate. Effective HCV outbreak investigation requires comprehensive surveillance and robust case investigation. We previously developed and validated a methodology for the rapid and cost-effective identification of HCV transmission clusters. Global Hepatitis Outbreak and Surveillance Technology (GHOST) is a cloud-based system enabling users, regardless of computational expertise, to analyze and visualize transmission clusters in an independent, accurate and reproducible way. Results: We present and explore performance of several GHOST implemented algorithms using next-generation sequencing data experimentally obtained from hypervariable region 1 of genetically related and unrelated HCV strains. GHOST processes data from an entire MiSeq run in approximately 3 h. A panel of seven specimens was used for preparation of six repeats of MiSeq libraries. Testing sequence data from these libraries by GHOST showed a consistent transmission linkage detection, testifying to high reproducibility of the system. Lack of linkage among genetically unrelated HCV strains and constant detection of genetic linkage between HCV strains from known transmission pairs and from follow-up specimens at different levels of MiSeq-read sampling indicate high specificity and sensitivity of GHOST in accurate detection of HCV transmission. Conclusions: GHOST enables automatic extraction of timely and relevant public health information suitable for guiding effective intervention measures. It is designed as a virtual diagnostic system intended for use in molecular surveillance and outbreak investigations rather than in research. The system produces accurate and reproducible information on HCV transmission clusters for all users, irrespective of their level of bioinformatics expertise. Improvement in molecular detection capacity will contribute to increasing the rate of transmission detection, thus providing opportunity for rapid, accurate and effective response to outbreaks of hepatitis C. Although GHOST was originally developed for hepatitis C surveillance, its modular structure is readily applicable to other infectious diseases. Worldwide availability of GHOST for the detection of HCV transmissions will foster deeper involvement of public health researchers and practitioners in hepatitis C outbreak investigation.
MeSH term(s)	Algorithms ; Cloud Computing ; Computational Biology/methods ; Disease Outbreaks/statistics & numerical data ; Epidemiological Monitoring ; Hepatitis C/epidemiology ; Humans ; Internationality ; Software ; User-Computer Interface
Language	English
Publishing date	2017-12-06
Publishing country	England
Document type	Journal Article
ISSN	1471-2164
ISSN (online)	1471-2164
DOI	10.1186/s12864-017-4268-3
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Article: The complete genome sequence of Bacillus thuringiensis Al Hakam.

Challacombe, Jean F / Altherr, Michael R / Xie, Gary / Bhotika, Smriti S / Brown, Nancy / Bruce, David / Campbell, Connie S / Campbell, Mary L / Chen, Jin / Chertkov, Olga / Cleland, Cathy / Dimitrijevic, Mira / Doggett, Norman A / Fawcett, John J / Glavina, Tijana / Goodwin, Lynne A / Green, Lance D / Han, Cliff S / Hill, Karen K /

Hitchcock, Penny / Jackson, Paul J / Keim, Paul / Kewalramani, Avinash Ramesh / Longmire, Jon / Lucas, Susan / Malfatti, Stephanie / Martinez, Diego / McMurry, Kim / Meincke, Linda J / Misra, Monica / Moseman, Bernice L / Mundt, Mark / Munk, A Christine / Okinaka, Richard T / Parson-Quintana, B / Reilly, Lee Philip / Richardson, Paul / Robinson, Donna L / Saunders, Elizabeth / Tapia, Roxanne / Tesmer, Judith G / Thayer, Nina / Thompson, Linda S / Tice, Hope / Ticknor, Lawrence O / Wills, Patti L / Gilna, Paul / Brettin, Thomas S

Journal of bacteriology

2007 Volume 189, Issue 9, Page(s) 3680–3681

Abstract: ... Crickmore, J. Van Rie, D. Lereclus, J. Baum, J. Feitelson, D. R. Zeigler, and D. H. Dean, Microbiol. Mol ...

Abstract	Bacillus thuringiensis is an insect pathogen that is widely used as a biopesticide (E. Schnepf, N. Crickmore, J. Van Rie, D. Lereclus, J. Baum, J. Feitelson, D. R. Zeigler, and D. H. Dean, Microbiol. Mol. Biol. Rev. 62:775-806, 1998). Here we report the finished, annotated genome sequence of B. thuringiensis Al Hakam, which was collected in Iraq by the United Nations Special Commission (L. Radnedge, P. Agron, K. Hill, P. Jackson, L. Ticknor, P. Keim, and G. Andersen, Appl. Environ. Microbiol. 69:2755-2764, 2003).
MeSH term(s)	Bacillus thuringiensis/genetics ; Base Sequence ; Genome, Bacterial ; Molecular Sequence Data ; Sequence Analysis, DNA
Language	English
Publishing date	2007-05
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2968-3
ISSN	1098-5530 ; 0021-9193
ISSN (online)	1098-5530
ISSN	0021-9193
DOI	10.1128/JB.00241-07
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