Amplification of Mutant NRAS in Melanocytic Tumors With Features of Spitz Tumors.

NRAS activating mutations are prevalent in melanocytic neoplasia, occurring in a subset of common acquired melanocytic nevi and ∼30% of cutaneous melanomas. In this study, we described a cohort of 7 distinctive melanocytic tumors characterized by activating point mutations in codon 61 of NRAS with amplification of the mutant NRAS allele and shared clinicopathologic features. These tumors occurred predominantly in younger patients, with a median age of 20 years (range, 6-56 years). They presented as papules on the helix of the ear (4 cases) or extremities (3 cases). Microscopically, the tumors were cellular, relatively well-circumscribed, compound, or intradermal proliferations. The tumor cells often extended into the deep reticular dermis and involved the superficial subcutaneous fat in some cases. The melanocytes were epithelioid to spindled with moderate amounts of cytoplasm and conspicuous nucleoli. They were arranged in short plexiform fascicles, nests, and cords. Some cases had occasional pleomorphic and multinucleated melanocytes. Rare dermal mitotic figures were present in all cases. The dermis contained thick collagen bundles and minimal solar elastosis. Follow-up data were available for 5 patients, with a median period of 4.2 years (range, 1-9 years), during which no recurrences or metastases were reported. Our series highlights a clinicopathologically and molecularly distinctive subset of NRAS-mutated tumors with amplification of the mutant NRAS allele.

Neutrophil-driven and interleukin-36γ-associated ocular surface inflammation in chronic Stevens-Johnson syndrome.

PURPOSE: This study aims to elucidate the tear proteome and understand the underlying molecular mechanisms involved in the ocular complications following Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). METHODS: Mass spectrometry (MS) was performed to quantify the tear fluid proteins from chronic SJS/TEN patients (n = 22 eyes) and age- and gender-matched controls (n = 22 eyes). The candidate proteins were validated using ELISA (n = 80 eyes) in tear samples and immunohistochemistry (IHC; n = 12) in eyelid margin specimens. These proteins were compared for significant differences based on age, gender, disease duration, and ocular severity. RESULTS: A total of 1692 tear fluid proteins were identified, of which 470 were significantly differentially regulated in chronic SJS/TEN. The top 10 significantly upregulated proteins were neutrophil secretions including neutrophil elastase (p < .0001), defensin (p < .0001), and matrix metalloproteinase 8 (p < .0001). The presence of neutrophils was confirmed by the upregulation of IL-8 (p < .001) in tears, a key cytokine known for recruiting neutrophils. Additionally, positive expression of myeloperoxidase was observed in the keratinized eyelid margins of SJS/TEN to validate the presence of neutrophils. Among 41 unique proteins identified by MS, IL-36γ (p < .01) was expressed in three SJS/TEN patients and was confirmed in SJS/TEN tears and eyelid margins by ELISA and IHC, respectively. IL-36γ was specifically expressed in the superficial layers of eyelid margin keratinized conjunctiva. The majority of the significantly downregulated proteins were lacrimal gland secretions such as lacritin (p < .0001) and opiorphin (p < .002). Neutrophil elastase (p < .02) was significantly elevated in patients with severe eyelid margin keratinization. CONCLUSION: Our observations indicate a clear correlation between eyelid margin keratinization and the expression of IL-36γ, potentially mediated by neutrophils recruited via IL-8. Future experimental studies are needed to test the role of therapies targeting IL-8 and/or IL-36γ in reducing eyelid margin keratinization and its associated ocular complications in SJS/TEN.

Socioeconomic impact of treatment with biological disease-modifying antirheumatic drugs in Japanese patients with rheumatoid arthritis.

OBJECTIVES: We evaluate the socioeconomic impact of treatment with biological and targeted synthetic disease-modifying antirheumatic drugs in Japanese patients with rheumatoid arthritis. METHODS: We analysed data retrospectively from the prospective observational CorEvitas RA Japan Registry (March 2016-February 2020). Patients were categorised into paid workers (PWs) and home workers (HWs) and further based on drug classes. We assessed medication persistence, treatment outcomes, health care resource utilisation, and socioeconomic impact over 12 months, including direct (drugs and health care resource utilisation) and indirect (loss of productivity) costs. RESULTS: Overall, 187 PWs and 114 HWs were identified. Over 12 months, medication persistence was high, treatment outcomes improved, and outpatient visits reduced in both groups. Following treatment initiation, direct costs increased, whereas indirect (loss of productivity) costs decreased in both groups. The unadjusted socioeconomic impact [Japanese yen (JPY)] increased across all drug classes in PWs (range: 29,700-151,700) and HWs (range: -28,700 to 83,000). Adjusted change in monthly socioeconomic impact was JPY 29,700-138,900 for PWs and JPY -28,000 to 92,800 for HWs. CONCLUSIONS: In this study of Japanese patients with rheumatoid arthritis, the socioeconomic burden increased across patient groups and drug classes. The decrease in indirect (loss of productivity) costs partially offset the increase in direct costs.

Cytokeratin profile and keratinocyte gene expression in keratinized lid margins of patients with chronic Stevens-Johnson syndrome.

