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Article ; Online: Lymphocytic thrombophilic arteritis: A distinct inflammatory type I interferon and C5b-9 mediated subcutaneous endovasculitis.

Magro, Cynthia M / Saab, Jad

2017 Volume 31, Page(s) 23–29

Abstract: Background: Lymphocytic thrombophilic arteritis is a recently recognized subcuticular larger vessel vasculitis characterized by striking vascular luminal thrombosis.: Methods: The clinical features, histopathology and phenotypic profile of ten ... ...

Abstract	Background: Lymphocytic thrombophilic arteritis is a recently recognized subcuticular larger vessel vasculitis characterized by striking vascular luminal thrombosis. Methods: The clinical features, histopathology and phenotypic profile of ten patients with lymphocytic thrombophilic arteritis were explored in an attempt to better define the entity from a clinical and pathophysiologic perspective. Results: The patients were all female (mean age of 43) presenting with generally asymptomatic lower and upper extremity hyperpigmented macules. A consistent picture diagnostic of a connective tissue disease syndrome was not seen. The disease was not progressive although it was typically persistent. The morphology was characterized by a temporally heterogeneous subcutaneous arteritis targeting the endothelium and intima with changes ranging from incipient intimal expansion by hyaluronic acid to concentric intimal fibrin deposition to one of an end stage acellular intraluminal obliterative fibrous arteriopathy. The infiltrate was predominated by lymphocytes and histiocytes. The intimal elastic lamina was intact in most cases. All tested cases showed intimal and endothelial C5b-9 deposition, an upregulated type I interferon microenvironment and marked upregulation of the inducible interferon gamma 16 protein. Conclusions: Lymphocytic thrombophilic arteritis is a unique form of C5b-9 mediated arteritic endotheliopathy where the brunt of the changes involves the endothelium and intima and that is morphologically distinct from the transmural arteritis of benign cutaneous polyarteritis nodosa.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Arteritis/metabolism ; Arteritis/pathology ; Complement Membrane Attack Complex/metabolism ; Female ; Humans ; Inflammation/metabolism ; Inflammation/pathology ; Interferon Type I/metabolism ; Lymphocytes/pathology ; Middle Aged ; Subcutaneous Tissue/metabolism ; Subcutaneous Tissue/pathology
Chemical Substances	Complement Membrane Attack Complex ; Interferon Type I
Language	English
Publishing date	2017-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	1440011-x
ISSN	1532-8198 ; 1092-9134
ISSN (online)	1532-8198
ISSN	1092-9134
DOI	10.1016/j.anndiagpath.2017.06.002
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Article ; Online: Enhanced cutaneous Rock2 expression as a marker of Rho Kinase pathway activation in autoimmune disease and Kohlemeier-Degos disease.

Magro, Cynthia / Schwartz, Ziv / Saab, Jad / Hedayat, Amin

Annals of diagnostic pathology

2019 Volume 44, Page(s) 151414

Abstract: The small guanosine triphosphatase Rho and its target Rho kinase are involved in a heterogeneous spectrum of cellular activities, many of which are integral to cytoskeletal organization. Furthermore, the Rho kinases result in NF kappa beta activation and ...

Abstract	The small guanosine triphosphatase Rho and its target Rho kinase are involved in a heterogeneous spectrum of cellular activities, many of which are integral to cytoskeletal organization. Furthermore, the Rho kinases result in NF kappa beta activation and hence the induction of various pro-inflammatory cytokines including TNF-alpha, IL-1B and IL-6. ROCK2 is a downstream protein, whose expression is indicative of Rho Kinase activation. Given the diverse effects of Rho-kinase, including a potentially critical role in augmenting inflammation, ROCK2 expression was examined in biopsies of select autoimmune connective tissue diseases as compared to control diagnoses. Select cases of lupus erythematosus, dermatomyositis, autoimmune sclerodermoid disorders and Kohlmeier-Degos disease (a distinctive vasculopathy that occurs in the other aforesaid conditions but also as a forme fruste microvascular and arteriopathic syndrome) were studied. Control biopsies included normal skin and cutaneous inflammatory conditions unrelated to collagen vascular disease/autoimmune disease. We found ROCK2 expression significantly increased in biopsies of lupus erythematosus, dermatomyositis, scleroderma and Kohlmeier-Degos disease. A pattern emerged of consistent marked ROCK2 upregulation in endothelium and variable expression in inflammatory cells and epithelium. While expression was undetectable in normal skin, it was found in inflamed skin unrelated to specific autoimmune disease. The staining pattern could approach that seen in study group cases but was less pronounced and preferentially upregulated in the endothelium, with a lesser extent of staining in the epidermis and inflammatory cells. Rho kinase is a driving factor in diverse cutaneous diseases especially autoimmune disease and Kohlmeier-Degos disease. This significantly upregulated pathway defines a potential target for biologic therapy.
MeSH term(s)	Adolescent ; Adult ; Aged ; Aged, 80 and over ; Autoimmune Diseases/enzymology ; Autoimmune Diseases/pathology ; Child, Preschool ; Female ; Gene Expression Regulation, Enzymologic ; Humans ; Infant ; Inflammation ; Male ; Malignant Atrophic Papulosis/enzymology ; Malignant Atrophic Papulosis/pathology ; Middle Aged ; Signal Transduction ; Skin Diseases/enzymology ; Skin Diseases/pathology ; Young Adult ; rho-Associated Kinases/genetics ; rho-Associated Kinases/metabolism
Chemical Substances	ROCK2 protein, human (EC 2.7.11.1) ; rho-Associated Kinases (EC 2.7.11.1)
Language	English
Publishing date	2019-10-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	1440011-x
ISSN	1532-8198 ; 1092-9134
ISSN (online)	1532-8198
ISSN	1092-9134
DOI	10.1016/j.anndiagpath.2019.151414
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Article ; Online: Next-generation sequencing analysis suggests varied multistep mutational pathogenesis for endocrine mucin-producing sweat gland carcinoma with comments on INSM1 and MUC2 suggesting a conjunctival origin.

