TP53 gene mutations predict the response to neoadjuvant treatment with 5-fluorouracil and mitomycin in locally advanced breast cancer.

PURPOSE: Recent studies have found an association between certain TP53 mutations and resistance to anthracycline-based primary medical therapy in breast cancer. The purpose of this study was to investigate whether TP53 mutational status also might influence the response to a non-anthracycline-containing regimen in primary breast cancer. EXPERIMENTAL DESIGN: Thirty-five patients with locally advanced breast cancer were investigated for TP53 mutations before receiving combination chemotherapy with 5-fluorouracil (1000 mg/m(2) on days 1 and 2) and mitomycin (6 mg/m(2) on day 2), administered every 3 weeks for 2-10 cycles in the neoadjuvant setting. RESULTS: Mutations in the TP53 gene, in particular those affecting loop domains L2 or L3 of the p53 protein, were associated with lack of response to chemotherapy (i.e., increase in the diameter product of tumor lesion by >/=25%; P = 0.177 for all mutations and P = 0.006 for those affecting L2/L3 domains, respectively). No statistically significant correlation between TP53 LOH and response to therapy was seen. CONCLUSION: This study revealed a significant association between lack of response to 5-fluorouracil and mitomycin and mutations affecting the L2/L3 domains of the p53 protein. Together with our previous finding that such mutations predict resistance to weekly doxorubicin, our data suggest that mutations affecting this particular domain of the p53 protein may cause resistance to several different cytotoxic compounds applied in breast cancer treatment.     

Law as a Tool for Preventing Chronic Diseases: Expanding the Spectrum of Effective Public Health Strategies

Law, which is a fundamental element of effective public health policy and practice, played a crucial role in many of public health's greatest achievements of the 20th century. Still, conceptual legal frameworks for the systematic application of law to chronic disease prevention and control have not been fully recognized and used to address public health needs. Development and implementation of legal frameworks could broaden the range of effective public health strategies and provide valuable tools for the public health workforce, especially for state and local health department program managers and state and national policy makers. In an effort to expand the range of effective public health interventions, the Centers for Disease Control and Prevention will work with its partners to explore the development of systematic legal frameworks as a tool for preventing chronic diseases and addressing the growing epidemic of obesity, heart disease, stroke, and other chronic diseases and their risk factors.     

Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer.

PURPOSE: We determined the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLT) of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when infused on days 1, 8, and 15 of a 28-day cycle in advanced solid tumor patients. We also characterized the pharmacokinetics of 17-AAG, its effect on chaperone and client proteins, and whether cytochrome P450 (CYP) 3A5 and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphisms affected 17-AAG disposition or toxicity. PATIENTS AND METHODS: An accelerated titration design was used. Biomarkers were measured in peripheral-blood mononuclear cells (PBMCs) at baseline and on days 1 and 15, and pharmacokinetic analysis was performed on day 1 of cycle 1. CYP3A5*3 and NQO1*2 genotypes were determined and correlated with pharmacokinetics and toxicity. RESULTS: Twenty-one patients received 52 courses at 11 dose levels. DLTs at 431 mg/m(2) were grade 3 bilirubin (n = 1), AST (n = 1), anemia (n = 1), nausea (n = 1), vomiting (n = 1), and myalgias (n = 1). No tumor responses were seen. 17-AAG consistently increased heat shock protein (Hsp) 70 levels in PBMCs. At the MTD, the clearance and half-life (t(1/2)) of 17-AAG were 11.6 L/h/m(2) and 4.15 hours, respectively; whereas the active metabolite 17-aminogeldanamycin had a t(1/2) of 7.63 hours. The CYP3A5*3 and NQO1*2 polymorphisms were not associated with 17-AAG toxicity. The CYP3A5*3 polymorphism was associated with higher 17-AAG clearance. CONCLUSION: The MTD of weekly 17-AAG is 308 mg/m(2). 17-AAG induced Hsp70 in PBMCs, indicating that Hsp90 has been affected. Further evaluation of 17-AAG is ongoing using a twice-weekly regimen, and this schedule of 17-AAG is being tested in combination with chemotherapy.     

Phase I and pharmacologic study of infusional topotecan and Carboplatin in relapsed and refractory acute leukemia.

