Rationale for targeting VEGF, FGF, and PDGF for the treatment of NSCLC

Lung cancer remains a leading cause of death globally, with the most frequent type, nonsmall cell lung cancer (NSCLC), having a 5-year survival rate of less than 20%. While platinum-based doublet chemotherapy is currently first-line therapy for advanced disease, it is associated with only modest clinical benefits at the cost of significant toxicities. In an effort to overcome these limitations, recent research has focused on targeted therapies, with recently approved agents targeting the epidermal growth factor receptor and vascular endothelial growth factor (VEGF) signaling pathways. However, these agents (gefitinib, erlotinib, and bevacizumab) provide antitumor activity for only a small proportion of patients, and patients whose tumors respond inevitably develop resistance to treatment. As angiogenesis is a crucial step in tumor growth and metastasis, antiangiogenic treatments might be expected to have antitumor activity. Important targets for the development of novel antiangiogenic therapies include VEGF, fibroblast growth factor, platelet-derived growth factor, and their receptors. It is hypothesized that targeting multiple angiogenic pathways may not only improve antitumor activity but also reduce the risk of resistance. Several novel agents, such as BIBF 1120, sorafenib, sunitinib, and cediranib have shown promising preliminary activity and tolerability in Phase II studies, and results of ongoing Phase III randomized studies will be necessary to establish the potential place of these new therapies in the management of individual patients with NSCLC

Characterization of Bacillus pumilus Strains Isolated from Bovine Uteri

Uterine infections are a major source of economic losses to dairy farmers. The uterine microbiota as well as opportunistic uterine contaminants can contribute to the development of endometritis in dairy cows during the postpartum period. Therefore, it is important to characterize potential pathogens and to further elucidate their role in the disease. In this study, we aimed to characterize Bacillus pumilus field isolates to obtain more details regarding their effect on uterine cells by using an in vitro endometrial epithelial primary cells model. We found that B. pumilus isolates possessed the keratinase genes ker1 and ker2 and therefore may produce keratinases. When primary endometrial epithelial cells were infected with 4 different B. pumilus strains, an effect on cellular viability was observed over the course of 72 h. The effect was dose-dependent and time-dependent. Nevertheless, significant differences between the strains were not observed. All tested strains reduced the viability of the primary cells after 72 h of incubation, indicating that B. pumilus potentially has a pathogenic effect on endometrial epithelial cells

Streptococcus uberis strains originating from bovine uteri provoke upregulation of pro-inflammatory factors mRNA expression of endometrial epithelial cells in vitro

Streptococcus uberis is an opportunistic pathogen involved in various infections of cattle. It is a well-known etiological agent of bovine mastitis and has recently also been linked to postpartum endometritis in dairy cows. S. uberis is frequently isolated from the uterus of postpartum cows but its actual contribution to host pathophysiology is unknown and information on S. uberis virulence factors potentially involved in the disease is lacking. To gain first insights into the role of S. uberis in the pathology of bovine endometritis, a cell-culture-based infection model was employed to study inflammatory host responses and investigate cytotoxic effects. A comprehensive strain panel, comprising 53 strains previously isolated from bovine uteri, was compiled and screened for known virulence factor genes. Isolates showing distinct virulence gene patterns were used to study their impact on cellular viability and influence on mRNA expression of pro-inflammatory factors in endometrial epithelial cells. Our study revealed that S. uberis negatively impacts the viability of endometrial epithelial cells and provokes an upregulation of specific pro-inflammatory factors, although with certain strains having a greater effect than others. Especially, mRNA expression of IL1A and CXCL8 as well as CXCL1/2 and PTGS2 was found to be stimulated by S. uberis. These results suggest that S. uberis might indeed contribute to the establishment of bovine endometritis

Genome-Wide Association Study Identifies Genetic Loci Associated with Iron Deficiency

The existence of multiple inherited disorders of iron metabolism in man, rodents and other vertebrates suggests genetic contributions to iron deficiency. To identify new genomic locations associated with iron deficiency, a genome-wide association study (GWAS) was performed using DNA collected from white men aged ≥25 y and women ≥50 y in the Hemochromatosis and Iron Overload Screening (HEIRS) Study with serum ferritin (SF) ≤ 12 µg/L (cases) and iron replete controls (SF>100 µg/L in men, SF>50 µg/L in women). Regression analysis was used to examine the association between case-control status (336 cases, 343 controls) and quantitative serum iron measures and 331,060 single nucleotide polymorphism (SNP) genotypes, with replication analyses performed in a sample of 71 cases and 161 controls from a population of white male and female veterans screened at a US Veterans Affairs (VA) medical center. Five SNPs identified in the GWAS met genome-wide statistical significance for association with at least one iron measure, rs2698530 on chr. 2p14; rs3811647 on chr. 3q22, a known SNP in the transferrin (TF) gene region; rs1800562 on chr. 6p22, the C282Y mutation in the HFE gene; rs7787204 on chr. 7p21; and rs987710 on chr. 22q11 (GWAS observed P<1.51×10−7 for all). An association between total iron binding capacity and SNP rs3811647 in the TF gene (GWAS observed P = 7.0×10−9, corrected P = 0.012) was replicated within the VA samples (observed P = 0.012). Associations with the C282Y mutation in the HFE gene also were replicated. The joint analysis of the HEIRS and VA samples revealed strong associations between rs2698530 on chr. 2p14 and iron status outcomes. These results confirm a previously-described TF polymorphism and implicate one potential new locus as a target for gene identification

