Update on Hedgehog Pathway Inhibitor Therapy for Patients with Basal Cell Naevus Syndrome or High-frequency Basal Cell Carcinoma.

Some patients with basal cell carcinoma develop a large number of basal cell carcinomas during their lives. The most common underlying genetic disease that causes multiple basal cell carcinomas is basal cell naevus syndrome. Basal cell naevus syndrome is caused by a germline mutation in patched-1 (PTCH1), a tumour suppressor gene of the hedgehog signalling pathway. However, in a significant portion of patients with multiple basal cell carcinomas, no underlying genetic cause is found. Nevertheless, these patients can experience a treatment burden comparable to that of patients with basal cell naevus syndrome. They are referred to as high-frequency basal cell carcinoma patients. Hedgehog pathway inhibitors were the first group of targeted therapy for basal cell carcinomas. This study reviews the literature on hedgehog pathway inhibitor therapy for patients with basal cell naevus syndrome and high-frequency basal cell carcinoma, to provide an overview on efficacy, safety, dosing regimens, tumour resistance and reoccurrence, and health-related quality of life.

Cumulative Sum Analysis for the Learning Curve of Optical Coherence Tomography Assisted Diagnosis of Basal Cell Carcinoma.

The amount of training needed to correctly interpret optical coherence tomography scans of the skin is undefined. The aim of this study was to illustrate how cumulative sum charts can be used to determine how many optical coherence tomography scans novice assessors should evaluate in order to obtain competence in diagnosing basal cell carcinoma. Four hundred lesions suspected for non-melanoma skin cancer were evaluated by optical coherence tomography in combination with clinical photographs, using a 5-point confidence scale. The diagnostic error rate (sum of false-negative and false-positive optical coherence tomography results/total number of cases) was used to evaluate performance, with histopathological diagnosis as the reference standard. Acceptable and unacceptable error rates were set at 16% and 25%, respectively. Adequate performance was reached after assessing 183-311 scans, dependent on the cut-off for a positive test result. In conclusion, cumulative sum analysis is useful to monitor the progress of optical coherence tomography trainees. The caseload necessary for training is substantial.

Surgery versus combined treatment with curettage and imiquimod for nodular basal cell carcinoma: One-year results of a noninferiority, randomized, controlled trial.

PURPOSE: Nodular basal cell carcinoma (nBCC) is mostly treated with surgical excision. Interest in minimally invasive treatment of these low-risk tumors is increasing. We assessed the effectiveness of nBCC treatment with curettage and imiquimod cream compared with surgical excision. METHODS: Patients with nBCC included in this randomized, controlled noninferiority trial were randomly assigned to either a curettage and imiquimod cream group or a surgical excision group. The primary endpoint was the proportion of patients free from treatment failure 1 year after the end of treatment. A prespecified noninferiority margin of 8% was used. A modified intention-to-treat and a per-protocol analysis was performed (ClinicalTrials.gov identifier NCT02242929). RESULTS: One hundred forty-five patients were randomized: 73 to the curettage and imiquimod cream group and 72 to the surgical excision group. The proportion of patients free of recurrence after 12 months was 86.3% (63/73) for the curettage and imiquimod group and 100% (72/72) for the surgical excision group. The difference in efficacy was -13.7% (95% confidence interval -21.6% to -5.8%; 1-sided P = .0004) favoring surgical excision. CONCLUSION: Noninferiority of curettage and imiquimod cream cannot be concluded. Given the still high efficacy of curettage and imiquimod cream and the indolent growth pattern of nBCC, curettage and imiquimod could still be a valuable treatment option with the possibility to prevent overuse of excisions. However, it cannot replace surgical excision.

Optical Coherence Tomography for Noninvasive Diagnosis and Subtyping of Basal Cell Carcinoma: A Prospective Cohort Study.

