Citation Details

Journal Article

B16-F10-luc2, Melanoma, B16F10-luc2, IVIS

In-transit metastasis (ITM) is a unique manifestation of intralymphatic tumor dissemination, characterized by the presence of melanoma cells between the primary lesion and the draining regional lymph node basin that is clinically associated with poor prognosis. In this study, we aimed to establish an experimental animal model of melanoma ITM, as research progress in this field has been hampered by a lack of suitable experimental models. We reproduced melanoma ITM in a mouse hind limb by transplanting melanoma cells into the footpad of a mouse with lymphedema (LE). The tumor cells at the ITM site were highly proliferative, and mice with ITMs were more likely than control mice to develop distant lymph node and lung metastases. Peritumoral lymphatic vessels and tumor-associated blood vessels were increased in the primary tumor site of the LE mice. Our established ITM melanoma mouse model enabled us to clarify the molecular determinants and pathophysiology of ITM. This ITM model is also comparable to the unfavorable clinical behavior of melanoma ITM in humans and, moreover, underlined the importance of lymphangiogenic factors in the tumor dissemination through the lymphatic system.Journal of Investigative Dermatology advance online publication, 6 September 2012; doi:10.1038/jid.2012.274.

Journal Article

Anti-Bacterial Agents; Bioware; Community-Acquired Infections; Humans; Methicillin Resistance; Staphylococcal Infections; Staphylococcus aureus; Xen29

Multiple resistant staphylococci that cause significant morbidity and mortality are the leading cause of nosocomial infections. Meanwhile, methicillin-resistant Staphylococcus aureus (MRSA) also spreads in the community, where highly virulent strains infect children and young adults who have no predisposing risk factors. Although some treatment options remain, the search for new antibacterial targets and lead compounds is urgently required to ensure that staphylococcal infections can be effectively treated in the future. Promising targets for new antibacterials are gene products that are involved in essential cell functions. In addition to antibacterials, active and passive immunization strategies are being developed that target surface components of staphylococci such as cell wall-linked adhesins, teichoic acids and capsule or immunodominant antigens.

Journal Article

Inflammation; Calcification; Atherosclerosis; Molecular imaging; in vivo imaging; ProSense; OsteoSense

Optical molecular imaging represents an emerging method that can detect pathobiological processes in vivo at the cellular and molecular levels, offering a dynamic link between imaging and biology. This review discusses the impact of molecular imaging methods in atherosclerosis research and preventive medicine and focuses on the inflammation-dependent mechanisms of arterial calcification.

Journal Article

Animals; Bacteremia; Bacterial Proteins; Cerebrospinal Fluid; Disease Models, Animal; Female; Lung; Meningitis, Pneumococcal; Mice; Mice, Inbred BALB C; Mutation; N-Acetylmuramoyl-L-alanine Amidase; Nasopharynx; Neuraminidase; Pneumococcal Infections; Pneumonia, Pneumococcal; Pyruvate Oxidase; Streptococcus pneumoniae; Streptolysins; Virulence Factors; Xen7

We assessed the ability of Streptococcus pneumoniae mutants deficient in either choline binding protein A (CbpA), pneumolysin (Pln), pyruvate oxidase (SpxB), autolysin (LytA), pneumococcal surface protein A, or neuraminidase A (NanA) to replicate in distinct anatomical sites and translocate from one site to the next. Intranasal, intratracheal, and intravenous models of disease were assessed in 4-week-old BALB/cJ mice by quantitation of bacterial titers in the relevant organs. Mice were also observed by use of real-time bioluminescent imaging (BLI). BLI allowed visualization of the bacteria in sites not tested by sampling. All mutants were created in D39 Xen7, a fully virulent derivative of capsular type 2 strain D39 that contains an optimized luxABCDE cassette. NanA, SpxB, and, to a lesser extent, CbpA contributed to prolonged nasopharyngeal colonization, whereas CbpA and NanA contributed to the transition to the lower respiratory tract. Once lung infection was established, Pln, SpxB, and LytA contributed to bacterial replication in the lungs and translocation to the bloodstream. In the bloodstream, only Pln and LytA were required for high-titer replication, whereas CbpA was required for invasion of the cerebrospinal fluid. We conclude that transitions between body sites require virulence determinants distinct from those involved in organ-specific replication.

Journal Article

Animals; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Bioware; Dacarbazine; DNA Damage; DNA Modification Methylases; DNA Repair; DNA Repair Enzymes; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; MDA-MB-231-D3H2LN cells; Mice; Mice, SCID; Neoplasm Metastasis; Neoplasm Transplantation; Tumor Suppressor Proteins

PURPOSE ABT-888, currently in phase 2 trials, is a potent oral poly(ADP-ribose) polymerase inhibitor that enhances the activity of multiple DNA-damaging agents, including temozolomide (TMZ). We investigated ABT-888+TMZ combination therapy in multiple xenograft models representing various human tumors having different responses to TMZ. EXPERIMENTAL DESIGN ABT-888+TMZ efficacy in xenograft tumors implanted in subcutaneous, orthotopic, and metastatic sites was assessed by tumor burden, expression of poly(ADP-ribose) polymer, and O(6)-methylguanine methyltransferase (MGMT). RESULTS Varying levels of ABT-888+TMZ sensitivity were evident across a broad histologic spectrum of models (55-100% tumor growth inhibition) in B-cell lymphoma, small cell lung carcinoma, non-small cell lung carcinoma, pancreatic, ovarian, breast, and prostate xenografts, including numerous regressions. Combination efficacy in otherwise TMZ nonresponsive tumors suggests that TMZ resistance may be overcome by poly(ADP-ribose) polymerase inhibition. Profound ABT-888+TMZ efficacy was seen in experimental metastases models that acquired resistance to TMZ. Moreover, TMZ resistance was overcome in crossover treatments, indicating that combination therapy may overcome acquired TMZ resistance. Neither tumor MGMT, mismatch repair, nor poly(ADP-ribose) polymer correlated with the degree of sensitivity to ABT-888+TMZ. CONCLUSIONS Robust ABT-888+TMZ efficacy is observed across a spectrum of tumor types, including orthotopic and metastatic implantation. As many TMZ nonresponsive tumors proved sensitive to ABT-888+TMZ, this novel combination may broaden the clinical use of TMZ beyond melanoma and glioma. Although TMZ resistance may be influenced by MGMT, neither MGMT nor other mechanisms of TMZ resistance (mismatch repair) precluded sensitivity to ABT-888+TMZ. Underlying mechanisms of TMZ resistance in these models are not completely understood but likely involve mechanisms independent of MGMT.