A systematic review of the management of eosinophilic dermatosis of hematological malignancy.

Eosinophilic dermatosis of hematologic malignancy (EDHM) is a cutaneous manifestation seen in patients with hematoproliferative and lymphoproliferative disorders, most commonly chronic lymphocytic leukemia. This systematic review aimed to summarize the therapeutic interventions of EDHM. A comprehensive search yielded 71 studies, predominantly case reports and series. The most frequently reported modalities were systemic and topical corticosteroids, as well as treatment of the underlying malignancy. Responses to these treatments varied. Targeted therapies, including dupilumab and omalizumab, showed promise, as did other modalities such as montelukast, dapsone, doxycycline, and phototherapy. Higher-quality studies should be conducted to facilitate higher-quality management recommendations for EDHM.

Does tocilizumab have a role in dermatology? A review of clinical applications, its adverse side effects and practical considerations.

Tocilizumab is a humanized monoclonal antibody to the interleukin-6 (IL-6) receptor which was first approved for use in refractory rheumatoid arthritis almost a decade ago. Since then, its use has expanded to a number of rheumatological and inflammatory conditions. In dermatology, off-label use of tocilizumab has been reported to be efficacious in morphoea, systemic sclerosis, psoriasis, atopic dermatitis, vitiligo, graft-versus-host disease, pyoderma gangrenosum, Behcet's disease, Schnitzler's syndrome, sarcoidosis, and cutaneous adverse reactions. That being said, the evidence demonstrating tocilizumab's efficacy in dermatology is predominantly low-level case-based evidence, and one must consider the potential for publication bias. In this review we will discuss the reported clinical applications of tocilizumab in dermatology, mechanisms of action, and the range of associated adverse effects (both cutaneous and non-cutaneous) that can occur. Additionally, we will discuss the role of tocilizumab in the management of COVID-19.

Device-independent quantum key distribution with random key basis.

Device-independent quantum key distribution (DIQKD) is the art of using untrusted devices to distribute secret keys in an insecure network. It thus represents the ultimate form of cryptography, offering not only information-theoretic security against channel attacks, but also against attacks exploiting implementation loopholes. In recent years, much progress has been made towards realising the first DIQKD experiments, but current proposals are just out of reach of today's loophole-free Bell experiments. Here, we significantly narrow the gap between the theory and practice of DIQKD with a simple variant of the original protocol based on the celebrated Clauser-Horne-Shimony-Holt (CHSH) Bell inequality. By using two randomly chosen key generating bases instead of one, we show that our protocol significantly improves over the original DIQKD protocol, enabling positive keys in the high noise regime for the first time. We also compute the finite-key security of the protocol for general attacks, showing that approximately 108-1010 measurement rounds are needed to achieve positive rates using state-of-the-art experimental parameters. Our proposed DIQKD protocol thus represents a highly promising path towards the first realisation of DIQKD in practice.

A simple technique to reconstruct medium to large scalp defects with exposed bone.

Medium to large scalp defects with exposed bone can pose particular challenges to the dermatologic surgeon. Most of the publications pertaining to the repair of such defects are presented in the plastic surgery literature. Dermatologic surgeons may have less experience in this area and be hesitant to pursue surgery when these defects may be encountered. The technique described below is a simple, one-stage reconstruction, with a short healing period, providing adequate cosmesis, and is within the capability of most dermatologic surgeons.

Advantage Distillation for Device-Independent Quantum Key Distribution.

Device-independent quantum key distribution (DIQKD) offers the prospect of distributing secret keys with only minimal security assumptions, by making use of a Bell violation. However, existing DIQKD security proofs have low noise tolerances, making a proof-of-principle demonstration currently infeasible. We investigate whether the noise tolerance can be improved by using advantage distillation, which refers to using two-way communication instead of the one-way error correction currently used in DIQKD security proofs. We derive an efficiently verifiable condition to certify that advantage distillation is secure against collective attacks in a variety of DIQKD scenarios, and use this to show that it can indeed allow higher noise tolerances, which could help to pave the way towards an experimental implementation of DIQKD.

The use of oral antibiotics in treating acne vulgaris: a new approach.

