Cutaneous metastasis from penile squamous cell carcinoma resembling carcinoma en cuirasse

Penile squamous cell carcinoma is a rare malignancy seen more frequently in developing nations. Metastasis occurs in a predictable manner, with superficial lymph node involvement occurring first, followed by deep lymph node involvement, and then distant spread. Brain, lung, liver, and bone are the typical sites of distant metastasis. We present the unusual case of an 81-year-old man with penile squamous cell carcinoma requiring total penectomy who developed a confluent red to violaceous, indurated suprapubic plaque with satellite papules and bulky inguinal lymphadenopathy. The shield-like clinical presentation and infiltrating strands and cords on histology resembled carcinoma en cuirasse, a rare form of cutaneous metastasis frequently associated with breast cancer but not reported with penile squamous cell carcinoma

Src Family Kinases Mediate Epithelial Na + Channel Inhibition by Endothelin

The epithelial Na(+) channel (ENaC) is implicated in the pathogenesis of salt-sensitive hypertension. Recent evidence from animal models suggests that the vasoactive peptide, endothelin (ET-1), may be an important negative regulator of ENaC in vivo. We investigated the signaling pathway involved in endothelin-mediated ENaC inhibition. Experiments were performed in NIH 3T3 cells stably expressing genes for the three (alpha, beta, and gamma) ENaC subunits. In whole cell patch clamp experiments, we found that ET-1 treatment induced a dose-dependent decrease in amiloride-sensitive currents. Using receptor-specific antagonists, we determined that the effects of ET-1 were attributed to activation of the ET(B) receptor. Moreover, the inhibitory effect of ET-1 on ENaC could be completely blocked when cells were pretreated with the selective Src family kinase inhibitor, PP2. Further studies revealed that basal Src family kinase activity strongly regulates ENaC whole cell currents and single channel gating. These results suggest that Src family kinases lie in a signaling pathway activated by ET-1 and are components of a novel negative regulatory cascade resulting in ENaC inhibition

Wheat and Maize Flour Fortification: Practical Recommendations for National Application

Joint statement by the World Health Organization, Food and Agriculture Organization of the United Nations, The United Nations Children s Fund, Global Alliance for Improved Nutrition, The Micronutrient Initiative and The Flour Fortification InitiativeREPRODUCTIVE HEALTHSURVEILLANCE AND INVESTIGATIONCURREN

Identification and Validation of Novel Cerebrospinal Fluid Biomarkers for Staging Early Alzheimer's Disease

Ideally, disease modifying therapies for Alzheimer disease (AD) will be applied during the 'preclinical' stage (pathology present with cognition intact) before severe neuronal damage occurs, or upon recognizing very mild cognitive impairment. Developing and judiciously administering such therapies will require biomarker panels to identify early AD pathology, classify disease stage, monitor pathological progression, and predict cognitive decline. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid (CSF) proteome.CSF samples from individuals with mild AD (Clinical Dementia Rating [CDR] 1) (n = 24) and cognitively normal controls (CDR 0) (n = 24) were subjected to two-dimensional difference-in-gel electrophoresis. Within 119 differentially-abundant gel features, mass spectrometry (LC-MS/MS) identified 47 proteins. For validation, eleven proteins were re-evaluated by enzyme-linked immunosorbent assays (ELISA). Six of these assays (NrCAM, YKL-40, chromogranin A, carnosinase I, transthyretin, cystatin C) distinguished CDR 1 and CDR 0 groups and were subsequently applied (with tau, p-tau181 and Aβ42 ELISAs) to a larger independent cohort (n = 292) that included individuals with very mild dementia (CDR 0.5). Receiver-operating characteristic curve analyses using stepwise logistic regression yielded optimal biomarker combinations to distinguish CDR 0 from CDR>0 (tau, YKL-40, NrCAM) and CDR 1 from CDR<1 (tau, chromogranin A, carnosinase I) with areas under the curve of 0.90 (0.85-0.94 95% confidence interval [CI]) and 0.88 (0.81-0.94 CI), respectively.Four novel CSF biomarkers for AD (NrCAM, YKL-40, chromogranin A, carnosinase I) can improve the diagnostic accuracy of Aβ42 and tau. Together, these six markers describe six clinicopathological stages from cognitive normalcy to mild dementia, including stages defined by increased risk of cognitive decline. Such a panel might improve clinical trial efficiency by guiding subject enrollment and monitoring disease progression. Further studies will be required to validate this panel and evaluate its potential for distinguishing AD from other dementing conditions

Elevated protein concentrations in newborn blood and the risks of autism spectrum disorder, and of social impairment, at age 10 years among infants born before the 28th week of gestation

Among the 1 of 10 children who are born preterm annually in the United States, 6% are born before the third trimester. Among children who survive birth before the 28th week of gestation, the risks of autism spectrum disorder (ASD) and non-autistic social impairment are severalfold higher than in the general population. We examined the relationship between top quartile inflammation-related protein concentrations among children born extremely preterm and ASD or, separately, a high score on the Social Responsiveness Scale (SRS total score ≥65) among those who did not meet ASD criteria, using information only from the subset of children whose DAS-II verbal or non-verbal IQ was ≥70, who were assessed for ASD, and who had proteins measured in blood collected on ≥2 days (N = 763). ASD (N = 36) assessed at age 10 years is associated with recurrent top quartile concentrations of inflammation-related proteins during the first post-natal month (e.g., SAA odds ratio (OR); 95% confidence interval (CI): 2.5; 1.2–5.3) and IL-6 (OR; 95% CI: 2.6; 1.03–6.4)). Top quartile concentrations of neurotrophic proteins appear to moderate the increased risk of ASD associated with repeated top quartile concentrations of inflammation-related proteins. High (top quartile) concentrations of SAA are associated with elevated risk of ASD (2.8; 1.2–6.7) when Ang-1 concentrations are below the top quartile, but not when Ang-1 concentrations are high (1.3; 0.3–5.8). Similarly, high concentrations of TNF-α are associated with heightened risk of SRS-defined social impairment (N = 130) (2.0; 1.1–3.8) when ANG-1 concentrations are not high, but not when ANG-1 concentrations are elevated (0.5; 0.1–4.2)

