Dental Caries, Race and Incident Ischemic Stroke, Coronary Heart Disease, and Death.

Background: Dental caries is a highly prevalent disease worldwide. In the United States, untreated dental caries is present in >1 in 5 adults. The objective of this study was to determine the relationship between dental caries and incident ischemic stroke, coronary heart disease (CHD) events, and death.

Periodontal Disease Treatment After Stroke or Transient Ischemic Attack: The PREMIERS Study, a Randomized Clinical Trial.

Background: Patients with stroke/transient ischemic attack and periodontal disease (PD) are at increased risk for cardiovascular events. PD treatments that can improve stroke risk factors were tested if they might assist patients with cerebrovascular disease.

Methods: In this multicenter phase II trial, patients with stroke/transient ischemic attack and moderately severe PD were randomly assigned to intensive or standard PD treatment arms.

mWTX-330, an IL-12 INDUKINE Molecule, Activates and Reshapes Tumor-Infiltrating CD8+ T and NK Cells to Generate Antitumor Immunity.

IL-12 is a pleotropic inflammatory cytokine, which has broad stimulatory effects on various immune cell populations, making it an attractive target for cancer immunotherapy. However, despite generating robust antitumor activity in syngeneic murine tumor models, clinical administration of IL-12 has been limited by severe toxicity. mWTX-330 is a selectively inducible INDUKINE molecule comprised of a half-life extension domain and an inactivation domain linked to chimeric IL-12 by tumor protease-sensitive linkers.

Discovery of a Conditionally Activated IL-2 that Promotes Antitumor Immunity and Induces Tumor Regression.

IL-2 is a cytokine clinically approved for the treatment of melanoma and renal cell carcinoma. Unfortunately, its clinical utility is hindered by serious side effects driven by the systemic activity of the cytokine. Here, we describe the design and characterization of a conditionally activated IL-2 prodrug, WTX-124, that takes advantage of the dysregulated protease milieu of tumors.

Early Identification, Intervention and Management of Post-stroke Spasticity: Expert Consensus Recommendations.

Stroke patients with spasticity usually require long-lasting care and interventions but frequently report that outpatient and community treatment is limited, reflecting a significant unmet need in health and social care provision. Rehabilitation and spasticity management services are essential for patient recovery, with improvements in both activity and participation reducing the burden on patients, family and society. Current clinical guidance provides scope for improvements in both post-stroke management and spasticity prevention.

Characterization of ASP8374, a fully-human, antagonistic anti-TIGIT monoclonal antibody.

The T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) is a validated immune checkpoint protein expressed on memory CD4T-cellls, Tregs, CD8T-cell and natural killer (NK) cells. ASP8374 is a fully human monoclonal immunoglobulin (Ig) G4 antibody designed to block the interaction of TIGIT with its ligands and inhibit TIGIT signaling. ASP8374 exhibited high affinity binding to TIGIT and increased interferon (IFN)-γ production of cultured peripheral blood mononuclear cells (PBMCs) in a titratable manner.

Periodontal Disease Association with Large-Artery Atherosclerotic Stroke.

Objectives: We investigated whether periodontal disease is associated with specific stroke subtype.

Materials And Methods: This is a single-center cross-sectional study. Periodontal disease was assessed in stroke and transient ischemic attack patients.

Can the early use of botulinum toxin in post stroke spasticity reduce contracture development? A randomised controlled trial.

Objective: Does early treatment of spasticity with botulinum-toxin (BoNTA), in (hyper)acute stroke patients without arm-function, reduce contractures and improve function.

Design: Randomised placebo-controlled-trial.

Setting: Specialised stroke-unit.

Ultrasound Structural Changes in Triceps Surae After a 1-Year Daily Self-stretch Program: A Prospective Randomized Controlled Trial in Chronic Hemiparesis.

Introduction: The effects of long-term stretching (>6 months) in hemiparesis are unknown. This prospective, randomized, single-blind controlled trial compared changes in architectural and clinical parameters in plantar flexors of individuals with chronic hemiparesis following a 1-year guided self-stretch program, compared with conventional rehabilitation alone.

