Discovery of lirafugratinib (RLY-4008), a highly selective irreversible small-molecule inhibitor of FGFR2.

Fibroblast growth factor receptor (FGFR) kinase inhibitors have been shown to be effective in the treatment of intrahepatic cholangiocarcinoma and other advanced solid tumors harboring alterations, but the toxicity of these drugs frequently leads to dose reduction or interruption of treatment such that maximum efficacy cannot be achieved. The most common adverse effects are hyperphosphatemia caused by FGFR1 inhibition and diarrhea due to FGFR4 inhibition, as current therapies are not selective among the FGFRs. Designing selective inhibitors has proved difficult with conventional approaches because the orthosteric sites of FGFR family members are observed to be highly similar in X-ray structures.

Discovering the anti-cancer potential of non-oncology drugs by systematic viability profiling.

Anti-cancer uses of non-oncology drugs have occasionally been found, but such discoveries have been serendipitous. We sought to create a public resource containing the growth inhibitory activity of 4,518 drugs tested across 578 human cancer cell lines. We used PRISM, a molecular barcoding method, to screen drugs against cell lines in pools.

Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate.

Optimization of isoquinolinone PI3K inhibitors led to the discovery of a potent inhibitor of PI3K-γ (26 or IPI-549) with >100-fold selectivity over other lipid and protein kinases. IPI-549 demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-γ mediated neutrophil migration in vivo and is currently in Phase 1 clinical evaluation in subjects with advanced solid tumors.

Synthetic silvestrol analogues as potent and selective protein synthesis inhibitors.

Misregulation of protein translation plays a critical role in human cancer pathogenesis at many levels. Silvestrol, a cyclopenta[b]benzofuran natural product, blocks translation at the initiation step by interfering with assembly of the eIF4F translation complex. Silvestrol has a complex chemical structure whose functional group requirements have not been systematically investigated.

Use of the red fluorescent protein as a marker of Kaposi's sarcoma-associated herpesvirus lytic gene expression.

A hallmark of all herpesvirus is the ability to exist in either a latent, or lytic, state of replication, enabling the lifelong infection of its host. Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) can efficiently establish a latent infection in a variety of cell types in vitro, making it a valuable model for the study of latency and reactivation. To facilitate the identification of KSHV lytic replication, and allow subsequent experiments with live cells, a recombinant virus, rKSHV.

Activation of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) lytic replication by human cytomegalovirus.

The majority of Kaposi's sarcoma-associated herpesvirus (KSHV)-infected cells identified in vivo contain latent KSHV, with lytic replication in only a few percent of cells, as is the case for the cells of Kaposi's sarcoma (KS) lesions. Factors that influence KSHV latent or lytic replication are not well defined. Because persons with KS are often immunosuppressed and susceptible to many infectious agents, including human cytomegalovirus (HCMV), we have investigated the potential for HCMV to influence the replication of KSHV.

Coordinating the care of the chronically ill in a world of managed care.

The systems required to provide coordinated health care to the chronically ill within a managed care contract are complex. As an integrated health care delivery system assuming shared financial risk of enrollees in a Medicare + Choice contract, many care processes need to be created to meet the needs of the clients and administrators. Nursing case management and physician partnering are integral to the creation of the care model.

The effects of pharmacological and lentivirus-induced immune suppression on orbivirus pathogenesis: assessment of virus burden in blood monocytes and tissues by reverse transcription-in situ PCR.

We investigated the effects of pharmacological and lentivirus-induced immunosuppression on bluetongue virus (BTV) pathogenesis as a mechanism for virus persistence and induction of clinical disease. Immunologically normal and immunosuppressed sheep were infected subcutaneously with BTV serotype 3 (BTV-3), a foreign isolate with unknown pathogenicity in North American livestock, and with North American serotype 11 (BTV-11). Erythrocyte-associated BTV RNA was detected earlier and at greater concentrations in sheep treated with immunosuppressive drugs.

Early defibrillation: lessons learned.

Recovery from nontraumatic cardiac arrest depends on the presence of all the elements in the chain of survival. Early defibrillation is critical because ventricular fibrillation is the most common initial dysrhythmia of sudden cardiac arrest, defibrillation is the only treatment, and survival from ventricular fibrillation is determined by time. Out-of-hospital studies have demonstrated that defibrillation provided by first responders improves survival.

Changes in immune and psychological measures as a function of anticipation and reaction to news of HIV-1 antibody status.

We assessed changes in psychological and immunological functioning during 5-week periods preceding and following notification of serostatus among gay males taking the HIV-1 antibody test. Forty-six asymptomatic homosexual men between the ages of 18 and 40 yrs were recruited from a gay men's organization and through advertisements in a local newspaper. Measures of cell-mediated immunity (lymphocyte phenotypic markers, mitogen responsivity, and natural killer cell cytotoxicity) and psychological functioning (state anxiety, intrusive thoughts, and avoidant behaviors) were obtained at baseline, five weeks later and 72 hr before serostatus notification, and 1 week, 3 weeks and 5 weeks postnotification.