Noninvasive diagnostic strategies such as optical coherence tomography (OCT) enable detailed examination of skin tissue architecture and have potential for identification and subtyping of basal cell carcinoma (BCC). To evaluate the additional diagnostic value of OCT, a prospective cohort study was performed in 182 patients with 250 lesions suspected for non-melanoma skin premalignancies requiring a biopsy. Accuracy of BCC diagnosis and subtype on the basis of clinical examination (CE) of patients was compared with that on the basis of OCT scans in conjunction with clinical images of lesions (cOCT). Confidence levels were recorded on a 5-point scale, where score 0 indicated absence of BCC and scores 1-4 indicated increasing suspicion of BCC. Diagnostic performance parameters were compared using histopathologic diagnosis as gold standard. The patient-based area under the receiver operating characteristic curve (AUC) increased from 85.6% for CE to 91.2% for cOCT (P = 0.061) and the lesion-based AUC from 82.7% to 91.3% (P < 0.001). When confidence scores 1-4 were defined as positive, patient-based specificity increased from 47.5% (CE alone) to 76.8% (cOCT) at similar sensitivity (97.6% and 95.2%, respectively). cOCT slightly improved the ability to discriminate between superficial and nonsuperficial BCC subtypes and seemed to be a valuable addition to CE alone in the diagnosis and subtyping of BCC.

Visible light communication using InGaN optical sources with AlInGaP nanomembrane down-converters.

We report free space visible light communication using InGaN sources, namely micro-LEDs and a laser diode, down-converted by a red-emitting AlInGaP multi-quantum-well nanomembrane. In the case of micro-LEDs, the AlInGaP nanomembrane is capillary-bonded between the sapphire window of a micro-LED array and a hemispherical sapphire lens to provide an integrated optical source. The sapphire lens improves the extraction efficiency of the color-converted light. For the case of the down-converted laser diode, one side of the nanomembrane is bonded to a sapphire lens and the other side optionally onto a dielectric mirror; this nanomembrane-lens structure is remotely excited by the laser diode. Data transmission up to 870 Mb/s using pulse amplitude modulation (PAM) with fractionally spaced decision feedback equalizer is demonstrated for the micro-LED-integrated nanomembrane. A data rate of 1.2 Gb/s is achieved using orthogonal frequency division multiplexing (ODFM) with the laser diode pumped sample.

Visible light communications using a directly modulated 422 nm GaN laser diode.

Visible light communications using a Gallium-nitride (GaN) laser diode is reported. Devices, which are cased in TO packages, show modulation bandwidths of up to 1.4 GHz. We demonstrate error-free data transmission, defined as transmission of 1×10(-9) bits without any errors, at 2.5 Gbit/s with a sensitivity of 11.5 dBm.

A semiconductor laser with monolithically integrated dynamic polarization control.

We report the first demonstration of a semiconductor laser monolithically integrated with an active polarization controller, which consists of a polarization mode converter followed by an active, differential phase shifter. High speed modulation of the device output polarization is demonstrated via current injection to the phase shifter section.

Costimulation of resting B lymphocytes alters the IL-4-activated IRS2 signaling pathway in a STAT6 independent manner: implications for cell survival and proliferation.

IL-4 is an important B cell survival and growth factor. IL-4 induced the tyrosine phosphorylation of IRS2 in resting B lymphocytes and in LPS- or CD40L-activated blasts. Phosphorylated IRS2 coprecipitated with the p85 subunit of PI 3' kinase in both resting and activated cells. By contrast, association of phosphorylated IRS2 with GRB2 was not detected in resting B cells after IL-4 treatment although both proteins were expressed. However, IL-4 induced association of IRS2 with GRB2 in B cell blasts. The pattern of IL-4-induced recruitment of p85 and GRB2 to IRS2 observed in B cells derived from STAT6 null mice was identical to that observed for normal mice. While IL-4 alone does not induce activation of MEK, a MEK1 inhibitor suppressed the IL-4-induced proliferative response of LPS-activated B cell blasts. These results demonstrate that costimulation of splenic B cells alters IL-4-induced signal transduction independent of STAT6 leading to proliferation. Furthermore, proliferation induced by IL-4 in LPS-activated blasts is dependent upon the MAP kinase pathway.

