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T-cell engager; Eeuroendocrine carcinoma; Small-cell lung cancer Acoplador de cèl·lula T; Carcinoma neuroendocrí; Càncer de pulmó de cèl·lules petites Acoplador de célula T; Carcinoma neuroendocrino; Cáncer de pulmón de células pequeñas Poorly differentiated neuroendocrine carcinomas such as small-cell lung cancer (SCLC) have poor survival and high relapse rates. DLL3 is found on these carcinomas and has become a target of increasing interest in recent years. The bispecific DLL3/CD3 T-cell engager BI 764532 has been shown to induce complete tumor regression in a human T cell-engrafted mouse model. Here, we describe the study design of a first-in-human, phase I, multicenter, open-label, non-randomized, dose-escalation study in patients with SCLC or other DLL3-positive neuroendocrine carcinomas. The study will determine the maximum tolerated dose and evaluate safety, tolerability, pharmacokinetics and preliminary efficacy of BI 764532 monotherapy. This study was funded by Boehringer Ingelheim. M Wermke received honoraria from Novartis, Pfizer, Roche, Lilly; reports consulting or advisory role for Bristol-Myers Squibb, Novartis, Pfizer, Cellex GmbH, Lilly, Boehringer Ingelheim, ISA Pharmaceuticals, GEMoaB, Roche, MSD, AstraZeneca, Amgen, Immatics; received research funding from Roche; travel, accommodations, expenses from Pfizer, Bristol-Myers Squibb, AstraZeneca, Roche Amgen, GEMoaB. E Felip received personal fees for advisory boards from AbbVie, Guardant Health, Janssen, Medscape, Merck KGaA, GlaxoSmithKline, Bayer; advisory board and speakers' bureau fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda; speakers' bureau fees from Prime Oncology, Touchime; research funding from Grant for Oncology Innovation (GOI), Fundacion Merck Salud; Grífols: independent member of the board. Y Kuboki received honoraria from Taiho, ONO, Bayer, Sanofi; consulting fees from Takeda, Boehringer Ingelheim, Taiho; grants or funds from Taiho, Takeda, ONO, AbbVie, AstraZeneca, Boehringer Ingelheim, Incyte, Amgen, Chugai, GSK, Genmab, Astellas, Daiichi-Sankyo. D Morgensztern received consulting fees from AbbVie, Gilead, PharmaMar, Lilly, Bristol-Myers Squibb, G1 Therapeutics, Mirati, Boehringer Ingelheim. ZO' Hamed, M Liu and M Studeny report employment with Boehringer Ingelheim. TK Owonikoko received consulting fees from Novartis, Celgene, Lilly, Sandoz, AbbVie, Eisai, G1 Therapeutics, Takeda, Seattle Genetics, Bristol-Myers Squibb, MedImmune, BerGenBio, Lilly, Amgen, AstraZeneca, PharmaMar, Boehringer Ingelheim, EMD Serono, XCovery, Bayer, Heron Pharmaceutical, ARMO BioSciences, Merck, Bayer, Jazz Pharmaceuticals; and research funding from Novartis, Astellas Pharma, Bayer, StemCentRx, Regeneron, AstraZeneca/MedImmune, AbbVie, G1 Therapeutics, Bristol-Myers, Corvus Pharmaceuticals, United Therapeutics, Amgen, Loxo/Lilly, Fujifilm, Pfizer, Aeglea Biotherapeutics, Incyte, Merck, Mersana, Turning Point, and Oncorus. V Gambardella reports no conflicts of interest. All authors met criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE) and did not receive payment related to the development of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key enzyme in the glycolytic pathway that catalyzes the conversion of D-glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate. Here, the full-length GAPDH type 1 from Escherichia coli (EcGAPDH1) was cloned and overexpressed, and the protein was purified. Biochemical analyses found that the optimum reaction temperature and pH of EcGAPDH1 were 55°C and 10.0, respectively. The protein has a certain amount of thermostability. Crystals of EcGAPDH1 were obtained using the sitting-drop vapor-diffusion technique and X-ray diffraction data were collected to 1.88 Å resolution. Characterization of the crystals showed that they belonged to space group P41212, with unit-cell parameters a = b = 89.651, c = 341.007 Å, α = β = γ = 90°. The structure of EcGAPDH1 contains four subunits, each of which includes an N-terminal NAD+-binding domain and a C-terminal catalytic domain. Analysis of the NAD+-bound form showed some differences between the structures of EcGAPDH1 and human GAPDH. As EcGAPDH1 shares 100% identity with GAPDH from Shigella sonnei, its structure may help in finding a drug for the treatment of shigellosis.

Fructose-1,6-bisphosphate aldolase is one of the most important enzymes in the glycolytic pathway and catalyzes the reversible cleavage of fructose-1,6-bisphosphate to dihydroxyacetone phosphate and glyceraldehyde 3-phosphate. The full-lengthfbaB gene encoding fructose-1,6-bisphosphate aldolase class I (FBPA I) was cloned fromEscherichia colistrain BL21. FBPA I was overexpressed inE. coliand purified. Biochemical analysis found that the optimum reaction temperature of FBPA I is 330.5 K and that the enzyme has a high temperature tolerance. Crystals of recombinant FBPA I were obtained by the sitting-drop vapour-diffusion technique in a condition consisting of 19 mg ml−1FBPA I in 0.1 MTris pH 9.0, 10%(w/v) polyethylene glycol 8000 and diffracted to 2.0 Å resolution. The crystals belonged to the monoclinic space groupC2, with unit-cell parametersa= 217.7,b= 114.9,c= 183.9 Å, β = 124.6°. The asymmetric unit of these crystals may contain ten molecules, giving a Matthews coefficient of 2.48 Å3 Da−1and a solvent content of 50.5%.

