MPDL3280A is a human monoclonal antibody that targets programmed cell death-1 ligand 1 (PD-L1), and exerts anti-tumor activity mainly by blocking PD-L1 interaction with programmed cell death-1 (PD-1) and B7.1. It is being investigated as a potential therapy for locally advanced or metastatic malignancies. The purpose of the study reported here was to characterize the pharmacokinetics, pharmacodynamics, tissue distribution and tumor penetration of MPDL3280A and/or a chimeric anti-PD-L1 antibody PRO304397 to help further clinical development.The pharmacokinetics of MPDL3280A in monkeys at 0.5, 5 and 20 mg¢kg ¡1 and the pharmacokinetics / pharmacodynamics of PRO304397 in mice at 1, 3 10 mg¢kg ¡1 were determined after a single intravenous dose. Tissue distribution and tumor penetration for radiolabeled PRO304397 in tumor-bearing mouse models were determined.The pharmacokinetics of MPDL3280A and PRO304397 were nonlinear in monkeys and mice, respectively. Complete saturation of PD-L1 in blood in mice was achieved at serum concentrations of PRO304397 above »0.5 mg¢mL ¡1 . Tissue distribution and tumor penetration studies of PRO304397 in tumor-bearing mice indicated that the minimum tumor interstitial to plasma radioactivity ratio was »0.3; saturation of target-mediated uptake in non-tumor tissues and desirable exposure in tumors were achieved at higher serum concentrations, and the distribution into tumors was dose-and time-dependent.The biodistribution data indicated that the efficacious dose is mostly likely higher than that estimated based on simple pharmacokinetics/pharmacodynamics in blood. These data also allowed for estimation of the target clinical dose for further development of MPDL3280A.

Trastuzumab-DM1 (T-DM1) is a novel antibody-drug conjugate under investigation for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. One challenge in oncologic drug development is determining the optimal dose and treatment schedule. A novel dose regimen-finding strategy was developed for T-DM1 using experimental data and pharmacokinetic/pharmacodynamic modeling. To characterize the disposition of T-DM1, pharmacokinetic studies were conducted in athymic nude and beige nude mice. The pharmacokinetics of T-DM1 were described well by a two-compartment model. Tumor response data were obtained from single-dose, multiple-dose and time-dose-fractionation studies of T-DM1 in animal models of HER2-positive breast cancer, specifically engineered to be insensitive to trastuzumab. A sequential population-based pharmacokinetic/pharmacodynamic modeling approach was developed to describe the anti-tumor activity of T-DM1. A cell-cycle-phase nonspecific tumor cell kill model incorporating transit compartments captured well the features of tumor growth and the activity of T-DM1. Key findings of the model were that tumor cell growth rate played a significant role in the sensitivity of tumors to T-DM1; anti-tumor activity was schedule independent; and tumor response was linked to the ratio of exposure to a concentration required for tumor stasis.

Abstract. The anticancer effect of baicalein has been known for a number of years. However, its anti-metastatic effect and associated mechanisms in colorectal cancer (CRC) remain unclear. The present study investigated the hypothesis that treatment with baicalein may inhibit the proliferation, motility and invasion of human CRC cell lines via regulation of the protein kinase B (AKT) signaling pathway. Baicalein was demonstrated to significantly inhibit the migration and invasion of CRC cells (P=0.01). Additionally, after treatment with baicalein for 24 h, the protein expression levels of matrix metalloproteinase-2 (MMP-2) and MMP-9 in CRC cells were significantly reduced in a dose-dependent manner (P=0.01). Furthermore, treatment with baicalein significantly reduced the expression levels of phosphorylated AKT (P=0.01). In conclusion, baicalein appears to inhibit CRC cell migration and invasion by reducing the expression of MMP-2 and MMP-9 via suppression of the AKT signaling pathway. Thus, baicalein is a potential novel therapeutic agent for patients with CRC.

