ABSTRACT
Background While studies of hospital dermatology have demonstrated diagnostic discordance between primary teams and dermatology consultants, little is known about the impact of biopsy and clinical-pathologic correlation (CPC) in consultation. This study compares biopsy performance based on diagnostic discordance and evaluates the impact of CPC on the diagnosis. Methods This was a retrospective review of 376 dermatologic consultations at a single academic medical center between July 1, 2017, and June 27, 2018. Results Biopsy was significantly less likely to be performed when the diagnosis by the referring primary team was unspecified (p < 0.001). In 24 percent of cases, the diagnosis based on histopathology alone differed from the diagnosis reached by formal CPC consensus review with either potential or significant impact on management. Conclusion Dermatologists who perform inpatient consultations and rely on hospital-based pathology services may consider a consensus review for CPC. Requests to perform a biopsy may be interpreted as a request for diagnostic assistance rather than pressure to perform a procedure.
ABSTRACT
Multiple human epidemiologic studies link caffeinated (but not decaffeinated) beverage intake with significant decreases in several types of cancer, including highly prevalent UV-associated skin carcinomas. The mechanism by which caffeine protects against skin cancer is unknown. Ataxia telangiectasia and Rad3-related (ATR) is a replication checkpoint kinase activated by DNA stresses and is one of several targets of caffeine. Suppression of ATR, or its downstream target checkpoint kinase 1 (Chk1), selectively sensitizes DNA-damaged and malignant cells to apoptosis. Agents that target this pathway are currently in clinical trials. Conversely, inhibition of other DNA damage response pathways, such as ataxia telangiectasia mutated (ATM) and BRCA1, promotes cancer. To determine the effect of replication checkpoint inhibition on carcinogenesis, we generated transgenic mice with diminished ATR function in skin and crossed them into a UV-sensitive background, Xpc(-/-). Unlike caffeine, this genetic approach was selective and had no effect on ATM activation. These transgenic mice were viable and showed no histological abnormalities in skin. Primary keratinocytes from these mice had diminished UV-induced Chk1 phosphorylation and twofold augmentation of apoptosis after UV exposure (P = 0.006). With chronic UV treatment, transgenic mice remained tumor-free for significantly longer (P = 0.003) and had 69% fewer tumors at the end of observation of the full cohort (P = 0.019), compared with littermate controls with the same genetic background. This study suggests that inhibition of replication checkpoint function can suppress skin carcinogenesis and supports ATR inhibition as the relevant mechanism for the protective effect of caffeinated beverage intake in human epidemiologic studies.
Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Keratinocytes/radiation effects , Protein Serine-Threonine Kinases/antagonists & inhibitors , Skin Neoplasms/prevention & control , Ultraviolet Rays/adverse effects , Animals , Apoptosis , Ataxia Telangiectasia Mutated Proteins , Caffeine/pharmacology , Cell Cycle Proteins/genetics , Checkpoint Kinase 1 , Keratinocytes/cytology , Mice , Mice, Transgenic , Protein Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Skin Neoplasms/etiology , Skin Neoplasms/pathologyABSTRACT
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Humans , Dermatology/trends , Skin Diseases/diagnosis , Skin Diseases/therapyABSTRACT
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Humans , Dermatology/trends , Periodicals as Topic/trendsABSTRACT
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History, 20th Century , Periodicals as Topic/historyABSTRACT
Kidins220, a protein predominantly expressed in neural tissues, is the first physiological substrate for protein kinase D (PKD). We show that Kidins220 is expressed in monocyte-derived and in peripheral blood immature dendritic cells (im DC). Immature DC (im DC) migrate onto extracellular matrices changing cyclically from a highly polarized morphology (monopolar (MP) stage) to a morphologically symmetrical shape (bipolar (BP) stage). Kidins220 was localized on membrane protrusions at the leading edge or on both poles in MP and BP cells, respectively. CD43, CD44, ICAM-3 and DC-SIGN, and signaling molecules PKD, Arp2/3 were found at the leading edge in MP or on both edges in BP cells, showing an intriguing parallelism between morphology and localization of molecular components on the poles of the motile DC. F-actin co-localized and it was necessary for Kidins220 localization on the membrane in MP and BP cells. Kidins220 was also found in a raft compartment. Disruption of rafts with methyl-beta-cyclodextrin induced rounding of the cells, inhibition of motility and lost of Kidins220 polarization. Our results describe for the first time the molecular components of the poles of motile im DC and indicate that a novel neuronal protein may be an important component among these molecules.
