Photodistributed Telangiectasia Induced by Amlodipine

Calcium channel blockers are widely used antihypertensive drugs, which are uncommonly associated with cutaneous reactions, such as pruritus, urticaria, or alopecia. Photosensitivity presenting with telangiectasia has rarely been described. We present here a case of photodistributed telangiectasia induced clinically by amlodipine and histologically by enlarged capillaries in the upper dermis without signs of vasculitis

A Case of Cicatricial Alopecia Associated with Erlotinib

Erlotinib is a small-molecule tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR). Erlotinib has been used primarily to treat non-small cell lung cancer. In addition to its role in tumor cells, EGFR is also an important regulator of growth and differentiation in the skin and hair. Therefore, EGFR-TKIs have been associated with a number of cutaneous side effects including follicular acneiform eruptions, cutaneous xerosis, chronic paronychia, desquamation, seborrheic dermatitis, and hair texture changes. Herein, we report a rare case of a 61-year-old woman who was treated with erlotinib and experienced cicatricial alopecia

ITDetect: a method to detect internal tandem duplication of FMS-like tyrosine kinase (FLT3) from next-generation sequencing data with high sensitivity and clinical application

Abstract Internal tandem duplication (ITD) of the FMS-like tyrosine kinase (FLT3) gene is associated with poor clinical outcomes in patients with acute myeloid leukemia. Although recent methods for detecting FLT3-ITD from next-generation sequencing (NGS) data have replaced traditional ITD detection approaches such as conventional PCR or fragment analysis, their use in the clinical field is still limited and requires further information. Here, we introduce ITDetect, an efficient FLT3-ITD detection approach that uses NGS data. Our proposed method allows for more precise detection and provides more detailed information than existing in silico methods. Further, it enables FLT3-ITD detection from exome sequencing or targeted panel sequencing data, thereby improving its clinical application. We validated the performance of ITDetect using NGS-based and experimental ITD detection methods and successfully demonstrated that ITDetect provides the highest concordance with the experimental methods. The program and data underlying this study are available in a public repository

A logical network-based drug-screening platform for Alzheimer’s disease representing pathological features of human brain organoids

Developing effective drugs for Alzheimer’s disease (AD), the most common cause of dementia, has been difficult because of complicated pathogenesis. Here, we report an efficient, network-based drug-screening platform developed by integrating mathematical modeling and the pathological features of AD with human iPSC-derived cerebral organoids (iCOs), including CRISPR-Cas9-edited isogenic lines. We use 1300 organoids from 11 participants to build a high-content screening (HCS) system and test blood–brain barrier-permeable FDA-approved drugs. Our study provides a strategy for precision medicine through the convergence of mathematical modeling and a miniature pathological brain model using iCOs. © 2021, The Author(s).1

Chemically treated plasma Aβ is a potential blood-based biomarker for screening cerebral amyloid deposition

Background Plasma β-amyloid (Aβ) is a potential candidate for an Alzheimers disease (AD) biomarker because blood is an easily accessible bio-fluid, which can be collected routinely, and Aβ is one of the major hallmarks of AD pathogenesis in the brain. However, the association between plasma Aβ levels and AD diagnosis is still unclear due to the instability and inaccurate measurements of plasma Aβ levels in the blood of patients with AD. If a consistent value of plasma Aβ from the blood can be obtained, this might help determine whether plasma Aβ is a potential biomarker for AD diagnosis. Methods We predicted the brain amyloid deposit by measuring the plasma Aβ levels. This cross-sectional study included 353 participants (215 cognitively normal, 79 with mild cognitive impairment, and 59 with AD dementia) who underwent Pittsburgh-compound B positron emission tomography (PiB-PET) scans. We treated a mixture of protease inhibitors and phosphatase inhibitors (MPP) and detected plasma Aβ42 and Aβ40 (MPP-Aβ42 and MPP-Aβ40) in a stable manner using xMAP technology. Results MPP-Aβ40 and MPP-Aβ42/40 (MPP-Aβs) were significantly different between subjects with positive amyloid deposition (PiB+) and those with negative amyloid deposition (PiB–) (P < 0.0001). Furthermore, MPP-Aβ40 (P < 0.0001, r = 0.23) and MPP-Aβ42/40 ratio (P < 0.0001, r = –0.23) showed significant correlation with global PiB deposition (standardized uptake value ratio). In addition, our integrated multivariable (MPP-Aβ42/40, gender, age, and apolipoprotein E genotypes) logistic regression model proposes a new standard for the prediction of cerebral amyloid deposition. Conclusions MPP-Aβ might be one of the potential blood biomarkers for the prediction of PiB-PET positivity in the brain