The ubiquitin-related modifier Urm1 can be covalently conjugated to lysine residues of other proteins, such as yeast Ahp1 and human MOCS3, through a mechanism involving the E1-like protein Uba4 (MOCS3 in humans). Similar to ubiquitination, urmylation requires a thioester intermediate and forms isopeptide bonds between Urm1 and its substrates. In addition, the urmylation process can be significantly enhanced by oxidative stress. Recent findings have demonstrated that Urm1 also acts as a sulfur carrier in the thiolation of eukaryotic tRNA via a mechanism that requires the formation of a thiocarboxylated Urm1. This role is very similar to that of prokaryotic sulfur carriers such as MoaD and ThiS. Evidence strongly supports the hypothesis that Urm1 is the molecular fossil in the evolutionary link between prokaryotic sulfur carriers and eukaryotic ubiquitin-like proteins. In the present review, we discuss the dual role of Urm1 in protein and tRNA modification.

Yeast tRNA-thiouridine modification protein 1 (Tum1p), a crucial component of the Urm1 system, is believed to play important roles in protein urmylation and tRNA-thiouridine modification. Previous studies have demonstrated that the conserved residue Cys259 in the C-terminal rhodanese-like domain of Tum1p is essential for these sulfur-transfer activities. Here, recombinant Tum1p protein has been cloned and overexpressed in Escherichia coli strain BL21 (DE3). After purification, crystals of Tum1p were obtained by the hanging-drop vapour-diffusion method and diffracted to 1.9 Å resolution. The preliminary X-ray data showed that the tetragonal Tum1p crystal belonged to space group I4(1), with unit-cell parameters a = b = 120.94, c = 48.35 Å. The asymmetric unit of the crystal was assumed to contain one protein molecule, giving a Matthews coefficient of 2.41 Å(3) Da(-1) and a solvent content of 49.0%.

Background: Atopic eczema (AE) is one of the most common skin diseases affecting children and adults worldwide. The “Atopic March” paradigm suggests AE is part of a complex condition with related airway disease. Objective: This study aimed to evaluate the prevalence of airway disease, environmental aeroallergens, and review factors associated with eczema severity and quality of life (QoL) when AE patients approached adulthood. Methods: Patients who were diagnosed with AE at a young age were included in the study and followed up till their adolescence at pediatric dermatology clinics from 2000 to 2017. Demographic characteristics, clinical laboratory parameters, treatment history, personal atopic history, as well as disease outcomes assessed by Nottingham Eczema Severity Score (NESS) and Children Dermatology Quality Life Index (CDLQI) were reviewed. Results: Three hundred and eighty-three patients (55.4% males) with latest NESS at mean (standard deviation) age 16.23 (2.50) years were reviewed. Personal history of asthma (45%), allergic rhinitis (74%), and family history of atopy were prevalent. Seventy-two percent of the patients were skin prick testing positive for house dust mite, 27% for cockroach, 33% for cat fur, and 13% for dog fur. Fourteen percent reported “smokers in family”. Multiple logistic regression showed “food avoidance ever” (adjusted odds ratio [OR] =3.00, 95% confidence interval [CI] =1.08–8.32; P = 0.035) and log-transformed immunoglobulin E (IgE) (adjusted OR = 1.45, 95% CI = 1.09–1.92; P = 0.011) were significantly associated with more severe AE. Linear regression showed “food avoidance ever” (β = 1.79, 95% CI = 0.34–3.24; P = 0.016), higher log-transformed IgE (β = 0.62; 95% CI = 0.22–1.03; P = 0.003), dog dander sensitization (β = 2.07, 95% CI = 0.24–3.89; P = 0.027), and severe disease (β = 2.97, 95% CI = 2.26–3.68; P < 0.001) were significantly associated with QoL impairment. Conclusions: A number of patients do not grow out of their eczema, and many of them have allergic rhinitis and asthma co-morbidities. Toward adulthood, AE severity and QoL are associated with food avoidance and high IgE, but generally independent of family or personal history of airway disease and allergen sensitization. Blood IgE measurement may help assess the risk for more severe eczema when patients are becoming adults.

Yeast tRNA-thiouridine modification protein 1 (Tum1) plays essential role in the sulfur transfer process of Urm1 system, which in turn is involved in many important cellular processes. In the rhodanese-like domain (RLD), conserved cysteine residue is proved to be the centre of active site of sulfurtransferases and crucial for the substrate recognition. In this report, we describe the crystal structure of Tum1 protein at 1.90 A resolution which, despite consisting of two RLDs, has only one conserved cysteine residue in the C-terminal RLD. An unaccounted electron density is found near the active site, which might point to the new cofactor in the sulfur transfer mechanism.