Helping construct desirable identities: a self-presentational view of psychotherapy.

The author reviews the research demonstrating not only that clients withhold personal information and reactions from their therapists but also that such discretion is associated with positive therapy process ratings and outcomes. These results run counter to traditional approaches to psychotherapy, which demand a high degree of openness from clients. These puzzling findings can be explained by conceptualizing psychotherapy as a self-presentational process, wherein clients come to benefit from therapy by perceiving that their therapists have favorable views of them. Creating these favorable impressions can involve clients' hiding some undesirable aspects of themselves from their therapists. The author offers findings from the psychotherapy and social-psychology literatures in support of this view and makes suggestions concerning what clients and therapists might optimally reveal in therapy.

Cutting edge: effects of an allergy-associated mutation in the human IL-4R alpha (Q576R) on human IL-4-induced signal transduction.

A mutation in the human (hu) IL-4R alpha, Q576R, has been linked with allergy in humans. Increased sensitivity of patients cells with this mutation to IL-4 suggest that a Q576R change enhances IL-4 signaling. To directly test this hypothesis, we analyzed the ability of huIL-4R alpha cDNA bearing the Q576R and Y575F mutations to signal tyrosine phosphorylation, DNA-binding activity, proliferation, protection from apoptosis, and CD23 induction in response to huIL-4 in murine cells. Responses generated by the Q576R and Y575F mutants were similar to those of the wild-type receptor, using various concentrations of huIL-4 and times of stimulation. These results indicate that neither the Q576R nor the Y575F mutations have a significant direct effect on IL-4 signal transduction, and that hypersensitive induction of CD23 in cells derived from human allergy patients may be due to different and/or additional alterations in the IL-4 signaling pathway.

Radon and lung cancer: a cost-effectiveness analysis.

OBJECTIVES: This study examined the cost-effectiveness of general and targeted strategies for residential radon testing and mitigation in the United States. METHODS: A decision-tree model was used to perform a cost-effectiveness analysis of preventing radon-associated deaths from lung cancer. RESULTS: For a radon threshold of 4 pCi/L, the estimated costs to prevent 1 lung cancer death are about $3 million (154 lung cancer deaths prevented), or $480,000 per life-year saved, based on universal radon screening and mitigation, and about $2 million (104 lung cancer deaths prevented), or $330,000 per life-year saved, if testing and mitigation are confined to geographic areas at high risk for radon exposure. For mitigation undertaken after a single screening test and after a second confirmatory test, the estimated costs are about $920,000 and $520,000, respectively, to prevent a lung cancer death with universal screening and $130,000 and $80,000 per life-year for high risk screening. The numbers of preventable lung cancer deaths are 811 and 527 for universal and targeted approaches, respectively. CONCLUSIONS: These data suggest possible alternatives to current recommendations.

Production of a chimeric form of CD23 that is oligomeric and blocks IgE binding to the Fc epsilonRI.

The low affinity receptor for IgE (Fc epsilonRII/CD23) has previously been shown to interact with IgE with a dual affinity. Three chimeric constructs were created containing the lectin domain (amino acids 172-188) or the "neck" and lectin domain (amino acids 157-188) attached to subunits of oligomeric proteins. All chimeras were incapable of interacting with IgE with either a high or low affinity, indicating that the alpha-helical stalk of CD23 is important for orienting the lectin heads such that an interaction with IgE can occur. This concept received further support in that a chimeric CD23 composed of the human CD23 stalk and the mouse CD23 lectin head bound mouse IgE with a dual affinity, but could only bind rat IgE with a low affinity. Effort was next concentrated on a construct consisting of the entire extracellular (EC) region of CD23. A mutation to the first cleavage site of CD23 (C1M) resulted in a more stable molecule as determined by a decrease of soluble CD23 release. A soluble chimeric EC-C1M was prepared by attaching an isoleucine zipper to the amino terminus (lzEC-C1M). The interaction with IgE by lzEC-C1M was found to be superior to that seen with EC-CD23. The lzEC-C1M could inhibit binding of IgE to both CD23 and the high affinity receptor for IgE, Fc epsilonRI, providing further evidence for a strong interaction with IgE. Fc epsilonRI inhibition (approximately 70%) was seen at equimolar concentrations of lzEC-C1M, implying the effectiveness of this chimera and suggesting its potential therapeutic value.