Mathew, Joseph G / Bowman, Anita S / Saab, Jad / Busam, Klaus J / Nehal, Kishwer / Pulitzer, Melissa

Journal of the American Academy of Dermatology

2021 Volume 86, Issue 5, Page(s) 1072–1079

Abstract: Endocrine mucin-producing sweat gland carcinoma is a low-grade eyelid tumor. Small biopsies and insensitive immunohistochemistry predispose to misdiagnosis. We aimed to identify clarifying immunohistochemical markers, molecular markers, or both. ... ...

Abstract	Endocrine mucin-producing sweat gland carcinoma is a low-grade eyelid tumor. Small biopsies and insensitive immunohistochemistry predispose to misdiagnosis. We aimed to identify clarifying immunohistochemical markers, molecular markers, or both. Clinicopathologic data (22 cases) were reviewed. Immunohistochemistry (insulinoma-associated protein 1, BCL-2, mucin 2 [MUC2], mucin 4, androgen receptor, β-catenin, and Merkel cell polyomavirus) and next-generation sequencing (Memorial Sloan Kettering integrated mutation profiling of actionable cancer targets, 468 genes) were performed (3 cases). Female patients (n = 15) and male patients (n = 7) (mean age 71.8 years; range 53-88 years) had eyelid or periorbital tumors (>90%) with mucin-containing solid or cystic neuroendocrine pathology. Immunohistochemistry (insulinoma-associated protein 1, BCL2, androgen receptor, retinoblastoma-associated protein 1, and β-catenin) was diffusely positive (5/5), MUC2 partial, mucin 4 focal, and Merkel cell polyomavirus negative. Memorial Sloan Kettering integrated mutation profiling of actionable cancer targets identified 12 single-nucleotide variants and 1 in-frame deletion in 3 cases, each with DNA damage response or repair (BRD4, PPP4R2, and RTEL1) and tumor-suppressor pathway (BRD4, TP53, TSC1, and LATS2) mutations. Microsatellite instability, copy number alterations, and structural alterations were absent. Insulinoma-associated protein 1 and MUC2 are positive in endocrine mucin-producing sweat gland carcinoma. MUC2 positivity suggests conjunctival origin. Multistep pathogenesis involving DNA damage repair and tumor-suppressor pathways may be implicated.
MeSH term(s)	Aged ; Aged, 80 and over ; Biomarkers, Tumor/analysis ; Biomarkers, Tumor/genetics ; Carcinoma, Skin Appendage ; Cell Cycle Proteins ; Female ; High-Throughput Nucleotide Sequencing ; Humans ; Insulinoma ; Male ; Merkel cell polyomavirus ; Middle Aged ; Mucin-2/genetics ; Mucin-2/metabolism ; Mucin-4/genetics ; Mucins/metabolism ; Mutation ; Nuclear Proteins/genetics ; Pancreatic Neoplasms ; Protein Serine-Threonine Kinases ; Receptors, Androgen/genetics ; Repressor Proteins ; Skin Neoplasms/genetics ; Sweat Gland Neoplasms/diagnosis ; Sweat Gland Neoplasms/genetics ; Sweat Glands/pathology ; Transcription Factors/genetics ; Tumor Suppressor Proteins ; beta Catenin/genetics
Chemical Substances	BRD4 protein, human ; Biomarkers, Tumor ; Cell Cycle Proteins ; MUC2 protein, human ; Mucin-2 ; Mucin-4 ; Mucins ; Nuclear Proteins ; Receptors, Androgen ; Repressor Proteins ; Transcription Factors ; Tumor Suppressor Proteins ; beta Catenin ; INSM1 protein, human (147955-03-1) ; LATS2 protein, human (EC 2.7.1.11) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2021-01-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	603641-7
ISSN	1097-6787 ; 0190-9622
ISSN (online)	1097-6787
ISSN	0190-9622
DOI	10.1016/j.jaad.2020.11.073
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Article ; Online: Regulation of Cutaneous Immunity In Vivo by Calcitonin Gene-Related Peptide Signaling through Endothelial Cells.

