Incidence of skin malignancies in patients with vitiligo or psoriasis who received narrowband ultraviolet B phototherapy (308 nm/311 nm): A retrospective review of 3730 patients.

BACKGROUND: Previous studies regarding the risk of skin malignancy with NBUVB have been performed in Caucasian patients, but few studies have been conducted in Asians. AIM: The aim of the study was to determine the risk of skin cancer in Asian patients with psoriasis and vitiligo receiving NBUVB phototherapy. METHODS: We performed a 9-year retrospective study including all patients with psoriasis and vitiligo receiving NBUVB (either 311 nm wavelength through cabin phototherapy or 308 nm through excimer lamp phototherapy) at the National Skin Centre. We matched the identification numbers of patients to the National Registry of Diseases Office database and collected data on all skin cancers diagnosed. RESULTS: A total of 3730 patients were included. During the course of the study, 12 cases of skin cancer were diagnosed, of which 10 were basal cell carcinomas, and 2 were squamous cell carcinomas. No cases of melanoma were detected in the study. The age-standardized incidence of skin cancer in psoriasis and vitiligo patients who received phototherapy was 47.5 and 26.5, respectively, which is higher than the incidence of skin cancers in the general population. Risk of skin malignancy was positively correlated with the cumulative (p = .008) and maximum dose of phototherapy (p = .011) as well as previous systemic treatments (p = .006). LIMITATIONS: Limitations include a relatively short follow-up period as well as the lack of quantification of solar exposure. CONCLUSIONS: NBUVB phototherapy in Asian skin increases the risk of skin malignancy. The risk of skin malignancy is higher with psoriasis patients, greater cumulative and maximal dose of phototherapy as well as the use of systemic therapy. Despite the increased risk, the absolute number of skin malignancies remains low, especially for vitiligo patients, with no cases of melanoma diagnosed-a reassuring finding that phototherapy remains a safe alternative in the treatment of psoriasis and vitiligo.

Ultraviolet-A1 phototherapy in Asian skin: A review of 159 cases in Singapore.

BACKGROUND: Ultraviolet-A1 phototherapy has been used to treat many inflammatory dermatoses. AIMS: To determine the efficacy and safety of ultraviolet-A1 phototherapy in Asian skin. MATERIALS AND METHODS: We performed a review of records of patients undergoing ultraviolet-A1 phototherapy at our dermatology unit in Singapore from January 2007 to January 2011. Their electronic medical records were reviewed and a standardized questionnaire was filled up for data collection and tabulation. Chi-square or Fisher's exact tests were used to compare the difference in response between various groups for each characteristic. P value of < 0.05 was considered statistically significant. RESULTS: Our study comprised of 159 patients, of which 103 were patients with hand and foot eczema, 21 with atopic dermatitis, 17 with scleroderma and the remaining with miscellaneous dermatoses. Of these patients, 47.6% of patients with hand and feet eczema had good response after 10 sessions, which increased to 75% after 20 sessions and to 84.6% after 30 sessions. After 10 sessions, 47.6% of patients with atopic dermatitis had good response, which increased to 66.7% after 20 sessions. After 30 sessions, all the three remaining patients with atopic dermatitis experienced good response. For patients with scleroderma, only 11.8 and 10% had good response after 10 and 20 sessions, respectively, which increased to 40% after 30 sessions. LIMITATIONS: Limitations of our study include its retrospective design and, consequently, the lack of standardized treatment protocol, as well as subjective assessment in terms of clinical improvement. CONCLUSIONS: Ultraviolet-A1 phototherapy appears to be efficacious for the treatment of hand and foot eczema as well as atopic dermatitis. However, in patients with scleroderma, the response was partial and needed a longer duration of treatment.

Correction to "Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3".

[This corrects the article DOI: 10.1021/acsmedchemlett.9b00170.].

Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3.

SMYD3 is a histone methyltransferase that regulates gene transcription, and its overexpression is associated with multiple human cancers. A novel class of tetrahydroacridine compounds which inhibit SMYD3 through a covalent mechanism of action is identified. Optimization of these irreversible inhibitors resulted in the discovery of 4-chloroquinolines, a new class of covalent warheads. Tool compound 29 exhibits high potency by inhibiting SMYD3's enzymatic activity and showing antiproliferative activity against HepG2 in 3D cell culture. Our findings suggest that covalent inhibition of SMYD3 may have an impact on SMYD3 biology by affecting expression levels, and this warrants further exploration.

Target mechanism-based whole-cell screening identifies bortezomib as an inhibitor of caseinolytic protease in mycobacteria.

