Vaccines against gonorrhea: Current status and future challenges

Gonorrhea occurs at high incidence throughout the world and significantly impacts reproductive health and the spread of human immunodeficiency virus. Current control measures are inadequate and seriously threatened by the rapid emergence of antibiotic resistance. Progress on gonorrhea vaccines has been slow; however, recent advances justify significant effort in this area. Conserved vaccine antigens have been identified that elicit bactericidal antibodies and, or play key roles in pathogenesis that could be targeted by a vaccine-induced response. A murine genital tract infection model is available for systematic testing of antigens, immunization routes and adjuvants, and transgenic mice exist to relieve some host restrictions. Furthermore, mechanisms by which Neisseria gonorrhoeae avoids inducing a protective adaptive response are being elucidated using human cells and the mouse model. Induction of a Th1 response in mice clears infection and induces a memory response, which suggests Th1-inducing adjuvants may be key in vaccine-induced protection. Continued research in this area should include human testing and clinical studies to confirm or negate findings from experimental systems and to define protective host factors.     

Reassessing the two-year rodent carcinogenicity bioassay: A review of the applicability to human risk and current perspectives

The 2-year rodent carcinogenicity test has been the regulatory standard for the prediction of human outcomes for exposure to industrial and agro-chemicals, food additives, pharmaceuticals and environmental pollutants for over 50 years. The extensive experience and data accumulated over that time has spurred a vigorous debate and assessment, particularly over the last 10 years, of the usefulness of this test in terms of cost and time for the information obtained. With renewed interest in the United States and globally, plus new regulations in the European Union, to reduce, refine and replace sentinel animals, this review offers the recommendation that reliance on information obtained from detailed shorter-term, 6 months rodent studies, combined with genotoxicity and chemical mode of action can realize effective prediction of human carcinogenicity instead of the classical two year rodent bioassay. The aim of carcinogenicity studies should not be on the length of time, and by obligation, number of animals expended but on the combined systemic pathophysiologic influence of a suspected chemical in determining disease. This perspective is in coordination with progressive regulatory standards and goals globally to utilize effectively resources of animal usage, time and cost for the goal of human disease predictability.     

Melanoma patient derived xenografts acquire distinct Vemurafenib resistance mechanisms

Variable clinical responses, tumor heterogeneity, and drug resistance reduce long-term survival outcomes for metastatic melanoma patients. To guide and accelerate drug development, we characterized tumor responses for five melanoma patient derived xenograft models treated with Vemurafenib. Three BRAF^V600E models showed acquired drug resistance, one BRAF^V600E model had a complete and durable response, and a BRAF^V600V model was expectedly unresponsive. In progressing tumors, a variety of resistance mechanisms to BRAF inhibition were uncovered, including mutant BRAF alternative splicing, NRAS mutation, COT (MAP3K8) overexpression, and increased mutant BRAF gene amplification and copy number. The resistance mechanisms among the patient derived xenograft models were similar to the resistance pathways identified in clinical specimens from patients progressing on BRAF inhibitor therapy. In addition, there was both inter- and intra-patient heterogeneity in resistance mechanisms, accompanied by heterogeneous pERK expression immunostaining profiles. MEK monotherapy of Vemurafenib-resistant tumors caused toxicity and acquired drug resistance. However, tumors were eradicated when Vemurafenib was combined the MEK inhibitor. The diversity of drug responses among the xenograft models; the distinct mechanisms of resistance; and the ability to overcome resistance by the addition of a MEK inhibitor provide a scheduling rationale for clinical trials of next-generation drug combinations.     

The boston qualitative scoring system for the rey-osterrieth complex figure: A study of children with attention deficit hyperactivity disorder

Abstract

The Boston Qualitative Scoring System (BQSS) for the Rey-Osterrieth Complex Figure (ROCF) was utilized to examine the qualitative features of ROCF performance of children with Attention Deficit Hyperactivity Disorder (ADHD). Thirty-nine children with ADHD were compared to age-matched controls (n = 39) on their reproduction of the ROCF. ADHD children performed more poorly than did control children on measures of attention to detail, expansion, accuracy, and neatness. Sensitivity and specificity of individual BQSS measures for discriminating ADHD from control subjects were determined, and a logistic regression model was derived, yielding an overall sensitivity of 64% and specificity of 97% for the classification of ADHD. Eighty-one percent of all children were correctly classified. Cross-validation of this model on an independent sample of ADHD and control subjects revealed good predictive accuracy. These findings suggest that the BQSS may be a useful measure in the neuropsychological evaluation of children with suspected ADHD.     

Toxicity profile of repeated doses of PEG‐asparaginase incorporated into a pediatric‐type regimen for adult acute lymphoblastic leukemia

Despite having been long regarded as too toxic for adult patients, pediatric‐like regimens containing L‐asparaginase have resulted in improved outcomes for adults with acute lymphoblastic leukemia (ALL). To characterize the spectrum of toxicity of repeated doses of polyethylene glycolated‐asparaginase (PEG‐asp) in adults, we reviewed all doses (2000 IU/m²) administered as part of a pediatric‐inspired regimen in adult ALL at our center. Subjects aged 18–60 yr with ALL (n = 152, 69.1% male) contributed 522 dose cycles to the study. Hepatotoxicity was the most common adverse event: grades 3–4 transaminitis and hyperbilirubinemia occurred in 53.9% and 23.7% of subjects, respectively. Hepatotoxicity was reversible; no cases of fulminate hepatic failure were observed. Other toxicities affecting at least 5% of subjects were grades 3–4 triglyceridemia in 50.9%, hypofibrinogenemia (<100 mg/dL) in 47.9%, clinical pancreatitis in 12.6%, venous thromboembolism in 11.2%, allergic reaction in 7.2%, and any grade bleeding in 5.3%. PEG‐asp was always discontinued after grades 3–4 pancreatitis or allergic reaction. Otherwise, toxicities did not preclude administration of additional cycles of the drug. Our results suggest that repeated PEG‐asp dosing is safe in adults aged 18–60 yr, even after occurrence of a drug‐related toxicity.