Ding, Wanhong / Stohl, Lori L / Saab, Jad / Azizi, Shayan / Zhou, Xi K / Mehta, Devina / Granstein, Richard D

Journal of immunology (Baltimore, Md. : 1950)

2022 Volume 208, Issue 3, Page(s) 633–641

Abstract: Calcitonin gene-related peptide (CGRP) can bias the outcome of Ag presentation to responsive T cells in vitro away from Th1-type immunity and toward the Th2 and Th17 poles through actions on endothelial cells (ECs). To test the in vivo significance of ... ...

Abstract	Calcitonin gene-related peptide (CGRP) can bias the outcome of Ag presentation to responsive T cells in vitro away from Th1-type immunity and toward the Th2 and Th17 poles through actions on endothelial cells (ECs). To test the in vivo significance of this observation, we engineered a mouse lacking functional CGRP receptors on ECs (EC receptor activity modifying protein 1 [RAMP1] knockout mice). On percutaneous immunization to 1-fluoro-2,4-dinitrobenzene, stimulated CD4
MeSH term(s)	Animals ; Antigen Presentation/immunology ; Calcitonin Gene-Related Peptide/genetics ; Calcitonin Gene-Related Peptide/metabolism ; Dermatitis, Contact/immunology ; Dinitrofluorobenzene/immunology ; Endothelial Cells/immunology ; GATA3 Transcription Factor/metabolism ; Interferon-gamma/biosynthesis ; Interleukin-17/biosynthesis ; Interleukin-4/biosynthesis ; Interleukins/biosynthesis ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nuclear Receptor Subfamily 1, Group F, Member 1/genetics ; Receptor Activity-Modifying Protein 1/genetics ; Skin/immunology ; Th1 Cells/immunology ; Th17 Cells/immunology ; Th2 Cells/immunology ; Interleukin-22
Chemical Substances	GATA3 Transcription Factor ; Gata3 protein, mouse ; IFNG protein, mouse ; Il17a protein, mouse ; Il4 protein, mouse ; Interleukin-17 ; Interleukins ; Nuclear Receptor Subfamily 1, Group F, Member 1 ; Ramp1 protein, mouse ; Receptor Activity-Modifying Protein 1 ; Rora protein, mouse ; Interleukin-4 (207137-56-2) ; Interferon-gamma (82115-62-6) ; Dinitrofluorobenzene (D241E059U6) ; Calcitonin Gene-Related Peptide (JHB2QIZ69Z)
Language	English
Publishing date	2022-01-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2100139
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Article ; Online: Evaluating the Cause of Death in Obese Individuals

Jad Saab / Steven P. Salvatore

Journal of Obesity, Vol

A Ten-Year Medical Autopsy Study

2015 Volume 2015

Keywords	Diseases of the endocrine glands. Clinical endocrinology ; RC648-665 ; Specialties of internal medicine ; RC581-951 ; Internal medicine ; RC31-1245 ; Medicine ; R
Language	English
Publishing date	2015-01-01T00:00:00Z
Publisher	Hindawi Publishing Corporation
Document type	Article ; Online
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Article ; Online: Evaluating the cause of death in obese individuals: a ten-year medical autopsy study.

Saab, Jad / Salvatore, Steven P

Journal of obesity

2015 Volume 2015, Page(s) 695374

Abstract: Background: Obesity is a growing public health problem associated with increased morbidity and rate of death. Postmortem examination is imperative to determine the cause of death, to detect clinically unsuspected disease entities, and consequently to ... ...