PURPOSE: To study the cytokeratin profile and keratinization-related gene expression in keratinized lid margins of chronic Stevens-Johnson syndrome (SJS) patients. METHODS: Posterior eyelid margins from 24 chronic SJS patients undergoing mucous membrane grafting and six healthy margins (orbital exenteration, fresh body donors) were studied using immunofluorescence staining (CK10, CK1, filaggrin, transglutaminase 1 (TGM1), (CK19, MUC5AC)) and quantitative PCR (keratinization-related genes-HBEGF, KGF, EGF, TGFα, TGFß, and TNFα). The staining and gene expression were studied separately in the lid margin epidermis (LME) and lid margin conjunctiva (LMC). RESULTS: The expression of CK 1/10, filaggrin, and TGM1 in the LMC was similar to the LME in SJS patients. CK19 was expressed only in the basal epithelial layer of the LMC with loss of MUC5AC expression. Increased expression of KGF (p ≤ 0.056), TNFα (p ≤ 0.02), and TGFα (p ≤ 0.01) was observed in the LME of SJS patients compared to normal LME. LMC of SJS patients showed an increased expression of HBEGF (p ≤ 0.002), EGF (p ≤ 0.0002), KGF (p ≤ 0.02), TNFα (p ≤ 0.04), TGFα (p ≤ 0.003), and TGFß (p ≤ 0.001) compared to normal LMC. Significant differences were observed in the expression of these genes between LME and LMC of SJS patients. These genes were validated using String analysis, which revealed the positive regulation of keratinization. CONCLUSION: In lid margins of SJS, there is an increased expression of keratinization-related genes compared to the normal lid margin. Keratinized LMC shares similar cytokeratin profile and keratinization gene expression as seen in cutaneous epithelium of SJS patients, indicating the possibility of the cutaneous epithelium as a source for keratinized LMC.

Social influence of adult children on parental health behavior among South Asian immigrants: findings from the MASALA (Mediators of Atherosclerosis in South Asians Living in America) study.

Objectives: Examine the social influence of adult children on the cardiovascular-related health behaviors of older South Asian (SA) immigrants to inform lifestyle interventions.Design: This mixed-methods study used data from an ancillary study of social networks (2014-2018) in the Mediators of Atherosclerosis in South Asians Living in America cohort. Phase 1 was a quantitative analysis of self-reported diet and physical activity among SA adults (n = 448, mean age = 58 years, SD 8.4) who named at least one adult child to their social network. The Alternative Healthy Eating Index (AHEI) was used to measure parents' diet; higher numbers indicate a healthier diet (range 0-110). Phase 2 was a thematic content analysis of in-depth qualitative interviews from a subsample of these parents (n = 23, mean age = 55, SD 7.6).Results: Parents with an adult child in their network who consumed uncooked vegetables daily had mean parental AHEI score 1.5 points higher (adjusted p-value = 0.03) than those who had a child in the network who ate uncooked vegetables less often. When at least one adult child in their network ate fresh fruit daily compared to less frequently or when at least one child ate non-SA food daily compared to less frequently, mean parental AHEI scores were higher by 2.0 (adjusted p-value = 0.01) and 1.6 (adjusted p-value = 0.03) points respectively. Parents with an adult child in their network who exercised at least weekly were more likely to meet guideline-recommended physical activity levels than parents with children who exercised less often (76% v. 56%, adjusted p-value = 0.02). Adult children provided social support and were seen as 'role models' for healthy behavior, especially when adopting Western health behaviors.Conclusion: Positive role modeling and support from adult children were important facilitators of healthy behavior change in older SA immigrants and can inform health behavior interventions for SA adults.

In Vivo Pharmacokinetic/Pharmacodynamic Targets of Levonadifloxacin against Staphylococcus aureus in a Neutropenic Murine Lung Infection Model.

Levonadifloxacin is a novel benzoquinolizine subclass of fluoroquinolone, active against quinolone-resistant Staphylococcus aureus A phase 3 trial for levonadifloxacin and its oral prodrug was recently completed. The present study identified area under the concentration-time curve for the free, unbound fraction of a drug divided by the MIC (fAUC/MIC) as an efficacy determinant for levonadifloxacin in a neutropenic murine lung infection model. Mean plasma fAUC/MIC requirement for static and 1 log10 kill effects against 9 S. aureus were 8.1 ± 6.0 and 25.8 ± 12.3, respectively. These targets were employed in the selection of phase 3 doses.

High voltage generation from lead-free magnetoelectric coaxial nanotube arrays and their applications in nano energy harvesters.