Methods: Adults with chronic stroke-induced hemiparesis (time since lesion >1 year) were randomized into 1 of 2, 1-year rehabilitation programs: conventional therapy (CONV) supplemented with the Guided Self-rehabilitation Contract (GSC) program, or CONV alone.

[Shift Work and Sleep].

Shift Work and Sleep Abstract. Shift work and night work are necessary in our society today. In Europe, on average about 20 % of the working population work shifts; in Switzerland it is slightly lower at 14.

Electronic cigarette explosions involving the oral cavity.

Background And Overview: The use of electronic cigarettes (e-cigarettes) is a rapidly growing trend throughout the United States. E-cigarettes have been linked to the risk of causing explosion and fire.

Case Description: Data are limited on the associated health hazards of e-cigarette use, particularly long-term effects, and available information often presents conflicting conclusions.

Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors.

A new subseries of substituted piperidines as p53-HDM2 inhibitors exemplified by 21 has been developed from the initial lead 1. Research focused on optimization of a crucial HDM2 Trp23-ligand interaction led to the identification of 2-(trifluoromethyl)thiophene as the preferred moiety. Further investigation of the Leu26 pocket resulted in potent, novel substituted piperidine inhibitors of the HDM2-p53 interaction that demonstrated tumor regression in several human cancer xenograft models in mice.

CCR 20th Anniversary commentary: in search of cetuximab's first indication-combination therapy with irinotecan in colorectal cancer.

The research article by Prewett and colleagues, published in the May 1, 2002, issue of Clinical Cancer Research, provided important translational data that extended earlier preclinical and clinical studies with the human-murine chimeric anti-EGFR monoclonal antibody C225. Subsequent clinical trials with C225 led to the demonstration of its efficacy in combination with irinotecan and regulatory approval for the treatment of metastatic colorectal cancer.

Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors.

The high frequency of activating RAS or BRAF mutations in cancer provides strong rationale for targeting the mitogen-activated protein kinase (MAPK) pathway. Selective BRAF and MAP-ERK kinase (MEK) inhibitors have shown clinical efficacy in patients with melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the extracellular signal-regulated kinase (ERK) signaling pathway.

Antiangiogenic therapy--evolving view based on clinical trial results.

Antiangiogenic therapies that target VEGF or its receptors have become a mainstay of cancer therapy in multiple malignancies. However, the clinical efficacy of these agents is less than originally anticipated and, in most settings, requires the addition of cytotoxic chemotherapy suggesting that, as for other targeted therapies, VEGF inhibitors will require selection of patient subpopulations to achieve maximal clinical benefit. Without the identification and use of predictive biomarkers for VEGF-targeted agents, and other agents that target the vasculature, further improvements in current clinical outcomes are unlikely.

SCH 1473759, a novel Aurora inhibitor, demonstrates enhanced anti-tumor activity in combination with taxanes and KSP inhibitors.

Purpose: Aurora kinases are required for orderly progression of cells through mitosis, and inhibition of these kinases by siRNA or small molecule inhibitors results in cell death. We previously reported the synthesis of SCH 1473759, a novel sub-nanomolar Aurora A/B inhibitor.

Methods: We utilized SCH 1473759 and a panel of tumor cell lines and xenograft models to gain knowledge about optimal dosing schedule and chemotherapeutic combinations for Aurora A/B inhibitors.

SCH 2047069, a novel oral kinesin spindle protein inhibitor, shows single-agent antitumor activity and enhances the efficacy of chemotherapeutics.

Kinesin spindle protein (KSP) is a mitotic kinesin required for the formation of the bipolar mitotic spindle, and inhibition of this motor protein results in mitotic arrest and cell death. KSP inhibitors show preclinical antitumor activity and are currently undergoing testing in clinical trials. These agents have been dosed intravenously using various dosing schedules.

Resistance to Targeted Therapies: Refining Anticancer Therapy in the Era of Molecular Oncology.

The advent of targeted therapy for treatment of human cancers has added significantly to our armamentarium as we strive to prolong patient survival while minimizing toxicity. In cancers driven by a dominant oncogene, targeted therapies have led to remarkable improvements in response and survival, whereas in others the outcome has been more modest. One key aspect toward realizing the potential of targeted therapies is a better understanding of the intrinsic or acquired resistance mechanisms that limit their efficacy.

