Pharmacokinetics and pharmacodynamics of once-weekly administration of JR-142, a long-acting albumin-fused human growth hormone: A rondemized, placebo-controlled phase 1 study.

OBJECTIVE: Under clinical development for patients with growth hormone deficiency, JR-142 is a long-acting growth hormone with a half-life extended by fusion with modified serum albumin. We conducted a Phase 1 study to investigate the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles of once-weekly subcutaneous administrations of JR-142. The study consisted of two parts: an open-label single ascending dosing study (Part 1), and a randomized, placebo-controlled, assessor-blinded multiple ascending dosing study (Part 2). DESIGN: A total of 31 healthy Japanese male participants were enrolled. In Part 1, seven of them received a single subcutaneous injection of JR-142 each at dosages of 0.15 mg/kg (n = 1), 0.25 mg/kg (n = 2), 0.5 mg/kg (n = 2), or 1.0 mg/kg (n = 2). In Part 2, one weekly subcutaneous injection of JR-142 at 0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg or a placebo were given for four weeks to each of the other 24 participants (six in each group). Plasma JR-142 and serum insulin-like growth factor-1 (IGF-1) concentrations were measured for PK and PD assessments. Safety was evaluated on the basis of adverse events (AEs), laboratory tests, and other measures. RESULTS: JR-142 induced dose-dependent increases in the maximum plasma JR-142 concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to τ (AUC0-τ). A similar dose-response relationship was observed in serum IGF-1 concentrations. All trough IGF-1 levels were well sustained one week after the final administrations of JR-142 at the three dosages, while the peak concentrations of IGF-1 remained mildly elevated. No serious AEs were observed, and laboratory tests, including assessment of anti-drug antibodies, uncovered no significant safety issues. CONCLUSIONS: Once-weekly subcutaneous injections of JR-142 produced positive dose-dependent PK and PD profiles over the dosage range. Drug accumulation was observed after the four-week administration period but did not raise safety concerns, indicating that JR-142 is well-tolerated in healthy participants. The PD profiles observed in terms of IGF-1 concentrations were also positive, and we believe the encouraging results of this study warrant substantiation in further clinical trials in patients with GHD. ETHICS: This clinical study was conducted at one investigational site in Osaka, Japan, where the clinical study and the non-clinical data of JR-142 were reviewed and approved by its Institutional Review Board on 9th May 2019. The study was conducted in compliance with the approved study protocol, the Declaration of Helsinki, 1964, as revised in 2013, and Good Clinical Practice.

Rare UV-resistant cells in clonal populations of Escherichia coli.

Water disinfection is one of the most important applications of ultraviolet light-emitting diodes (UV-LEDs), though bacterial regrowth remains a serious problem. In this study, we showed that UV-resistant cells, though rare, exist in an Escherichia coli clonal population. The UV-resistance of stationary phase cells was higher than that of exponential phase cells. Regrowth cell populations showed identical UV sensitivity before and after UV treatment, indicating that UV resistance is not acquired genetically, but is generated stochastically. The characteristics of these UV-resistant cells are similar to those of non-heritable antibiotic-resistant cells, termed persisters. The induction of persister formation increased the number of viable cells after UV treatment. The toxin-antitoxin system gene hipA (high persistence A) is a key factor in persister cell formation. We observed that hipA was strongly expressed in the stationary phase cells, while regrowth cells after UV treatment lost hipA expression, suggesting that the regrowth cells lost their persistence. Compared to UV batch radiation, we demonstrated that intermittent UV irradiation, which included the induction of regrowth between UV treatments, significantly reduced the number of viable E. coli cells.

Enhanced Expression of Integrin αvß3 Induced by TGF-ß Is Required for the Enhancing Effect of Fibroblast Growth Factor 1 (FGF1) in TGF-ß-Induced Epithelial-Mesenchymal Transition (EMT) in Mammary Epithelial Cells.

Epithelial-to-mesenchymal transition (EMT) plays a critical role in cancer metastasis, and is regulated by growth factors such as transforming growth factor ß (TGF-ß) and fibroblast growth factors (FGF) secreted from the stromal and tumor cells. However, the role of growth factors in EMT has not been fully established. Several integrins are upregulated by TGF-ß1 during EMT. Integrins are involved in growth factor signaling through integrin-growth factor receptor crosstalk. We previously reported that FGF1 directly binds to integrin αvß3 and the interaction was required for FGF1 functions such as cell proliferation and migration. We studied the role of αvß3 induced by TGF-ß on TGF-ß-induced EMT. Here, we describe that FGF1 augmented EMT induced by TGF-ß1 in MCF10A and MCF12A mammary epithelial cells. TGF-ß1 markedly amplified integrin αvß3 and FGFR1 (but not FGFR2). We studied if the enhancing effect of FGF1 on TGF-ß1-induced EMT requires enhanced levels of both integrin αvß3 expression and FGFR1. Knockdown of ß3 suppressed the enhancement by FGF1 of TGF-ß1-induced EMT in MCF10A cells. Antagonists to FGFR suppressed the enhancing effect of FGF1 on EMT. Integrin-binding defective FGF1 mutant did not augment TGF-ß1-induced EMT in MCF10A cells. These findings suggest that enhanced integrin αvß3 expression in addition to enhanced FGFR1 expression is critical for FGF1 to augment TGF-ß1-induced EMT in mammary epithelial cells.