Incidence, Mortality, and Survival of Merkel Cell Carcinoma: A Systematic Review of Population Based-Studies.

BACKGROUND: Merkel Cell Carcinoma (MCC) is a rare, aggressive skin cancer that most commonly occurs in UV-exposed body sites. Its epidemiology in different geographies and populations is not well characterised. OBJECTIVE: The objective of this systematic review is to summarize evidence on the incidence, mortality, and survival rates of MCC from population-based studies. METHODS: We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from database inception to June 6th, 2023. No geographic, age or date exclusions were applied. We included population-based studies of MCC that reported the incidence, survival, or mortality rate, and considered systematic reviews. A data-charting form was created and validated to identify variables to extract. Two reviewers then independently charted the data for each included study with patient characteristics, and estimates of incidence rate, mortality rate, and survival rate and assessed the quality of included studies using the Joanna Briggs Institute Checklist for Prevalence studies, Newcastle-Ottawa Scale and Assessment of Multiple Systematic Reviews. We abstracted age-, sex-, stage- and race-stratified outcomes, and synthesized comparisons between strata narratively and using vote counting. We assessed the certainty of evidence for those comparisons using the Grading of Recommendations, Assessments, Developments and Evaluations framework. RESULTS: We identified 11,472 citations, of which 52 studies from 24 countries met our inclusion criteria. Stage 1 and the head and neck were the most frequently reported stage and location at diagnosis. The incidence of MCC is increasing over time (high certainty), with the highest reported incidences reported in Southern hemisphere countries (Australia [2.5 per 100,000], New Zealand [0.96 per 100,000]) (high certainty). Male patients generally had higher incidence rates compared to female patients (high certainty), although there were some variations over time periods. Survival rates varied, with lower survival and/or higher mortality associated with male sex (moderate certainty), higher stage at diagnosis (moderate-to-high certainty), older age (moderate certainty), and immunosuppression (low-to-moderate certainty). CONCLUSIONS: MCC is increasing in incidence and may increase further given the ageing population of many countries. The prognosis of MCC is poor, particularly for males, those who are immunosuppressed, and patients diagnosed at higher stages or at an older age.

Defective Influenza A Virus RNA Products Mediate MAVS-Dependent Upregulation of Human Leukocyte Antigen Class I Proteins.

Influenza A virus (IAV) increases the presentation of class I human leukocyte antigen (HLA) proteins that limit antiviral responses mediated by natural killer (NK) cells, but molecular mechanisms for these processes have not yet been fully elucidated. We observed that infection with A/Fort Monmouth/1/1947(H1N1) IAV significantly increased the presentation of HLA-B, -C, and -E on lung epithelial cells. Virus entry was not sufficient to induce HLA upregulation because UV-inactivated virus had no effect. Aberrant internally deleted viral RNAs (vRNAs) known as mini viral RNAs (mvRNAs) and defective interfering RNAs (DI RNAs) expressed from an IAV minireplicon were sufficient for inducing HLA upregulation. These defective RNAs bind to retinoic acid-inducible gene I (RIG-I) and initiate mitochondrial antiviral signaling (MAVS) protein-dependent antiviral interferon (IFN) responses. Indeed, MAVS was required for HLA upregulation in response to IAV infection or ectopic mvRNA/DI RNA expression. The effect was partially due to paracrine signaling, as we observed that IAV infection or mvRNA/DI RNA-expression stimulated production of IFN-ß and IFN-λ1 and conditioned media from these cells elicited a modest increase in HLA surface levels in naive epithelial cells. HLA upregulation in response to aberrant viral RNAs could be prevented by the Janus kinase (JAK) inhibitor ruxolitinib. While HLA upregulation would seem to be advantageous to the virus, it is kept in check by the viral nonstructural 1 (NS1) protein; we determined that NS1 limits cell-intrinsic and paracrine mechanisms of HLA upregulation. Taken together, our findings indicate that aberrant IAV RNAs stimulate HLA presentation, which may aid viral evasion of innate immunity.IMPORTANCE Human leukocyte antigens (HLAs) are cell surface proteins that regulate innate and adaptive immune responses to viral infection by engaging with receptors on immune cells. Many viruses have evolved ways to evade host immune responses by modulating HLA expression and/or processing. Here, we provide evidence that aberrant RNA products of influenza virus genome replication can trigger retinoic acid-inducible gene I (RIG-I)/mitochondrial antiviral signaling (MAVS)-dependent remodeling of the cell surface, increasing surface presentation of HLA proteins known to inhibit the activation of an immune cell known as a natural killer (NK) cell. While this HLA upregulation would seem to be advantageous to the virus, it is kept in check by the viral nonstructural 1 (NS1) protein, which limits RIG-I activation and interferon production by the infected cell.

The use of noninvasive imaging techniques in the diagnosis of melanoma: a prospective diagnostic accuracy study.

