Publications

The fungus Cryptococcus neoformans is a leading cause of mortality and morbidity among HIV-infected individuals. We utilized the completed genome sequence and optimized methods for homologous DNA replacement using high-velocity particle bombardment to engineer 1201 gene knockout mutants. We screened this resource in vivo for proliferation in murine lung tissue and in vitro for three well-recognized virulence attributes-polysaccharide capsule formation, melanization, and growth at body temperature. We identified dozens of previously uncharacterized genes that affect these known attributes as well as 40 infectivity mutants without obvious defects in these traits. The latter mutants affect predicted regulatory factors, secreted proteins, and immune-related factors, and represent powerful tools for elucidating novel virulence mechanisms. In particular, we describe a GATA family transcription factor that inhibits phagocytosis by murine macrophages independently of the capsule, indicating a previously unknown mechanism of innate immune modulation.

BACKGROUND

We conducted subanalyses of the combined results of the Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) 1 and MOTIVATE 2 studies to better characterize the efficacy and safety of maraviroc in key subgroups of patients.

METHODS

We analyzed pooled data from week 48 from the two studies according to sex, race or ethnic group, clade, CC chemokine receptor 5 (CCR5) delta32 genotype, viral load at the time of screening, the use or nonuse of enfuvirtide in optimized background therapy (OBT), the baseline CD4 cell count, the number of active antiretroviral drugs coadministered, the first use of selected background agents, and tropism at baseline. Changes in viral tropism and the CD4 count at treatment failure were evaluated. Data on aminotransferase levels in patients coinfected with hepatitis B virus (HBV) or hepatitis C virus (HCV) were also analyzed.

RESULTS

A treatment benefit of maraviroc plus OBT over placebo plus OBT was shown in all subgroups, including patients with a low CD4 cell count at baseline, those with a high viral load at screening, and those who had not received active agents in OBT. Analyses of the virologic response according to the first use of selected background drugs showed the additional benefit of adding a potent new drug to maraviroc at the initiation of maraviroc therapy. More patients in whom maraviroc failed had a virus binding to the CXC chemokine receptor 4 (CXCR4) at failure, but there was no evidence of a decrease in the CD4 cell count at failure in such patients as compared with those in whom placebo failed. Subanalyses involving patients coinfected with HBV or HCV revealed no evidence of excess hepatotoxic effects as compared with baseline.

CONCLUSIONS

Subanalyses of pooled data from week 48 indicate that maraviroc provides a valuable treatment option for a wide spectrum of patients with R5 HIV-1 infection who have been treated previously. (ClinicalTrials.gov numbers, NCT00098306 and NCT00098722.)

While p53 has been extensively characterized as a tumor suppressor, it has been more difficult to determine whether p63 and/or p73 play a similar role. Every system in which these family members have been studied, from cells to animal models to human tissues, seems to create more questions than answers. Tomasini and colleagues (2677-2691) demonstrate that one isoform of p73 is responsible for preventing tumor formation in vivo, providing critical validation of an isoform-based model of p73 function.

We examined a novel human feeder cell layer of mesenchymal stem cells harvested from human adipose tissues. Gene expression analyses and colony-forming assay with human primary epithelial cells showed that the adipose tissue-derived mesenchymal stem cells produced various factors to support epithelial stem/progenitor maintenance and cell growth. Using the mesenchymal stem cells as novel feeder layers, transplantable epithelial cell sheets could be effectively generated ex vivo on temperature-responsive cell-culture surfaces.

Because falls are highly prevalent, harmful events for older adults, identification of patients at risk is a high priority for home health care agencies. Using routine administrative data, we demonstrated that patients with depressive symptoms on the Outcome and Assessment Information Set are at risk for falls. A prospective case-control study that matched 54 patients who experienced an adverse fall with 854 controls showed that patients who fell had twice the odds of being depressed (odds ratio = 1.90, 95% confidence interval = 1.01 to 3.59). Bowel incontinence, high medical comorbidity, stair use, injury and poisoning, memory deficit, and antipsychotic medication use were also predictors, but no association was found for antidepressant medications. These data suggest the potential benefit of including depression screening for multifactorial fall prevention interventions.