SummaryBackground and objectives The purpose of this study was to determine whether glomerular hyperfiltration (GH) occurring early in autosomal dominant polycystic kidney disease (ADPKD) is indicative of more rapid disease progression in children.Design, setting, participants, & measurements One hundred eighty children with ADPKD (ages 4 to 18 years) with normal renal function were examined by renal ultrasound. Renal volume was calculated using a standard formula for a modified ellipsoid. Creatinine clearance was calculated from serum creatinine and 24-hour urine creatinine. GH was defined as creatinine clearance Ն140 ml/min per 1.73 m 2 .Results Thirty-two children had GH (mean age 11.4 Ϯ 3.6 years) and 148 had normal renal function (mean age 10.8 Ϯ 3.9 years). Patients with GH at baseline demonstrated an increased rate of total renal volume growth (␤: rate of change ϭ ϩ19.3 Ϯ 10.8 cm 3 /year) over 5 years compared with those without GH at baseline (␤ ϭ Ϫ4.3 Ϯ 7.7 cm 3 /year), P ϭ 0.008. Those with GH at baseline experienced a faster decline in creatinine clearance in subsequent years (␤ ϭ Ϫ5.0 Ϯ 0.8 ml/min per 1.73 m 2 per year) compared with those without GH at baseline (␤ ϭ ϩ1.0 Ϯ 0.4 ml/min per 1.73 m 2 per year), P Ͻ 0.0001. ConclusionsThis study revealed that occurrence of GH in ADPKD children is associated with a significantly faster decline in renal function and higher rate of kidney enlargement over time. GH combined with the increased renal volume may therefore be used as an early marker for a more severe progression of ADPKD in children.

Background: This study evaluates the prevalence of cardiovascular events in autosomal dominant polycystic kidney disease (ADPKD) patients. Methods: We distributed surveys to 1,439 subjects from our ADPKD research database. In total, 426 subjects completed and returned surveys; 7 of these were from children and were excluded from the study. Results: The patients who responded were female (63.2%), nonHispanic (88.1%) and white (93.6%). The mean age of the total group was 53.2 ± 13.7 years; 82.8% had a family history of ADPKD and 32.5% had reached end-stage renal disease (ESRD). With respect to cardiovascular risk factors, 86.6% were hypertensive with a mean age at diagnosis of 36.9 ± 12.9 years and hypertension was significantly more prevalent in males. In addition, 19.6% of the subjects were obese, 20.8% were smokers, 8.7% had diabetes, 45.7% had high cholesterol and 17.8% were sedentary. The most prevalent self-reported cardiovascular events were arrhythmias (25.9%), evidence of peripheral vascular disease (16.5%), heart valve problems (14.4%), cardiac enlargement (9.5%), stroke or cerebral bleeding (7.5%), myocardial infarction (6%) and brain aneurysm (5.0%). The most commonly used antihypertensive medications were renin-angiotensin inhibitors used by 75% of ADPKD patients.Older ADPKD patients and those at ESRD had a significantly higher incidence of cardiovascular events. Conclusion: These findings support the high prevalence of cardiovascular risk factors and events in ADPKD patients which contribute to a greater mortality risk. Due to the prevalence of cardiovascular risk factors in the ADPKD population, early diagnosis and clinical intervention are recommended.

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Mounting evidence has illustrated the vital roles of long non‐coding RNAs (lncRNAs in gastric cancer (GC). Nevertheless, the majority of their roles and mechanisms in GC are still largely unknown. In this study, we investigate the roles of lncRNA SLC25A5‐AS1 on tumourigenesis and explore its potential mechanisms in GC. The results showed that the expressions of SLC25A5‐AS1 in GC were significantly lower than that of adjacent normal tissues, which were significantly associated with tumour size, TNM stage and lymph node metastasis. Moreover, SLC25A5‐AS1 could inhibit GC cell proliferation, induce G1/G1 cell cycle arrest and cell apoptosis in vitro, as well as GC growth in vivo. Dual‐luciferase reporter assay confirmed the direct interaction between SLC25A5‐AS1 and miR‐19a‐3p, rescue experiment showed that co‐transfection miR‐19a‐3p mimics and pcDNA‐SLC25A5‐AS1 could partially restore the ability of GC cell proliferation and the inhibition of cell apoptosis. The mechanism analyses further found that SLC25A5‐AS1 might act as a competing endogenous RNAs (ceRNA), which was involved in the derepression of PTEN expression, a target gene of miR‐19a‐3p, and regulate malignant phenotype via PI3K/AKT signalling pathway in GC. Taken together, this study indicated that SLC25A5‐AS1 was down‐regulated in GC and functioned as a suppressor in the progression of GC. Moreover, it could act as a ceRNA to regulate cellular behaviours via miR‐19a‐3p/PTEN/PI3K/AKT signalling pathway. Thus, SLC25A5‐AS1 might be served as a potential target for cancer therapeutics in GC.