Harvesting energy from surrounding vibrations and developing self-powered portable devices for wireless and mobile electronics have recently become popular. Here the authors demonstrate the synthesis of piezoelectric energy harvesters based on nanotube arrays by a wet chemical route, which requires no sophisticated instruments. The energy harvester gives an output voltage of 400 mV. Harvesting energy from a sinusoidal magnetic field is another interesting phenomenon for which the authors fabricated a magnetoelectric energy harvester based on piezoelectric-magnetostrictive coaxial nanotube arrays. Piezoelectric K0.5Na0.5NbO3 (KNN) is fabricated as the shell and magnetostrictive CoFe2O4 (CFO) as the core of the composite coaxial nanotubes. The delivered voltages are as high as 300 mV at 500 Hz and at a weak ac magnetic field of 100 Oe. Further tailoring of the thickness of the piezoelectric and magnetic layers can enhance the output voltage by several orders. Easy, single-step wet chemical synthesis enhances the industrial upscaling potential of these nanotubes as energy harvesters. In view of the excellent properties reported here, the lead-free piezoelectric component (KNN) in this nanocomposite should be explored for eco-friendly piezoelectric as well as magnetoelectric power generators in nanoelectromechanical systems (NEMS).

NTRK3 kinase fusions in Spitz tumours.

Oncogenic fusions in TRK family receptor tyrosine kinases have been identified in several cancers and can serve as therapeutic targets. We identified ETV6-NTRK3, MYO5A-NTRK3 and MYH9-NTRK3 fusions in Spitz tumours, and demonstrated that NTRK3 fusions constitutively activate the mitogen-activated protein kinase, phosphoinositide 3-kinase and phospholipase Cγ1 pathways in melanocytes. This signalling was inhibited by DS-6051a, a small-molecule inhibitor of NTRK1/2/3 and ROS1. NTRK3 fusions expand the range of oncogenic kinase fusions in melanocytic neoplasms and offer targets for a small subset of melanomas for which no targeted options currently exist. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Simple Limbal Epithelial Transplantation: Long-Term Clinical Outcomes in 125 Cases of Unilateral Chronic Ocular Surface Burns.

PURPOSE: This study describes the long-term clinical outcomes of autologous simple limbal epithelial transplantation (SLET), a relatively new technique of limbal stem cell transplantation. DESIGN: This was a single-center prospective interventional cases series. PARTICIPANTS: This study included 125 patients, 65 adults and 60 children who developed unilateral limbal stem cell deficiency (LSCD) after suffering with ocular surface burns and underwent SLET between 2010 and 2014. METHODS: A 1-clock hour limbal biopsy sample was obtained from the unaffected eye. At the same sitting, the recipient eye was surgically prepared and the donor tissue was divided into small pieces and transplanted using an amniotic membrane scaffold with fibrin glue. MAIN OUTCOME MEASURES: The diagnosis and outcome in every case was validated by 5 independent masked assessors. The primary outcome measure was restoration of a completely epithelized, stable, and avascular corneal surface. The secondary outcome measure was improvement in visual acuity. Complications, risk factors for failure, and immunohistochemistry analysis of corneas that underwent SLET also were described. RESULTS: At a median postoperative follow-up of 1.5 years (range, 1-4 years), 95 of 125 eyes (76%; 95% confidence interval, 68.5%-83.5%) maintained a successful outcome. Kaplan-Meier analysis revealed a comparable survival probability at 1 year of 80% in adults and 72% in children (P = 0.304). Two-line improvement in visual acuity was seen in 75.2%, and 67% of successful cases attained 20/60 or better vision (P < 0.0001). Progressive conjunctivalization occurred in 18.4% of eyes. The clinical factors associated with failure were identified as acid injury, severe symblepharon, SLET combined with keratoplasty, and postoperative loss of transplants (P ≤ 0.0075). Success rates were comparable among faculty and trainees (P = 0.71). Immunohistochemistry revealed successful regeneration of normal corneal epithelium (CK3(+)/12(+)) without admixture of conjunctiva cells (Muc5AC(-)/CK19(-)) and replenishment of limbal stem cell (ΔNp63α(+)/ABCG2(+)) reserve. CONCLUSIONS: Autologous SLET is an effective, reliable and replicable technique for long-lasting corneal regeneration and vision restoration in unilateral chronic ocular surface burns. Simple limbal epithelial transplantation is probably preferable to other techniques of limbal stem cell transplantation, particularly where cell cultivation facilities are unavailable.

Qualitative Process Evaluation of a Community-Based Culturally Tailored Lifestyle Intervention for Underserved South Asians.

Introduction There are few examples of effective cardiovascular disease prevention interventions for South Asians (SAs). We describe the results of a process evaluation of the South Asian Heart Lifestyle Intervention for medically underserved SAs implemented at a community-based organization (CBO) using community-based participatory research methods and a randomized control design (n = 63). Method Interviews were conducted with 23 intervention participants and 5 study staff using a semistructured interview guide focused on participant and staff perceptions about the intervention's feasibility and efficacy. Data were thematically analyzed. Results Intervention success was attributed to trusted CBO setting, culturally concordant study staff, and culturally tailored experiential activities. Participants said that these activities helped increase knowledge and behavior change. Some participants, especially men, found that self-monitoring with pedometers helped motivate increased physical activity. Participants said that the intervention could be strengthened by greater family involvement and by providing women-only exercise classes. Staff identified the need to reduce participant burden due to multicomponent intervention and agreed that the CBO needed greater financial resources to address participant barriers. Conclusion Community-based delivery and cultural adaptation of an evidence-based lifestyle intervention were effective and essential components for reaching and retaining medically underserved SAs in a cardiovascular disease prevention intervention study.