Cutaneous metastasis from penile squamous cell carcinoma resembling carcinoma en cuirasse

Penile squamous cell carcinoma is a rare malignancy seen more frequently in developing nations. Metastasis occurs in a predictable manner, with superficial lymph node involvement occurring first, followed by deep lymph node involvement, and then distant spread. Brain, lung, liver, and bone are the typical sites of distant metastasis. We present the unusual case of an 81-year-old man with penile squamous cell carcinoma requiring total penectomy who developed a confluent red to violaceous, indurated suprapubic plaque with satellite papules and bulky inguinal lymphadenopathy. The shield-like clinical presentation and infiltrating strands and cords on histology resembled carcinoma en cuirasse, a rare form of cutaneous metastasis frequently associated with breast cancer but not reported with penile squamous cell carcinoma

Evaluation of the Relationship between Alopecia Areata and Viral Antigen Exposure

BACKGROUND: Alopecia areata (AA) is an autoimmune disease characterized by non-scarring alopecia with T-cell infiltration at the affected hair follicle. OBJECTIVE: Our aim was to study the potential link between hepatitis B virus (HBV) antigen exposure and AA. METHODS: Two pediatric patients with AA following hepatitis B vaccination were identified in a general dermatology clinic. A bioinformatics analysis and an electronic medical record (EMR) database query were performed at the University of Rochester Medical Center to identify patients with AA, coexisting viral infections, vaccinations, or interferon (IFN) therapy in order to determine if the presence of AA and these conditions was higher than in AA patients without these associated conditions or therapy. RESULTS: An increased frequency of AA among those who received the HBV surface protein antigen [odds ratio (OR) 2.7, p \u3c 0.0001] was identified, and an independent analysis revealed an increased frequency of AA in those receiving IFN-β treatment (OR 8.1, p \u3c 0.05). One potential antigenic target identified was SLC45A2, a melanosomal transport protein important in skin and hair pigmentation. The longest potential vaccine peptide fragment match (8-mer) was to a segment of natural killer (NK) cell inhibitory receptors, KIR3DL2 and KIR3DL1. Predictive modeling of major histocompatibility complex (MHC)-peptide binding demonstrated potential binding of this peptide to MHC relevant to AA. LIMITATIONS: The results will need to be verified in additional patient databases allowing analysis of temporal relationships, and with molecular experiments of the identified antigens. CONCLUSIONS: Our data confirm associations between viral infection and IFN treatment with AA. It establishes that the hepatitis B surface protein antigen has shared epitopes with human killer immunoglobulin-like receptors

Randomized Mechlorethamine/Chlormethine Induced Dermatitis Assessment Study (MIDAS) Establishes Benefit of Topical Triamcinolone 0.1% Ointment Cotreatment in Mycosis Fungoides

INTRODUCTION: Treatment of early-stage mycosis fungoides (MF) requires safe, skin-directed therapies. Medication side effects can lead to underutilization of effective therapies. The objective of this study was to assess the use of topical triamcinolone 0.1% ointment as a means of reducing contact dermatitis associated with topical mechlorethamine/chlormethine gel for the treatment of MF. METHODS: This prospective, randomized, open-label study evaluated 28 adults with mycosis fungoides who were eligible for treatment with topical mechlorethamine/chlormethine gel from December 17, 2017 to December 23, 2020. Patients were treated for 4 months with clinical follow-up through 12 months. Patients had half of their lesions also treated with topical triamcinolone 0.1% ointment (while the other half were treated with mechlorethamine/chlormethine alone). The study was self-controlled with separate lesions in the same patient receiving each treatment arm. Treatment arms were determined by the flip of a coin. RESULTS: Twenty-eight patients enrolled (17 men (61%) and 11 women (39%)). Demographics included 25 White, 2 African Americans, and 1 Asian patient. Twenty-five completed the 12-month follow-up. Triamcinolone 0.1% ointment led to increased tolerability of mechlorethamine/chlormethine gel but did not change the efficacy of mechlorethamine/chlormethine. There was a statistically significant 50% decrease in dermatitis (SCORD score) at month 2 in the triamcinolone-treated arm. CONCLUSIONS: Topical triamcinolone ointment is a helpful adjuvant therapy when treating patients with topical mechlorethamine/chlormethine gel. It diminishes inflammation and does not reduce efficacy. The peak incidence of dermatitis in the study occurred in the second and third months. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03380026

PKK deletion in basal keratinocytes promotes tumorigenesis after chemical carcinogenesis

Squamous cell carcinoma (SCC) of the skin is a keratinocyte malignancy characterized by tumors presenting on sun-exposed areas with surgery being the mainstay treatment. Despite advances in targeted therapy in other skin cancers, such as basal cell carcinoma and melanoma, there have been no such advances in the treatment of SCC. This is partly due to an incomplete knowledge of the pathogenesis of SCC. We have recently identified a protein kinase C-associated kinase (PKK) as a potential tumor suppressor in SCC. We now describe a novel conditional PKK knockout mouse model, which demonstrates that PKK deficiency promotes SCC formation during chemically induced tumorigenesis. Our results further support that PKK functions as a tumor suppressor in skin keratinocytes and is important in the pathogenesis of SCC of the skin. We further define the interactions of keratinocyte PKK with TP63 and NF-κB signaling, highlighting the importance of this protein as a tumor suppressor in SCC development