Analysis of murine soluble Fc epsilon RII sites of cleavage and requirements for dual-affinity interaction with IgE.

The low-affinity receptor for IgE (Fc epsilon RII/CD23) is a type II integral membrane protein with an extracellular C-terminal sequence homologous to C-type animal lectins. Between this region and the membrane is a repetitive sequence predicted to form an alpha-helical coiled-coil and is termed the stalk region. The Fc epsilon RII is proteolytically cleaved when at the cell surface in this stalk region. Both the 38 Kd and 28 Kd major released fragments were isolated from culture media and N-terminal sequencing demonstrated that the cleavage sites were in the third and fourth repeat domains, respectively. The identified sites show no apparent similarity with the cleavage sites previously identified in human Fc epsilon RII. Recent studies have demonstrated that the intact Fc epsilon RII interacts with IgE with a dual-affinity, resulting from a multivalent interaction with the IgE Fc region; mutant Fc epsilon RII that have a disruption of the alpha-helical coiled-coil have a single low-affinity interaction consistent with a monomeric interaction with IgE. The soluble Fc epsilon RII were shown to interact with IgE with an affinity similar to these mutant Fc epsilon RII. Preparation of a chimeric Fc epsilon RII in which the transmembrane and cytoplasmic regions were replaced with sequences from Ly-49 revealed that these regions played no role in the multimeric association of the Fc epsilon RII necessary for dual-affinity interaction with IgE. In addition, a full-sized soluble Fc epsilon RII construct was expressed, and this molecule demonstrated increased capacity to interact with IgE.

More than the sum of their parts: Martha Rogers and Hildegard Peplau.

Nursing practice is guided by a variety of theoretical models. Therefore, nursing theories are commonly selected by service institutions to focus practice. Both Rogers and Peplau made major contributions to the theory and practice of nursing, and both are appropriate models for the discipline of psychiatric and mental health nursing. This article explores the grand theory of Martha Rogers in conjunction with the use of the middle-range theory of Hildegard Peplau. Points of resonance, theoretical fit, and differences between theories are discussed. Appropriateness to practice of both theories are identified and the need for both perspectives is articulated.

Confidants' feedback and traumatic life events.

One hundred six undergraduate (83 women and 23 men) completed surveys concerning their most traumatic life event, the feedback they received following their disclosure of the event to others, and how they felt after the disclosure. Results indicated that the better they felt after disclosure, the less disturbed they were by thoughts of the event at the time of the study. In addition, the more personal the trauma was, the worse they felt after their disclosure, and the more disturbed they were about the trauma. However, no significant relation existed between the positivity (e.g., supportiveness) of their confidant's feedback and their present degree of disturbance. Implications for understanding the complex relation between confiding traumatic events and resolving feelings surrounding those events were discussed.

Enhancing staff nurses' interpersonal skills: theory to practice.

Nurses working with psychiatric-mental health patients require a repertoire of skills to assess patient behavior and needs, design creative interventions, and evaluate care. The work of interpersonal psychiatric nursing exists within the therapeutic relationship between nurse and patient. A coordinated series of classes and clinical supervision sessions that present an approach to psychiatric nursing care using three major themes of Peplau's model: learning acquisition, language competencies, and anxiety reduction are described. Clinical supervision was strongly encouraged for participants and one clinical supervisor decided to model supervisory sessions using elements of Peplau's theory. Utilizing selected aspects of Peplau's interventional techniques during clinical supervision and reflecting on the experience provided an opportunity to validate and integrate new knowledge and skills. Nurses who sought supervision thus had the advantage of experimental learning through participation in clinical supervision.