Expediting dental treatment for patients with diabetes mellitus in a university-based dental clinic.

PURPOSE: This pilot project was implemented to minimize barriers in access to care, reduce the risk for oral health and systemic diabetes complications, and optimize the health outcomes for patients with diabetes seeking comprehensive dental treatment. METHODS: The intervention group included patients with diabetes who participated in hemoglobin A1c (HbA1c) testing during their initial dental screening appointment. The participants whose HbA1c value was ≤ 9.0% were expedited into the scheduling queue for the next comprehensive examination appointment. Health literacy was assessed regarding patients' understanding of the connection between oral health and diabetes. RESULTS: The mean number of days between screening and treatment plan development was decreased by 38.4%. Of the participants in the intervention group with an HbA1c value ≤ 9.0%, 44% rated their understanding of the connection between diabetes and gum disease as "poor", whereas 86% of the patients who were ineligible due to an HbA1c value ≥ 9.1% rated their understanding as "very good" or "excellent". CONCLUSIONS: Patients with diabetes will continue to benefit from this quality improvement project to minimize barriers to dental care and improve overall health outcomes as this intervention is adopted as a permanent practice change. The need has been highlighted for comprehensive education in practice settings concerning medical and dental collaboration, and patient awareness of the interrelationship between diabetes mellitus and oral disease. An increase in oral examinations, assessment of routine oral health behaviors, and referral to dental providers from the primary care setting is warranted.

Upregulation of RNA Processing Factors in Poorly Differentiated Lung Cancer Cells.

Intratumoral heterogeneity in non-small cell lung cancer (NSCLC) has been appreciated at the histological and cellular levels, but the association of less differentiated pathology with poor clinical outcome is not understood at the molecular level. Gene expression profiling of intact human tumors fails to reveal the molecular nature of functionally distinct epithelial cell subpopulations, in particular the tumor cells that fuel tumor growth, metastasis, and disease relapse. We generated primary serum-free cultures of NSCLC and then exposed them to conditions known to promote differentiation: the air-liquid interface (ALI) and serum. The transcriptional network of the primary cultures was associated with stem cells, indicating a poorly differentiated state, and worse overall survival of NSCLC patients. Strikingly, the overexpression of RNA splicing and processing factors was a prominent feature of the poorly differentiated cells and was also observed in clinical datasets. A genome-wide analysis of splice isoform expression revealed many alternative splicing events that were specific to the differentiation state of the cells, including an unexpectedly high frequency of events on chromosome 19. The poorly differentiated cells exhibited alternative splicing in many genes associated with tumor progression, as exemplified by the preferential expression of the short isoform of telomeric repeat-binding factor 1 (TERF1), also known as Pin2. Our findings demonstrate the utility of the ALI method for probing the molecular mechanisms that underlie NSCLC pathogenesis and provide novel insight into posttranscriptional mechanisms in poorly differentiated lung cancer cells.

Delineation of a cellular hierarchy in lung cancer reveals an oncofetal antigen expressed on tumor-initiating cells.

Poorly differentiated tumors in non-small cell lung cancer (NSCLC) have been associated with shorter patient survival and shorter time to recurrence following treatment. Here, we integrate multiple experimental models with clinicopathologic analysis of patient tumors to delineate a cellular hierarchy in NSCLC. We show that the oncofetal protein 5T4 is expressed on tumor-initiating cells and associated with worse clinical outcome in NSCLC. Coexpression of 5T4 and factors involved in the epithelial-to-mesenchymal transition were observed in undifferentiated but not in differentiated tumor cells. Despite heterogeneous expression of 5T4 in NSCLC patient-derived xenografts, treatment with an anti-5T4 antibody-drug conjugate resulted in complete and sustained tumor regression. Thus, the aggressive growth of heterogeneous solid tumors can be blocked by therapeutic agents that target a subpopulation of cells near the top of the cellular hierarchy.

Preclinical pharmacologic evaluation of MST-997, an orally active taxane with superior in vitro and in vivo efficacy in paclitaxel- and docetaxel-resistant tumor models.