Subject(s)
Cell Differentiation/physiology , Dendritic Cells/metabolism , Membrane Microdomains/metabolism , Membrane Proteins/metabolism , Nerve Tissue Proteins/metabolism , Phosphoproteins/metabolism , Actins/metabolism , HumansSubject(s)
Interferon-alpha/adverse effects , Melanoma/drug therapy , Oligospermia/chemically induced , Skin Neoplasms/drug therapy , Adult , Dose-Response Relationship, Drug , Drug Administration Schedule , Follow-Up Studies , Humans , Interferon alpha-2 , Interferon-alpha/therapeutic use , Male , Melanoma/pathology , Neoplasm Staging , Oligospermia/physiopathology , Recombinant Proteins , Risk Assessment , Skin Neoplasms/pathology , Sperm CountABSTRACT
Cutaneous lichen planus has been associated in patients with chronic hepatitis C virus infection. It is still unknown whether hepatitis C virus infects keratinocytes of lichen planus lesions. In this report we have analyzed the presence of genomic and anti-genomic hepatitis C virus RNA in skin biopsies from 26 patients with chronic hepatitis C and healthy skin and from 24 patients with cutaneous lichen planus (five with and 19 without hepatitis C virus infection) by in situ hybridization. Hepatitis C virus RNA was detected in the keratinocytes of 69% of the patients with healthy skin and chronic hepatitis C, in 100% of the patients with lichen planus and hepatitis C virus infection, and in none of lichen planus patients without hepatitis C virus infection. The percentage of keratinocytes showing genomic or anti-genomic hepatitis C virus RNA was statistically lower (p < 0.01 in all cases) in patients with healthy skin (mean +/- SD: 5.7 +/- 3.5% and 2.7 +/- 3.1% of keratinocytes with genomic or anti-genomic hepatitis C virus RNA, respectively) than in those with lichen planus lesions (31.7 +/- 7.9% and 18.8 +/- 7.4%, mean +/- SD) or the unaffected adjacent skin (24.8 +/- 6.9% and 14.3 +/- 3.8%, mean +/- SD). In conclusion, we have demonstrated that hepatitis C virus infects keratinocytes from patients with lichen planus and hepatitis C virus infection.
Subject(s)
Hepatitis C, Chronic/virology , Keratinocytes/virology , Lichen Planus/virology , RNA, Viral/analysis , Viral Core Proteins/analysis , Adult , Aged , Female , Hepacivirus/chemistry , Hepacivirus/genetics , Humans , Immunohistochemistry , In Situ Hybridization , Male , Middle Aged , RNA, Viral/blood , S100 Proteins/analysisABSTRACT
Hepatitis C virus (HCV) replicates in salivary glands of chronic hepatitis C patients and is released into the saliva, suggesting that HCV may replicate in other exocrine glands. The presence of positive and negative HCV RNA strands was demonstrated by in situ hybridization, and of HCV core protein by immunohistochemistry, in sweat glands and keratinocytes in healthy skin biopsies from 15 patients with chronic hepatitis C and 10 anti-HCV negative patients with chronic liver disease. Positive and negative HCV RNA strands were detected in 9.6 +/- 5.2% and 4.2 +/- 3.8%, respectively, of the epithelial cells of eccrine sweat glands. Core protein was detected in 6.0 +/- 3.93% of these cells. HCV RNA resistant to RNase digestion (encapsidated HCV RNA) was detected in 10/10 sweat samples from HCV-infected patients. Positive and negative HCV RNA strands were detected in 6.7 +/- 2.97% and 3.0 +/- 3.08% of the keratinocytes, respectively. HCV core protein was found in 4.5 +/- 2.76% of these cells. No HCV RNA or HCV core protein was detected in the skin biopsies from the 10 anti-HCV negative patients. In conclusion, HCV replicates in eccrine sweat glands cells and keratinocytes in healthy skin and is released into the sweat.