Although acne is not an infectious disease, oral antibiotics have remained a mainstay of treatment over the last 40 years. The anti-inflammatory properties of oral antibiotics, particularly the tetracyclines, are efficacious in treating inflammatory acne lesions. Common prescribing practices in Dermatology exert significant selection pressure on bacteria, contributing to the development of antibiotic resistance. Antibiotic use for acne not only promotes resistance in Propionibacterium acnes, but also affects other host bacteria with pathogenic potential. This review will summarize the commonly used treatments for acne vulgaris, and how they should be combined as rational treatment. The indications for using oral antibiotics in acne will be highlighted. Strategies described in the literature to conserve the utility of oral antibiotics will be summarized. These include limiting the duration of antibiotic therapy, concomitant use of a topical non-antibiotic agent, use of subantimicrobial dose doxycycline, and the introduction of topical dapsone.

Mohs surgery histopathology concordance in Australia.

BACKGROUND: Mohs micrographic surgery is an important technique for dealing with difficult non-melanoma skin cancers. The ability of the Mohs surgeon to correctly interpret the histopathology is crucial to the practice of this surgery. This study sought to assess the concordance between a Mohs surgeon and a dermatopathologist in the reading of Mohs section histopathology slides. METHODS: This study was a retrospective study of Mohs frozen section histopathology slides of patients from a private Mohs practice. The slides were provided for assessment by a dermatopathologist who had to interpret the histopathology and mark on a Mohs map the location of the tumour. RESULTS: We demonstrate a 95% agreement between the Mohs surgeon and the dermatopathologist in the interpretation of Mohs frozen section histopathology slides. CONCLUSION: An Australian Mohs surgeon is capable of correctly identifying and interpreting histopathology in non-melanoma skin cancers, and this compares favourably to an overseas study.

Insulin receptor substrate-2 regulates aerobic glycolysis in mouse mammary tumor cells via glucose transporter 1.

The insulin receptor substrate (IRS) proteins are cytoplasmic adaptor molecules that function as signaling intermediates downstream of activated cell surface receptors. Based on data implicating IRS-2 but not IRS-1 in breast cancer invasion, survival, and metastasis, we assessed the contribution of IRS-1 and IRS-2 to aerobic glycolysis, which is known to impact tumor growth and progression. For this purpose, we used tumor cell lines derived from transgenic mice that express the polyoma virus middle T antigen (PyV-MT) in the mammary gland and that are wild-type (WT) or null for either Irs-1 (Irs-1-/-) or Irs-2 (Irs-2-/-). Aerobic glycolysis, as assessed by the rate of lactic acid production and glucose consumption, was diminished significantly in Irs-2-/- cells when compared with WT and Irs-1-/- cells. Expression of exogenous Irs-2 in Irs-2-/- cells restored the rate of glycolysis to that observed in WT cells. The transcription factor FoxO1 does not appear to be involved in Irs-2-mediated glycolysis. However, Irs-2 does regulate the surface expression of glucose transporter 1 (Glut1) as assessed by flow cytometry using a Glut1-specific ligand. Suppression of Glut1 expression inhibits Irs-2-dependent invasion, which links glycolysis to mammary tumor progression. Irs-2 was shown to be important for mammalian target of rapamycin (mTor) activation, and Irs-2-dependent regulation of Glut1 surface expression is rapamycin-sensitive. Collectively, our data indicate that Irs-2, but not Irs-1, promotes invasion by sustaining the aerobic glycolysis of mouse mammary tumor cells and that it does so by regulating the mTor-dependent surface expression of Glut1.

Adenosine upregulates CXCR4 and enhances the proliferative and migratory responses of human carcinoma cells to CXCL12/SDF-1alpha.

The level of expression of the chemokine receptor CXCR4 has been shown to play a crucial role in determining the ability of cancer cells to metastasize from the primary tumor and become established in tissue sites that are rich in the CXCR4 ligand CXCL12/SDF-1alpha. High CXCR4 expression on cancer cells is associated with an increased risk of recurrence and poorer overall survival. We propose that local tissue mediators within the primary tumor or at secondary sites may modulate the level of CXCR4 expression and, therefore, potentially affect the ability of the cancer cells to metastasize. The purine nucleoside adenine-9-beta-D-ribofuranoside (adenosine) is generated at high concentrations within the extracellular fluid of solid tumors because of their hypoxia. We show here that adenosine acts through A(2A) and A(2B) adenosine receptors on human colorectal carcinoma cells to upregulate CXCR4 mRNA expression up to 10-fold and selectively increases cell-surface CXCR4 protein up to 3-fold. This increase in cell-surface CXCR4 enables the carcinoma cells to migrate toward CXCL12, and enhances their proliferation in response to CXCL12. Adenosine may therefore be one of the factors within the tumor microenvironment that facilitates tumor dissemination, by upregulating CXCR4 on certain cancer cells and enhancing cellular responses to CXCL12.