PURPOSE: To assess the maximum tolerated dose, toxicities, pharmacokinetics, and antileukemic activity of topotecan and carboplatin in adults with recurrent or refractory acute leukemias. EXPERIMENTAL DESIGN: Patients received topotecan and carboplatin by 5-day continuous infusion at nine dose levels. Patients achieving a complete remission received up to two additional courses for consolidation. Plasma topotecan and ultrafilterable platinum were assayed on days 1 to 5. In addition, pretreatment levels of various polypeptides in leukemic cells were examined by immunoblotting to assess possible correlations with response. RESULTS: Fifty-one patients received a total of 69 courses of therapy. Dose-limiting toxicity consisted of grade 4/5 typhlitis and grade 3/4 mucositis after one course of therapy or grade 4 neutropenia and thrombocytopenia lasting >50 days when a second course was administered on day 21. Among 45 evaluable patients, there were 7 complete remissions, 2 partial remissions, 1 incomplete complete remission, and 1 reversion to chronic-phase chronic myelogenous leukemia. Topotecan steady-state plasma concentrations increased with dose. No accumulation of topotecan or ultrafilterable platinum occurred between days 1 and 5 of therapy. Leukemic cell levels of topoisomerase I, checkpoint kinase 1, checkpoint kinase 2, and Mcl-1 correlated with proliferating cell nuclear antigen but not with response. In contrast, low Bcl-2 expression correlated with response (P = 0.014, Mann-Whitney U test). CONCLUSIONS: The maximum tolerated dose was 1.6 mg/m(2)/d topotecan plus 150 mg/m(2)/d carboplatin. The complete remission rate in a heavily pretreated population was 16% (33% at the highest three dose levels). Responses seem to correlate with low pretreatment blast cell Bcl-2 expression.     

In situ polymerization and electrical conductivity of polypyrrole/cellulose nanocomposites using Schweizer's reagent

Cellulose-based composites have attracted interest given the shift towards ‘green’ materials, but achieving uniform dispersions of cellulose in polymer matrices and/or enhancement of interfacial interactions between components remains challenging. Herein we report the preparation of polypyrrole/cellulose nanocomposites in [Cu(NH₃)₄(H₂O)₂](OH)₂ (Schweizer''s reagent/cuoxam)-based reaction media via in situ polymerization. The effect of cellulose template morphology and reaction media on the microstructure, electrical conductivity, and surface wettability was studied. Aqueous reaction media favored the formation of a uniform polypyrrole coating encapsulating the cellulose fibers; concentrated cuoxam solutions promoted inhomogeneity and exhibited a progressive decline in conductivity. The maximum conductivity attained was 3.08 S cm⁻¹ from a bacterial cellulose-templated composite prepared in aqueous reaction media and afforded an approximately threefold increase in conductivity when compared with pure PPy at 1.14 S cm⁻¹. Generally, the composites resembled wetting surfaces – with highly concentrated cuoxam solutions yielding improved hydrophilicity, while substitution of bacterial cellulose with nanocrystalline cellulose engendered a shift towards hydrophobicity. Most composites displayed a contact angle of less than 90° suggesting PPy/cellulose composites tended towards hydrophilic behavior. This study highlights investigations into the viability of cellulose solvents as a facile means to control the structure and performance of in situ functionalized cellulose nanocomposites.

The in situ polymerization of polypyrrole/cellulose nanocomposites using Schweizer''s reagent is demonstrated and measured against a number of structural, electrical, and colligative properties.     

Risk Factors for SARS-CoV-2 Infection and Illness in Cats and Dogs

We tested swab specimens from pets in households in Ontario, Canada, with human COVID-19 cases by quantitative PCR for SARS-CoV-2 and surveyed pet owners for risk factors associated with infection and seropositivity. We tested serum samples for spike protein IgG and IgM in household pets and also in animals from shelters and low-cost neuter clinics. Among household pets, 2% (1/49) of swab specimens from dogs and 7.7% (5/65) from cats were PCR positive, but 41% of dog serum samples and 52% of cat serum samples were positive for SARS-CoV-2 IgG or IgM. The likelihood of SARS-CoV-2 seropositivity in pet samples was higher for cats but not dogs that slept on owners’ beds and for dogs and cats that contracted a new illness. Seropositivity in neuter-clinic samples was 16% (35/221); in shelter samples, 9.3% (7/75). Our findings indicate a high likelihood for pets in households of humans with COVID-19 to seroconvert and become ill.