Abstract	Background: Obesity is a growing public health problem associated with increased morbidity and rate of death. Postmortem examination is imperative to determine the cause of death, to detect clinically unsuspected disease entities, and consequently to determine the actual impact of obesity on patient mortality. Methods: A total of 849 adult autopsies were retrospectively reviewed. Obese (BMI ≥ 30 kg/m(2)) and nonobese patients were separately studied. The primary cause of death in each group was categorized into malignancy, infection, stroke, ischemic and nonischemic heart disease, pulmonary embolism, hemorrhage, and primary nonneoplastic diseases of different organ systems. Results: Of 849 autopsies, 32.3% were obese. The leading causes of death in the obese population were malignancy (31.4%), infection (25.9%), ischemic heart disease (12.8%), and pulmonary embolism (6.2%). Obese individuals were statistically more likely to die from pulmonary embolism and liver disease and less likely to die from neurologic diseases and nonischemic heart disease. Conclusion: Autopsies on obese individuals constitute a third of all adult medical autopsies in our center. Increased death rates in the obese due to pulmonary embolism and liver disease should receive special clinical attention. Autopsy findings in the obese population should contribute to overall premortem disease detection, prevention, and management.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Autopsy ; Bacterial Infections/etiology ; Bacterial Infections/mortality ; Bacterial Infections/pathology ; Cause of Death ; Female ; Humans ; Liver Diseases/etiology ; Liver Diseases/mortality ; Liver Diseases/pathology ; Male ; Middle Aged ; Neoplasms/etiology ; Neoplasms/mortality ; Neoplasms/pathology ; Obesity/complications ; Obesity/mortality ; Obesity/pathology ; Public Health ; Pulmonary Embolism/etiology ; Pulmonary Embolism/mortality ; Pulmonary Embolism/pathology ; Time Factors
Language	English
Publishing date	2015
Publishing country	United States
Document type	Journal Article
ZDB-ID	2573566-4
ISSN	2090-0716 ; 2090-0708
ISSN (online)	2090-0716
ISSN	2090-0708
DOI	10.1155/2015/695374
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Article ; Online: Evaluating the Cause of Death in Obese Individuals

Jad Saab / Steven P. Salvatore

Journal of Obesity, Vol

A Ten-Year Medical Autopsy Study

2015 Volume 2015

Abstract: Background. Obesity is a growing public health problem associated with increased morbidity and rate of death. Postmortem examination is imperative to determine the cause of death, to detect clinically unsuspected disease entities, and consequently to ... ...

Abstract	Background. Obesity is a growing public health problem associated with increased morbidity and rate of death. Postmortem examination is imperative to determine the cause of death, to detect clinically unsuspected disease entities, and consequently to determine the actual impact of obesity on patient mortality. Methods. A total of 849 adult autopsies were retrospectively reviewed. Obese (BMI ≥ 30 kg/m2) and nonobese patients were separately studied. The primary cause of death in each group was categorized into malignancy, infection, stroke, ischemic and nonischemic heart disease, pulmonary embolism, hemorrhage, and primary nonneoplastic diseases of different organ systems. Results. Of 849 autopsies, 32.3% were obese. The leading causes of death in the obese population were malignancy (31.4%), infection (25.9%), ischemic heart disease (12.8%), and pulmonary embolism (6.2%). Obese individuals were statistically more likely to die from pulmonary embolism and liver disease and less likely to die from neurologic diseases and nonischemic heart disease. Conclusion. Autopsies on obese individuals constitute a third of all adult medical autopsies in our center. Increased death rates in the obese due to pulmonary embolism and liver disease should receive special clinical attention. Autopsy findings in the obese population should contribute to overall premortem disease detection, prevention, and management.
Keywords	Internal medicine ; RC31-1245
Subject code	610 ; 630
Language	English
Publishing date	2015-01-01T00:00:00Z
Publisher	Hindawi Publishing Corporation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Folliculocentric Herpes: A Clinicopathological Study of 28 Patients.

Crowson, A Neil / Saab, Jad / Magro, Cynthia M

The American Journal of dermatopathology

2017 Volume 39, Issue 2, Page(s) 89–94

Abstract: Background: The cutaneous manifestations of herpes infection are primarily in the context of active infection and of the post-herpetic zosteriform eruption. The former manifests cytopathic alterations diagnostic of herpes. The latter includes lichen ... ...

