Impact of metallic coating on the retention of Ac and its daugthers within core-shell nanocarriers.

Currently, alpha-emitting radionuclide Ac is one of the most promising isotopes in alpha therapy due to its high linear energy transfer during four sequential alpha decays. However, the main obstacle preventing the full introduction of Ac into clinical practice is the lack of stable retention of radionuclides, leading to free circulation of toxic isotopes in the body. In this work, the surface of silica nanoparticles (SiO NPs) has been modified with metallic shells composed of titanium dioxide (TiO) and gold (Au) nanostructures to improve the retention of Ac and its decay products within the developed nanocarriers.

Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.

Background: Chemoradiotherapy is the standard of care for unresected locally advanced squamous cell carcinoma of the head and neck. We aimed to assess if addition of avelumab (anti-PD-L1) to chemoradiotherapy could improve treatment outcomes for this patient population.

Methods: In this randomised, double-blind, placebo-controlled, phase 3 study, patients were recruited from 196 hospitals and cancer treatment centres in 22 countries.

Long-term evaluation of cardiac and vascular toxicity in patients with Philadelphia chromosome-positive leukemias treated with bosutinib.

Vascular and cardiac safety during tyrosine kinase inhibitor (TKI) therapy is an emerging issue. We evaluated vascular/cardiac toxicities associated with long-term bosutinib treatment for Philadelphia chromosome-positive (Ph+) leukemia based on treatment-emergent adverse events (TEAEs) and changes in QTc intervals and ejection fraction in two studies: a phase 1/2 study of second-/third-/fourth-line bosutinib for Ph+ leukemia resistant/intolerant to prior TKIs (N = 570) and a phase 3 study of first-line bosutinib (n = 248) versus imatinib (n = 251) in chronic phase chronic myeloid leukemia. Follow-up time was ≥48 months (both studies).

Caveolin-1 scaffolding domain residue phenylalanine 92 modulates Akt signaling.

Caveolin-1 (Cav-1), the homo-oligomeric coat protein of cholesterol-rich caveolae signalosomes, regulates signaling proteins including endothelial nitric oxide synthase (eNOS). The Cav-1 scaffolding domain (a.a.

Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-month follow-up of the BELA trial.

Bosutinib is an oral, dual SRC/ABL1 tyrosine kinase inhibitor for resistant/intolerant chronic myeloid leukaemia (CML). We assessed the efficacy and safety of bosutinib 500 mg/d (n = 250) versus imatinib 400 mg/d (n = 252) after >24 months from accrual completion in newly diagnosed chronic phase (CP)-CML (Bosutinib Efficacy and Safety in Newly Diagnosed CML trial [BELA]). Cumulative complete cytogenetic response (CCyR) rates by 24 months were similar (bosutinib, 79%; imatinib, 80%); cumulative major molecular response (MMR) rates were 59% for bosutinib and 49% for imatinib.

Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia.

Bosutinib, an orally active, Src/Abl tyrosine kinase inhibitor, has demonstrated clinical activity and acceptable tolerability in chronic phase chronic myeloid leukemia (CP CML). This updated analysis of the BELA trial assessed the safety profile and management of toxicities of bosutinib versus imatinib in adults with newly diagnosed (≤6 months) CP CML after >30 months from accrual completion. Among patients randomized to bosutinib 500 mg/d (n = 250) or imatinib 400 mg/d (n = 252), 248 and 251, respectively, received ≥1 dose of study treatment.

Population pharmacokinetic and pharmacodynamic analysis of tremelimumab in patients with metastatic melanoma.

Tremelimumab, a fully human monoclonal antibody specific for human cytotoxic T-lymphocyte-associated antigen 4, has been studied in clinical trials. We have reported the results of population pharmacokinetics for tremelimumab in 654 metastatic melanoma patients. Population estimates (inter-individual variability [IIV]) for pharmacokinetic parameters in a final model were clearance (CL), 0.

Deciphering the binding of caveolin-1 to client protein endothelial nitric-oxide synthase (eNOS): scaffolding subdomain identification, interaction modeling, and biological significance.

Caveolin-1 (Cav-1) gene inactivation interferes with caveolae formation and causes a range of cardiovascular and pulmonary complications in vivo. Recent evidence suggests that blunted Cav-1/endothelial nitric-oxide synthase (eNOS) interaction, which occurs specifically in vascular endothelial cells, is responsible for the multiple phenotypes observed in Cav-1-null animals. Under basal conditions, Cav-1 binds eNOS and inhibits nitric oxide (NO) production via the Cav-1 scaffolding domain (CAV; amino acids 82-101).

Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial.

Background: Population pharmacokinetic data suggest axitinib plasma exposure correlates with efficacy in metastatic renal-cell carcinoma. Axitinib dose titration might optimise exposure and improve outcomes. We prospectively assessed the efficacy and safety of axitinib dose titration in previously untreated patients with metastatic renal-cell carcinoma.

Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma.

Purpose: In phase I/II trials, the cytotoxic T lymphocyte-associated antigen-4-blocking monoclonal antibody tremelimumab induced durable responses in a subset of patients with advanced melanoma. This phase III study evaluated overall survival (OS) and other safety and efficacy end points in patients with advanced melanoma treated with tremelimumab or standard-of-care chemotherapy.

Patients And Methods: Patients with treatment-naive, unresectable stage IIIc or IV melanoma were randomly assigned at a ratio of one to one to tremelimumab (15 mg/kg once every 90 days) or physician's choice of standard-of-care chemotherapy (temozolomide or dacarbazine).

Phase I/II trial of tremelimumab in patients with metastatic melanoma.

Purpose: Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade with tremelimumab (CP-675,206), a fully human anti-CTLA4 monoclonal antibody, was tolerated and demonstrated antitumor activity in a single dose, dose-escalation phase I trial in patients with solid tumors. This phase I/II trial was conducted to examine safety of multiple doses of tremelimumab, to further assess efficacy, and to identify an appropriate dosing regimen for further development.

Patients And Methods: Twenty-eight patients with metastatic melanoma received monthly intravenous infusions of tremelimumab at 3, 6, or 10 mg/kg for up to 1 year to determine recommended monthly phase II dose.

Familial hypertrophic cardiomyopathy-related cardiac troponin C mutation L29Q affects Ca2+ binding and myofilament contractility.

The cardiac troponin C (cTnC) mutation, L29Q, has been found in a patient with familial hypertrophic cardiomyopathy. We previously showed that L29, together with neighboring residues, Asp2, Val28, and Gly30, plays an important role in determining the Ca(2+) affinity of site II, the regulatory site of mammalian cardiac troponin C (McTnC). Here we report on the Ca(2+) binding characteristics of L29Q McTnC and D2N/V28I/L29Q/G30D McTnC (NIQD) utilizing the Phe(27) --> Trp (F27W) substitution, allowing one to monitor Ca(2+) binding and release.

Comorbidities and the risk of late-stage prostate cancer.

The degree to which comorbidities affect the diagnosis of prostate cancer is not clear. The purpose of this study was to determine how comorbidities affect the stage at which prostate cancer is diagnosed in elderly white and black men. We obtained data from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute merged with Medicare claims data.

Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206.

Purpose: Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade with CP-675,206, a fully human anti-CTLA4 monoclonal antibody, may break peripheral immunologic tolerance leading to effective immune responses to cancer in humans. A phase I trial was conducted to test the safety of CP-675,206.

Patients And Methods: Thirty-nine patients with solid malignancies (melanoma, n = 34; renal cell, n = 4; colon, n = 1) received an intravenous (IV) infusion of CP-675,206 at seven dose levels.

Comorbidity as a predictor of stage of illness for patients with breast cancer.

Objective: The purpose of this research was to determine whether comorbidity affects the stage at which breast cancer is diagnosed.

Methods: Data from the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute (NCI) was merged with Medicare claims for 17,468 women diagnosed with breast cancer from 1993 to 1995.

Results: Women with cardiovascular disease, musculoskeletal disorders, mild-to-moderate gastrointestinal disease, and nonmalignant benign breast disease had a 13%, 7%, 14%, and 24% lower odds, respectively, of being diagnosed with advanced breast cancer.

The development and validation of a comorbidity index for prostate cancer among Black men.

Background And Objectives: The purpose of this study was to develop a comorbidity index specific to Black Men with prostate cancer, because certain comorbidities and prostate cancer are particularly prevalent among this racial group.

Methods: This research used the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database to develop an index of comorbidity burden based on survival, and the presence/absence of comorbid illness in 2,931 Black males diagnosed with prostate cancer. Comorbidity burden was recognized using inpatient, outpatient, and physician claims for a 2-year period prior to the diagnosis of prostate cancer.