Characterization of <i>Bacillus pumilus</i> Strains Isolated from Bovine Uteri

Uterine infections are a major source of economic losses to dairy farmers. The uterine microbiota as well as opportunistic uterine contaminants can contribute to the development of endometritis in dairy cows during the postpartum period. Therefore, it is important to characterize potential pathogens and to further elucidate their role in the disease. In this study, we aimed to characterize Bacillus pumilus field isolates to obtain more details regarding their effect on uterine cells by using an in vitro endometrial epithelial primary cells model. We found that B. pumilus isolates possessed the keratinase genes ker1 and ker2 and therefore may produce keratinases. When primary endometrial epithelial cells were infected with 4 different B. pumilus strains, an effect on cellular viability was observed over the course of 72 h. The effect was dose-dependent and time-dependent. Nevertheless, significant differences between the strains were not observed. All tested strains reduced the viability of the primary cells after 72 h of incubation, indicating that B. pumilus potentially has a pathogenic effect on endometrial epithelial cells

A phase I/II study of pemetrexed with sirolimus in advanced, previously treated non-small cell lung cancer

Background: Single-agent pemetrexed is a treatment for recurrent non-squamous non-small cell lung cancer (NSCLC) that provides limited benefit. Preclinical studies showed promising synergistic effects when the mammalian target of rapamycin (mTOR) inhibitor sirolimus was added to pemetrexed. Methods: This was a single-institution phase I/II study of pemetrexed in combination with sirolimus. The primary endpoint for the phase I was to determine the maximum tolerated dose (MTD) and safety of the combination. The primary endpoint for the phase II portion was to determine the overall response rate at the MTD. Key eligibility criteria included recurrent, metastatic NSCLC, ECOG performance status of 0–2, and adequate organ function. Sirolimus was administered orally daily after an initial loading dose, and pemetrexed was given intravenously on day 1 of every 21-day cycle. Results: Forty-two patients with recurrent, metastatic NSCLC were enrolled, 22 in phase I and 20 in phase II. The MTD was pemetrexed 500 mg/m2 every 3 weeks, and sirolimus 10 mg on day 1, and 3 mg daily thereafter. Treatment-related adverse events (AEs) occurred in 38 (90.5%) patients. The most common grade 3–4 treatment-related AEs were lymphopenia (31%) and hypophosphatemia (19%). Two treatment-related deaths occurred due to febrile neutropenia and infection, respectively. Among 27 total patients treated at the MTD, 6 (22.2%) had a partial response (PR), 12 (44.4%) had stable disease (SD) and 5 (18.5%) had progressive disease. Median progression-free survival (PFS) was 18.4 weeks (95% CI: 7.0–29.4). Conclusions: The combination of pemetrexed and sirolimus is active in heavily-pretreated NSCLC (ClinicalTrials.gov Identifier: NCT00923273)

Dynamics and Diversity of Intrauterine Anaerobic Microbiota in Dairy Cows with Clinical and Subclinical Endometritis

The aim of the study was to characterize the dynamics of anaerobic cultivable postpartum microbiota in the uterus of dairy cows. In total, 122 dairy cows were enrolled and sampled on day 0 (day of calving) and on days 3, 9, 15, 21, and 28 postpartum (pp). Samples were cultivated anaerobically and analyzed by MALDI-TOF MS. In total, 1858 isolates were recovered. The most prevalent facultative anaerobic genera were Trueperella (27.8%), Streptococcus (25.4%), and Escherichia (13.1%). The most prevalent obligate anaerobes were Peptoniphilus (9.3%), Bacteroides (3.3%), and Clostridium (2.4%). The microbial communities were highly dynamic and diverse. On the animal level, Trueperella pyogenes on day 21 and 28 pp was associated with clinical endometritis, and E. coli on day 21 pp was associated with subclinical endometritis. The occurrence of Streptococcus pluranimalium on day 28 was related to uterine health. The presence of T. pyogenes, Streptococcus, and Peptoniphilus was significantly associated with an increased risk for purulent vaginal discharge. Primiparous cows showed a higher prevalence of T. pyogenes, Fusobacterium necrophorum, Porphyromonas levii, and Peptoniphilus spp. than multiparous cows but were not more susceptible to uterine diseases. This study might provide a suitable basis for future co-cultivation studies to elucidate potential synergistic interactions between microbiota