Adenosine downregulates DPPIV on HT-29 colon cancer cells by stimulating protein tyrosine phosphatase(s) and reducing ERK1/2 activity via a novel pathway.

The multifunctional cell-surface protein dipeptidyl peptidase IV (DPPIV/CD26) is aberrantly expressed in many cancers and plays a key role in tumorigenesis and metastasis. Its diverse cellular roles include modulation of chemokine activity by cleaving dipeptides from the chemokine NH(2)-terminus, perturbation of extracellular nucleoside metabolism by binding the ecto-enzyme adenosine deaminase, and interaction with the extracellular matrix by binding proteins such as collagen and fibronectin. We have recently shown that DPPIV can be downregulated from the cell surface of HT-29 colorectal carcinoma cells by adenosine, which is a metabolite that becomes concentrated in the extracellular fluid of hypoxic solid tumors. Most of the known responses to adenosine are mediated through four different subtypes of G protein-coupled adenosine receptors: A(1), A(2A), A(2B), and A(3). We report here that adenosine downregulation of DPPIV from the surface of HT-29 cells occurs independently of these classic receptor subtypes, and is mediated by a novel cell-surface mechanism that induces an increase in protein tyrosine phosphatase activity. The increase in protein tyrosine phosphatase activity leads to a decrease in the tyrosine phosphorylation of ERK1/2 MAP kinase that in turn links to the decline in DPPIV mRNA and protein. The downregulation of DPPIV occurs independently of changes in the activities of protein kinases A or C, phosphatidylinositol 3-kinase, other serine/threonine phosphatases, or the p38 or JNK MAP kinases. This novel action of adenosine has implications for our ability to manipulate adenosine-dependent events within the solid tumor microenvironment.

Adenosine down-regulates the surface expression of dipeptidyl peptidase IV on HT-29 human colorectal carcinoma cells: implications for cancer cell behavior.

Dipeptidyl peptidase IV (DPPIV) is a multifunctional cell-surface protein that, as well as having dipeptidase activity, is the major binding protein for adenosine deaminase (ADA) and also binds extracellular matrix proteins such as fibronectin and collagen. It typically reduces the activity of chemokines and other peptide mediators as a result of its enzymatic activity. DPPIV is aberrantly expressed in many cancers, and decreased expression has been linked to increases in invasion and metastasis. We asked whether adenosine, a purine nucleoside that is present at increased levels in the hypoxic tumor microenvironment, might affect the expression of DPPIV at the cell surface. Treatment with a single dose of adenosine produced an initial transient (1 to 4 hours) modest (approximately 10%) increase in DPPIV, followed by a more profound (approximately 40%) depression of DPPIV protein expression at the surface of HT-29 human colon carcinoma cells, with a maximal decline being reached after 48 hours, and persisting for at least a week with daily exposure to adenosine. This down-regulation ofDPPIV occurred at adenosine concentrations comparable to those present within the extracellular fluid of colorectal tumors growing in vivo, and was not elicited by inosine or guanosine. Neither cellular uptake of adenosine nor its phosphorylation was necessary for the down-regulation of DPPIV. The decrease in DPPIV protein at the cell surface was paralleled by decreases in DPPIV enzyme activity, binding of ADA, and the ability of the cells to bind to and migrate on cellular fibronectin. Adenosine, at concentrations that exist within solid tumors, therefore acts at the surface of colorectal carcinoma cells to decrease levels and activities of DPPIV. This down-regulation of DPPIV may increase the sensitivity of cancer cells to the tumor-promoting effects of adenosine and their response to chemokines and the extracellular matrix, facilitating their expansion and metastasis.

Cytokines as therapeutic targets for the gastrointestinal manifestations of scleroderma.

Systemic sclerosis (SSc), or scleroderma, is a connective tissue disorder characterized by progressive fibrosis of the skin and internal organs. It has significance for gastroenterologists because the gastrointestinal tract is involved in 90% of SSc patients, who often present with esophageal dysfunction. Though the exact pathogenesis of SSc is unknown, there is increasing evidence supporting an immune mechanism. Cytokines are the soluble mediators of immune activation, altered fibroblast proliferation and extracellular matrix accumulation in SSc and thereby provide important therapeutic targets. In the present review, the involvement of cytokines in SSc is discussed with particular emphasis on cytokines and growth factors that have been implicated in the disease process and likely play an important role in the gastrointestinal manifestations of scleroderma. The role of cytokines as therapeutic targets in scleroderma forms the basis of this timely review.