PURPOSE: Because resistance to paclitaxel and docetaxel is frequently observed in the clinic, new anti-microtubule agents have been sought. The aim of this study was to evaluate the efficacy and oral activity of a novel taxane (MST-997) in paclitaxel- and docetaxel-resistant tumor models in vitro and in vivo. EXPERIMENTAL DESIGN: Tubulin polymerization assays, immunohistochemistry, and cell cycle analysis was used to evaluate mechanism of action of MST-997. The effect of MST-997 on growth inhibition in a panel of paclitaxel- and docetaxel-resistant cell lines that overexpressed P-glycoprotein (MDR1) or harbored beta-tubulin mutations were assayed in vitro and in murine xenografts. RESULTS: MST-997 induced microtubule polymerization (EC50 = 0.9 micromol/L) and bundling, resulting in G2-M arrest and apoptosis. In addition, MST-997 was a potent inhibitor of paclitaxel- and docetaxel-sensitive tumor cell lines that did not have detectable P-glycoprotein (IC50 = 1.8 +/- 1.5 nmol/L). Minimal resistance (1- to 8-fold) to MST-997 was found in cell lines that either overexpressed MDR1 or harbored point mutations in beta-tubulin. Most notable, MST-997 displayed superior in vivo efficacy as a single i.v. or p.o. dose either partially or completely inhibited tumor growth in paclitaxel- and docetaxel-resistant xenografts. CONCLUSIONS: MST-997 represents a potent and orally active microtubule-stabilizing agent that has greater pharmacologic efficacy in vitro and in vivo than the currently approved taxanes. Our findings suggest that MST-997, which has entered phase I clinical trials, may have broad therapeutic value.

Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase.

HER-2 belongs to the ErbB family of receptor tyrosine kinases, which has been implicated in a variety of cancers. Overexpression of HER-2 is seen in 25-30% of breast cancer patients and predicts a poor outcome in patients with primary disease. Trastuzumab (Herceptin), a monoclonal antibody to HER-2, is specifically approved for HER-2-positive breast cancer but is active only in a subset of these tumors. Blocking HER-2 function by a small molecule kinase inhibitor, therefore, represents an attractive alternate strategy to inhibit the growth of HER-2-positive tumors. HKI-272 is a potent inhibitor of HER-2 and is highly active against HER-2-overexpressing human breast cancer cell lines in vitro. It also inhibits the epidermal growth factor receptor (EGFR) kinase and the proliferation of EGFR-dependent cells. HKI-272 reduces HER-2 receptor autophosphorylation in cells at doses consistent with inhibition of cell proliferation and functions as an irreversible binding inhibitor, most likely by targeting a cysteine residue in the ATP-binding pocket of the receptor. In agreement with the predicted effects of HER-2 inactivation, HKI-272 treatment of cells results in inhibition of downstream signal transduction events and cell cycle regulatory pathways. This leads to arrest at the G(1)-S (Gap 1/DNA synthesis)-phase transition of the cell division cycle, ultimately resulting in decreased cell proliferation. In vivo, HKI-272 is active in HER-2- and EGFR-dependent tumor xenograft models when dosed orally on a once daily schedule. On the basis of its favorable preclinical pharmacological profile, HKI-272 has been selected as a candidate for additional development as an antitumor agent in breast and other HER-2-dependent cancers.

HTI-286, a synthetic analogue of the tripeptide hemiasterlin, is a potent antimicrotubule agent that circumvents P-glycoprotein-mediated resistance in vitro and in vivo.

Hemiasterlin is a natural product derived from marine sponges that, like other structurally diverse peptide-like molecules, binds to the Vinca-peptide site in tubulin, disrupts normal microtubule dynamics, and, at stoichiometric amounts, depolymerizes microtubules. Total synthesis of hemiasterlin and its analogues has been accomplished, and optimal pharmacological features of the series have been explored. The biological profile of one analogue, HTI-286, was studied here. HTI-286 inhibited the polymerization of purified tubulin, disrupted microtubule organization in cells, and induced mitotic arrest, as well as apoptosis. HTI-286 was a potent inhibitor of proliferation (mean IC(50) = 2.5 +/- 2.1 nM in 18 human tumor cell lines) and had substantially less interaction with multidrug resistance protein (P-glycoprotein) than currently used antimicrotubule agents, including paclitaxel, docetaxel, vinorelbine, or vinblastine. Resistance to HTI-286 was not detected in cells overexpressing the drug transporters MRP1 or MXR. In athymic mice implanted with human tumor xenografts, HTI-286 administered i.v. in saline inhibited the growth of numerous human tumors derived from carcinoma of the skin, breast, prostate, brain, and colon. Marked tumor regression was observed when used on established tumors that were >1 gram in size. Moreover, HTI-286 inhibited the growth of human tumor xenografts (e.g., HCT-15, DLD-1, MX-1W, and KB-8-5) where paclitaxel and vincristine were ineffective because of inherent or acquired resistance associated with P-glycoprotein. Efficacy was also achieved with p.o. administration of HTI-286. These data suggest that HTI-286 has excellent preclinical properties that may translate into superior clinical activity, as well as provide a useful synthetic reagent to probe the drug contact sites of peptide-like molecules that interact with tubulin.