Comparison of Monthly Ibandronate Versus Weekly Risedronate in Preference, Convenience, and Bone Turnover Markers in Korean Postmenopausal Osteoporotic Women

Patient preferences, convenience, and bone turnover markers were evaluated for the monthly ibandronate over the weekly risedronate regimen in Korean postmenopausal osteoporotic women. This was a 6-month, prospective, randomized, open-label, multicenter study with a two-period and two-sequence crossover treatment design. After a 30-day screening period, eligible participants with postmenopausal osteoporosis were randomized to receive either monthly oral ibandronate 150 mg for 3 months followed by weekly oral risedronate 35 mg for 12 weeks (sequence A) or the same regimen in reverse order (sequence B). Patient preference and convenience were evaluated by questionnaire. The changes in serum C-telopeptide after 3 months of treatment were analyzed. A total of 365 patients were enrolled in this study (sequence A 182, sequence B 183). Of patients expressing a preference (83.4%), 74.8% preferred the monthly ibandronate regimen over the weekly regimen (25.2%). More women stated that the monthly ibandronate regimen was more convenient (84.2%) than the weekly regimen (15.8%). There was no significant difference in the change in bone turnover marker between the two treatments. The two regimens were similarly tolerable. There were fewer adverse events in the monthly ibandronate group compared to the weekly risedronate group in terms of gastrointestinal side effects (nausea and abdominal distension). This study revealed a strong preference and convenience for monthly ibandronate over weekly risedronate in Korean postmenopausal osteoporotic women. There was no significant difference in change of bone turnover marker and safety profile between the two regimens

Enzymatic Synthesis of D-pipecolic Acid by Engineering the Substrate Specificity of Trypanosoma cruzi Proline Racemase and Its Molecular Docking Study

Pipecolic acid is an unnatural amino acid mostly used for pharmaceutical purposes. Pipecolic acid has two types of enantiomers with different roles in the synthesis of drugs. The development of efficient catalytic methods for the production of enantiopure pipecolic acid is currently a crucial topic of research. Few chemo- or biosynthetic methods have been proposed for the synthesis of pure enantiomers; however, enzymatic conversion of the chirality of pipecolic acid has not been demonstrated because no pipecolic acid racemase has been reported yet. In this work, we attempted to engineer pipecolic acid racemase activity into Trypanosoma cruzi proline racemase (TcPRAC) for the enzymatic synthesis of D-pipecolic acid from L-pipecolic acid. For the binding of pipecolic acid (C6 ring) into the active site of TcPRAC, which was optimized for the original substrate proline (C5 ring), four bulky aromatic residues (Phe102, Phe120, Phe220, and Phe 290) of TcPRAC were mutated to smaller hydrophobic residues. Among the mutants, six single-point mutants (F102A, F102I, F102L, F102V, F290L, and F290V) exhibited significant racemase activity against L-pipecolic acid. The most efficient variant, F102V, showed 74% racemization. Molecular docking simulations revealed that lowering the binding energy of L-pipecolic acid to the active site was important for achieving high racemization activity of TcPRAC mutant proteins

Backbone assignment and inhibitor binding studies of IL-33 mutants by NMR spectroscopy

Abstract Interleukin-33 (IL-33) is an IL-1 family protein that induces a type-2 immune response. IL-33 is constitutively expressed in epithelial cells and released in response to the cell damage or stimulation by an allergen. The secreted protein is activated when the N-terminal domain is cleaved by a protease, and the active form signals downstream immune cells, such as eosinophils, by binding to the heterodimeric ST2:IL-1RAcP receptor complex on the cell surface. The binding stimulates an inflammatory response, and the abnormal inflammatory response can cause allergic diseases such as atopic dermatitis and asthma. Inhibition of the interaction between IL-33 and ST2 is an attractive target to control the inflammatory disease at the upstream of the signaling. However, discovering the chemical moieties that bind to the protein–protein interaction interface is a challenging task due to the relatively wide and shallow binding pocket compared to the enzyme’s active site. For the IL-33-specific binder discovery, a series of IL-33 mutants were designed, and an electrophile chemical library was screened. Herein, we described the backbone 1H, 15N, and 13C resonance assignments of three IL-33 (117–270) mutants. Based on the assignments, the binding site of a selected compound by this approach was determined by 2D NMR. These results provide valuable information for further studies in drug discovery targeting the IL-33 and ST2 interaction