UNLABELLED: A novel type of antibacterial screening method, a target mechanism-based whole-cell screening method, was developed to combine the advantages of target mechanism- and whole-cell-based approaches. A mycobacterial reporter strain with a synthetic phenotype for caseinolytic protease (ClpP1P2) activity was engineered, allowing the detection of inhibitors of this enzyme inside intact bacilli. A high-throughput screening method identified bortezomib, a human 26S proteasome drug, as a potent inhibitor of ClpP1P2 activity and bacterial growth. A battery of secondary assays was employed to demonstrate that bortezomib indeed exerts its antimicrobial activity via inhibition of ClpP1P2: Down- or upmodulation of the intracellular protease level resulted in hyper- or hyposensitivity of the bacteria, the drug showed specific potentiation of translation error-inducing aminoglycosides, ClpP1P2-specific substrate WhiB1 accumulated upon exposure, and growth inhibition potencies of bortezomib derivatives correlated with ClpP1P2 inhibition potencies. Furthermore, molecular modeling showed that the drug can bind to the catalytic sites of ClpP1P2. This work demonstrates the feasibility of target mechanism-based whole-cell screening, provides chemical validation of ClpP1P2 as a target, and identifies a drug in clinical use as a new lead compound for tuberculosis therapy. IMPORTANCE: During the last decade, antibacterial drug discovery relied on biochemical assays, rather than whole-cell approaches, to identify molecules that interact with purified target proteins derived by genomics. This approach failed to deliver antibacterial compounds with whole-cell activity, either because of cell permeability issues that medicinal chemistry cannot easily fix or because genomic data of essentiality insufficiently predicted the vulnerability of the target identified. As a consequence, the field largely moved back to a whole-cell approach whose main limitation is its black-box nature, i.e., that it requires trial-and-error chemistry because the cellular target is unknown. We developed a novel type of antibacterial screening method, target mechanism-based whole-cell screening, to combine the advantages of both approaches. We engineered a mycobacterial reporter strain with a synthetic phenotype allowing us to identify inhibitors of the caseinolytic protease (ClpP1P2) inside the cell. This approach identified bortezomib, an anticancer drug, as a specific inhibitor of ClpP1P2. We further confirmed the specific "on-target" activity of bortezomib by independent approaches including, but not limited to, genetic manipulation of the target level (over- and underexpressing strains) and by establishing a dynamic structure-activity relationship between ClpP1P2 and growth inhibition. Identifying an "on-target" compound is critical to optimize the efficacy of the compound without compromising its specificity. This work demonstrates the feasibility of target mechanism-based whole-cell screening methods, validates ClpP1P2 as a druggable target, and delivers a lead compound for tuberculosis therapy.

Systematic review on the efficacy, safety, and cost-effectiveness of topical calcineurin inhibitors in atopic dermatitis.

BACKGROUND: Topical calcineurin inhibitors (TCIs) are widely used as an alternative to topical corticosteroids (TCSs) in treating of atopic dermatitis, but their risk versus benefit compared with TCSs remains unclear. OBJECTIVE: We performed a systematic review of the efficacy, safety, and cost-effectiveness of TCI compared with TCS and emollients. METHODS: Published meta-analysis, systematic reviews, and individual studies from January 2005 to January 2015 on the comparative efficacy, safety, and cost-effectiveness of TCI against emollients and TCS were included. RESULTS: Tacrolimus is comparable to TCS in efficacy, safety profile, and cost-effectiveness. Pimecrolimus has a similar safety profile compared with TCS, emollients, and tacrolimus. It is superior to emollients but inferior to TCS and tacrolimus in efficacy and cost-effectiveness. The association of tacrolimus with malignancy remains uncertain. CONCLUSIONS: Tacrolimus is an efficacious and cost-effective alternative to TCS, but its benefits need to be weighed against its still uncertain risk for malignancy. Pimecrolimus is appropriate for mild atopic dermatitis when TCS or tacrolimus is unsuitable.

C-terminal substitution of MDM2 interacting peptides modulates binding affinity by distinctive mechanisms.

The complex between the proteins MDM2 and p53 is a promising drug target for cancer therapy. The residues 19-26 of p53 have been biochemically and structurally demonstrated to be a most critical region to maintain the association of MDM2 and p53. Variation of the amino acid sequence in this range obviously alters the binding affinity. Surprisingly, suitable substitutions contiguous to this region of the p53 peptides can yield tightly binding peptides. The peptide variants may differ by a single residue that vary little in their structural conformations and yet are characterized by large differences in their binding affinities. In this study a systematic analysis into the role of single C-terminal mutations of a 12 residue fragment of the p53 transactivation domain (TD) and an equivalent phage optimized peptide (12/1) were undertaken to elucidate their mechanistic and thermodynamic differences in interacting with the N-terminal of MDM2. The experimental results together with atomistically detailed dynamics simulations provide insight into the principles that govern peptide design protocols with regard to protein-protein interactions and peptidomimetic design.

Interaction of antimicrobial peptides from Australian amphibians with lipid membranes.

Solid-state NMR and CD spectroscopy were used to study the effect of antimicrobial peptides (aurein 1.2, citropin 1.1, maculatin 1.1 and caerin 1.1) from Australian tree frogs on phospholipid membranes. 31P NMR results revealed some effect on the phospholipid headgroups when the peptides interact with DMPC/DHPC (dimyristoylphosphatidylcholine/dihexanoylphosphatidylcholine) bicelles and aligned DMPC multilayers. 2H NMR showed a small effect of the peptides on the acyl chains of DMPC in bicelles or aligned multilayers, suggesting interaction with the membrane surface for the shorter peptides and partial insertion for the longer peptides. 15N NMR of selectively labelled peptides in aligned membranes and oriented CD spectra indicated an alpha-helical conformation with helix long axis approximately 50 degrees to the bilayer surface at high peptide concentrations. The peptides did not appear to insert deeply into PC membranes, which may explain why these positively charged peptides preferentially lyse bacterial rather than eucaryotic cells.

Cooperative binding interactions of glycopeptide antibiotics.

Glycopeptide antibiotics of the vancomycin group bind to bacterial cell wall analogue precursors, and typically also form dimers. We have studied the interplay between these two sets of noncovalent bonds formed at separate interfaces. Indole-2-carboxylic acid (L) forms a set of hydrogen bonds to the glycopeptide antibiotic chloroeremomycin (CE) that are analogous to those formed by N-Ac-D-Ala. The ligand/CE dimer interactions (in L/CE/CE/L) are shown to occur with positive cooperativity and structural tightening at the dimer interface. From theoretical considerations and from other data, it is inferred, but not proven, that in the exercise of positive cooperativity, the interface that will be tightened to the greatest degree is the one that lies in the shallowest free energy well.