BACKGROUND: Early detection of melanoma is crucial to improving the detection of thin curable melanomas. Noninvasive, computer-assisted methods have been developed to use at the bedside to aid in diagnoses but have not been compared directly in a clinical setting. OBJECTIVE: We conducted a prospective diagnostic accuracy study comparing a dermatologist's clinical examination at the bedside, teledermatology, and noninvasive imaging techniques (FotoFinder, MelaFind, and Verisante Aura). METHODS: A total of 184 patients were recruited prospectively from an outpatient dermatology clinic, with lesions imaged, assessed, and excised. Skin specimens were assessed by 2 blinded pathologists, providing the gold standard comparison. RESULTS: Fifty-nine lesions from 56 patients had a histopathologic diagnosis of melanoma, whereas 150 lesions from 128 patients were diagnosed as benign. Sensitivities and specificities were, respectively, MelaFind (82.5%, 52.4%), Verisante Aura (21.4%, 86.2%), and FotoFinder Moleanalyzer Pro (88.1%, 78.8%). The sensitivity and specificity of the teledermoscopist (84.5% and 82.6%, respectively) and local dermatologist (96.6% and 32.2%, respectively) were also compared. LIMITATIONS: There are inherent limitations in using pathology as the gold standard to compare sensitivities and specificities. CONCLUSION: This study demonstrates that the highest sensitivity and specificity of the instruments were established with the FotoFinder Moleanalyzer Pro, which could be a valuable tool to assist with, but not replace, clinical decision making.

AAGAB Mutations in 18 Canadian Families With Punctate Palmoplantar Keratoderma and a Possible Link to Cancer.

BACKGROUND: Punctate palmoplantar keratoderma type 1 (PPPK1) presents in late childhood to adulthood with multiple small discrete hyperkeratotic papules on palms and soles. PPPK1 is an autosomal dominant skin disease caused by AAGAB mutations. It has been suggested that PPPK1 may be associated with an increased predisposition to systemic malignancies. OBJECTIVES: To evaluate the presence of AAGAB mutations in Canadian families with PPPK1 and the possible increased predisposition to systemic malignancies. METHODS: Eighteen unrelated Canadian families with PPPK1 were recruited for this study. Genomic DNA was extracted from saliva and PCR amplification was performed for all AAGAB exons and exon/intron junctions. PCR products were sequenced and analyzed for mutations. A family history of malignancy was obtained from the index case and, when possible, from other family members. RESULTS: We have identified 5 heterozygous AAGAB loss of function mutations in 11 families. The mutation c.370 C>T, p.Arg124* was the most prevalent and was identified in 6 families. A splice site mutation, c.451+3delAAGT, was identified in 2 families. The other mutations c.473delG, p.Gly158Glufs*0; c.550-551insAAT, p.Gly183*; and c.505-506 dupAA, p.Asn169Lysfs*6 were each identified in 1 family. Different cancers were reported in 11 families (Table 1 and Supplemental Figure S1). CONCLUSIONS: AAGAB mutations were found in 11 of 18 families with PPPK1. In some families there appears to be an association with cancer.

The Influenza A Virus Endoribonuclease PA-X Usurps Host mRNA Processing Machinery to Limit Host Gene Expression.

Many viruses shut off host gene expression to inhibit antiviral responses. Viral proteins and host proteins required for viral replication are typically spared in this process, but the mechanisms of target selectivity during host shutoff remain poorly understood. Using transcriptome-wide and targeted reporter experiments, we demonstrate that the influenza A virus endoribonuclease PA-X usurps RNA splicing to selectively target host RNAs for destruction. Proximity-labeling proteomics reveals that PA-X interacts with cellular RNA processing proteins, some of which are partially required for host shutoff. Thus, PA-X taps into host nuclear pre-mRNA processing mechanisms to destroy nascent mRNAs shortly after their synthesis. This mechanism sets PA-X apart from other viral host shutoff proteins that target actively translating mRNAs in the cytoplasm. Our study reveals a unique mechanism of host shutoff that helps us understand how influenza viruses suppress host gene expression.

Effect of exercise on intraocular pressure and pulsatile ocular blood flow in a young normal population.

PURPOSE: The hypotensive effect of exercise on intraocular pressure is well documented, however, little is known about the effect of exercise on pulsatile ocular blood flow. This study examines this effect and follows the recovery of intraocular pressure and pulsatile ocular blood flow after a standard exercise period. METHODS: Eighteen visually normal subjects participated in a 4-min period of bicycle ergometry. Intraocular pressure and pulsatile ocular blood flow were measured by pneumotonometry before, immediately after exercise, and at regular intervals during the recovery period. RESULTS: Intraocular pressure was found to decrease significantly with strenuous exercise and recovered gradually toward baseline over a period of 30 min. Pulsatile ocular blood flow increased significantly immediately after exercise then returned to baseline levels between 5 and 10 min after stopping exercise. CONCLUSIONS: This study confirms the hypotensive effect of exercise on intraocular pressure and shows that exercise significantly increases pulsatile ocular blood flow.