Prioritization of EGFR/IGF-IR/VEGFR2 combination targeted therapies utilizing cancer models.

Background: Rational strategies utilizing anticancer efficacy and biological principles are needed for the prioritization of specific combination targeted therapy approaches for clinical development, from among the many with experimental support.

Materials And Methods: Antibodies targeting epidermal growth factor receptor (EGFR) (cetuximab), insulin-like growth factor-1 receptor (IGF-IR) (IMC-A12) or vascular endothelial growth factor receptor 2 (VEGFR2) (DC101), were dosed alone or in combination, in 11 human tumor xenograft models established in mice. Efficacy readouts included the tumor burden and incidence of metastasis, as well as tumor active hypoxia inducible factor-1 (HIF-1), human VEGF and blood vessel density.

Vascular endothelial growth factor receptor 2 (VEGFR-2) functions to promote uterine decidual angiogenesis during early pregnancy in the mouse.

Implantation of an embryo induces rapid proliferation and differentiation of uterine stromal cells, forming a new structure, the decidua. One salient feature of decidua formation is a marked increase in maternal angiogenesis. Vascular endothelial growth factor (VEGF)-dependent pathways are active in the ovary, uterus, and embryo, and inactivation of VEGF function in any of these structures might prevent normal pregnancy development.

In vivo method for establishing synergy between antibodies to epidermal growth factor receptor and vascular endothelial growth factor receptor-2.

Targeted therapy for cancer is shifting towards an approach of inhibiting multiple pathways, justified in part by the ability of cancer cells to overcome the inhibition of a single pathway. However the literature is replete with preclinical data supporting the anticancer potential of numerous combinations of targeted agents, making it difficult to select the combination strategies to invest in through clinical development. One characteristic of a combination strategy that can be utilized for prioritization is synergy.

Anti-epidermal growth factor receptor monoclonal antibody cetuximab inhibits EGFR/HER-2 heterodimerization and activation.

Human carcinomas frequently express one or more members of the epidermal growth factor receptor family. Two family members, epidermal growth factor receptor (EGFR) and c-erbB2/neu (HER2), homodimerize or heterodimerize upon activation with ligand and trigger potent mechanisms of cellular proliferation, differentiation and migration. In this study, we examined the effect of the anti-EGFR monoclonal antibody Erbitux (cetuximab) on human tumor cells expressing both EGFR and HER2.

Enhanced suppression of melanoma tumor growth and metastasis by combined therapy with anti-VEGF receptor and anti-TYRP-1/gp75 monoclonal antibodies.

Targeted immunotherapy against tumors or angiogenesis has shown promise as an alternative approach for the treatment of malignant disease. Whether or not combining these two treatment modalities would enhance the antitumor effect was tested in mouse models of malignant melanoma. C57BL/6 mice bearing established subcutaneous B16 tumors were treated with anti-vascular endothelial growth factor receptor (anti-VEGFR) fetal liver kinase-1 (Flk-1) monoclonal antibody (mAb) DC101 and/or anti-TYRP-1/gp75 (tyrosinase-related protein-1) mAb TA99.

Pathways mediating resistance to vascular endothelial growth factor-targeted therapy.

Vascular endothelial growth factor (VEGF)-targeted therapy has become an important treatment option for the management of a number of human malignancies. Unfortunately, a significant number of patients do not respond to VEGF-targeted therapy when used as a single agent or in combination with chemotherapy. Furthermore, the duration of benefit from VEGF-targeted therapy can be relatively short (weeks to months).

VEGF-targeted therapy: mechanisms of anti-tumour activity.

Several vascular endothelial growth factor (VEGF)-targeted agents, administered either as single agents or in combination with chemotherapy, have been shown to benefit patients with advanced-stage malignancies. VEGF-targeted therapies were initially developed with the notion that they would inhibit new blood vessel growth and thus starve tumours of necessary oxygen and nutrients. It has become increasingly apparent, however, that the therapeutic benefit associated with VEGF-targeted therapy is complex, and probably involves multiple mechanisms.