Abstract	Background: The cutaneous manifestations of herpes infection are primarily in the context of active infection and of the post-herpetic zosteriform eruption. The former manifests cytopathic alterations diagnostic of herpes. The latter includes lichen planus-like and granuloma annulare-like eruptions and lymphocytoma cutis. Methods: We encountered skin biopsies from 28 patients whose acute or chronic herpetic or post-herpetic zosteriform lesions manifested folliculocentricity. The clinical appearance of the lesions was correlated with the histopathologic and immunohistochemical features of paraffin-embedded skin biopsies to determine the specific viral etiology. A history of underlying medical disease was noted if present. Results: There were 16 men and 12 women with a folliculocentric eruption occurring after a known herpetic eruption or manifesting cytopathic changes and/or immunohistochemical findings compatible with herpes virus in lesional skin biopsies. Underlying immune dysregulatory states were present in most cases, namely, malignancy, anticonvulsant or antidepressant therapy, diabetes mellitus, psoriasis, Crohn disease, and other conditions. All biopsies demonstrated dense lymphohistiocytic infiltrates in or around hair follicles with variable necrosis, while active infections also showed cytopathic and/or immunohistochemical evidence of herpetic alterations, most commonly varicella zoster. Other features included interfollicular interface dermatitis, lymphocytic eccrine hidradenitis, neuritis, and folliculocentric vasculitis. Conclusions: Cutaneous herpetic eruptions can evoke a predominantly folliculocentric mononuclear cell reaction and vasculitis; there is an association with underlying endogenous and/or iatrogenic immune dysregulation. Most cases are secondary to reactivation of varicella zoster. The histomorphology suggests a role for cell-mediated immunity. Antigenic homology of an endogenous 72-kd heat shock protein in follicles with that of a herpetic heat shock protein, in concert with an intrafollicular proliferative response of γ-δ T lymphocytes, may explain the follicular localization and composition of the infiltrate.
MeSH term(s)	Adolescent ; Adult ; Aged ; Aged, 80 and over ; Female ; Hair Diseases/pathology ; Hair Diseases/virology ; Hair Follicle/pathology ; Herpes Zoster/pathology ; Humans ; Male ; Middle Aged ; Skin Diseases, Viral/pathology ; Young Adult
Language	English
Publishing date	2017-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	448469-1
ISSN	1533-0311 ; 0193-1091
ISSN (online)	1533-0311
ISSN	0193-1091
DOI	10.1097/DAD.0000000000000585
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Article ; Online: Figure Correction: Using Social Media to Help Understand Patient-Reported Health Outcomes of Post-COVID-19 Condition: Natural Language Processing Approach.

Journal of medical Internet research

2023 Volume 25, Page(s) e55010

Abstract: This corrects the article DOI: 10.2196/45767.]. ...

Abstract	[This corrects the article DOI: 10.2196/45767.].
Language	English
Publishing date	2023-12-08
Publishing country	Canada
Document type	Published Erratum
ZDB-ID	2028830-X
ISSN	1438-8871 ; 1438-8871
ISSN (online)	1438-8871
ISSN	1438-8871
DOI	10.2196/55010
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Article ; Online: Granulomatous Insulitis as a Cause of Acute-Onset Insulin-Dependent Diabetes Mellitus in a Patient With a Pancreatic Endocrine Carcinoma.

Saab, Jad / Qin, Lihui / Jessurun, Jose

International journal of surgical pathology

2016 Volume 24, Issue 7, Page(s) 648–652

Abstract: Autoimmune destruction of β cells is the cause of most cases of type 1 diabetes mellitus. Lymphocytic insulitis has been documented in the early phases of this disease as well as in recurrent diabetes after pancreas transplantation and in certain viral ... ...

Abstract	Autoimmune destruction of β cells is the cause of most cases of type 1 diabetes mellitus. Lymphocytic insulitis has been documented in the early phases of this disease as well as in recurrent diabetes after pancreas transplantation and in certain viral infections. We report a unique case of granulomatous insulitis in a patient with an endocrine tumor of the pancreas that clinically manifested as acute-onset insulin-dependent diabetes mellitus. Granulomata were present in islets with complete disappearance of β cells, as well as in the primary tumor, metastases, and lymph nodes. We postulate that these granulomata represent a sarcoid-like reaction to the tumor with secondary injury to nonneoplastic endocrine cells through a mechanism of molecular mimicry.
MeSH term(s)	Aged ; Biomarkers, Tumor/analysis ; Breast Neoplasms/pathology ; Carcinoma, Neuroendocrine/complications ; Carcinoma, Neuroendocrine/pathology ; Comorbidity ; Diabetes Mellitus, Type 1/etiology ; Female ; Granuloma/etiology ; Granuloma/pathology ; Graves Disease/complications ; Graves Disease/epidemiology ; Humans ; Immunohistochemistry ; Neoplasms, Second Primary/pathology ; Pancreatic Neoplasms/complications ; Pancreatic Neoplasms/pathology
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2016-10
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	1336393-1
ISSN	1940-2465 ; 1066-8969
ISSN (online)	1940-2465
ISSN	1066-8969
DOI	10.1177/1066896916648770
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