Do current therapeutic anti-Aβ antibodies for Alzheimer’s disease engage the target?

Reducing amyloid-β peptide (Aβ) burden at the pre-symptomatic stages of Alzheimer’s disease (AD) is currently the advocated clinical strategy for treating this disease. The most developed method for targeting Aβ is the use of monoclonal antibodies including bapineuzumab, solanezumab and crenezumab. We have synthesized these antibodies and used surface plasmon resonance (SPR) and mass spectrometry to characterize and compare the ability of these antibodies to target Aβ in transgenic mouse tissue as well as human AD tissue. SPR analysis showed that the antibodies were able to bind Aβ with high affinity. All of the antibodies were able to bind Aβ in mouse tissue. However, significant differences were observed in human brain tissue. While bapineuzumab was able to capture a variety of N-terminally truncated Aβ species, the Aβ detected using solanezumab was barely above detection limits while crenezumab did not detect any Aβ. None of the antibodies were able to detect any Aβ species in human blood. Immunoprecipitation experiments using plasma from AD subjects showed that both solanezumab and crenezumab have extensive cross-reactivity with non-Aβ related proteins. Bapineuzumab demonstrated target engagement with brain Aβ, consistent with published clinical data. Solanezumab and crenezumab did not, most likely as a result of a lack of specificity due to cross-reactivity with other proteins containing epitope overlap. This lack of target engagement raises questions as to whether solanezumab and crenezumab are suitable drug candidates for the preventative clinical trials for AD.     

Risk factors and treatment of childhood and adolescent Burkitt lymphoma/leukaemia

Burkitt lymphoma/leukaemia is the most common (40%) form of non-Hodgkin lymphoma that occurs in children and adolescents. The prognosis of advanced (disseminated) Burkitt lymphoma/leukaemia in children and adolescents three decades ago had a 5-year event-free survival (EFS) of <40%, and required combination chemotherapy and radiation therapy over a 1-2?year period. Currently, the prognosis for the same advanced stage has a 5-year EFS of 85-90% with <6?months of chemotherapy only. Radiation therapy has been eliminated for children and adolescents with Burkitt lymphoma/leukaemia except in emergencies, such as superior vena cava syndrome and acute neurological impairment or in patients with relapse/progression. Current risk factors in the prognosis of childhood and adolescent Burkitt lymphoma/leukaemia include: lactate dehydrogenase level?≥?2× the upper normal limit at diagnosis, bone marrow and central nervous system involvement, poor response to cyclophosphamide, vincristine and prednisone reduction therapy and poor risk cytogenetics. New and novel therapeutic approaches include monoclonal antibody (anti-CD20) therapy, targeted cellular immune therapy and small molecule inhibitors. Future strategies should include improved staging and risk classification, reduction of cytotoxic chemotherapy, the investigation of targeted therapy, an increased understanding of the underlying biology of Burkitt lymphoma/leukaemia, strategies for prevention and approaches to reduce acute and chronic toxicities.     

The Habit Cough Syndrome and Its Variations

Involuntary cough without an identified underlying organic reason has been given various names and recommended treatments. Current experience suggests that “habit cough” best describes this entity. Suggestion therapy in its various forms is the treatment of choice. Successful therapy is directed at demonstrating to the patient that he/she has the ability to resist the urge to cough. Attempts at medical treatment or use of placebo therapy, even with the suggestion that the “medicine” will stop the cough, are generally not successful. Continued symptoms for years can occur in the absence of suggestion therapy. Sustained relapse after suggestion therapy is uncommon.     

Direct Effects of Exendin-(9,39) and GLP-1-(9,36)amide on Insulin Action, β-Cell Function,and Glucose Metabolism in Nondiabetic Subjects

Exendin-(9,39) is a competitive antagonist of glucagon-like peptide-1 (GLP-1) at its receptor. However, it is unclear if it has direct and unique effects of its own. We tested the hypothesis that exendin-(9,39) and GLP-1-(9,36)amide have direct effects on hormone secretion and β-cell function as well as glucose metabolism in healthy subjects. Glucose containing [3-³H]glucose was infused to mimic the systemic appearance of glucose after a meal. Saline, GLP-1-(9,36)amide, or exendin-(9,39) at 30 pmol/kg/min (Ex 30) or 300 pmol/kg/min (Ex 300) were infused in random order on separate days. Integrated glucose concentrations were slightly but significantly increased by exendin-(9,39) (365 ± 43 vs. 383 ± 35 vs. 492 ± 49 vs. 337 ± 50 mmol per 6 h, saline, Ex 30, Ex 300, and GLP-1-[9,36]amide, respectively; P = 0.05). Insulin secretion did not differ among groups. However, insulin action was lowered by exendin-(9,39) (25 ± 4 vs. 20 ± 4 vs. 18 ± 3 vs. 21 ± 4 10⁻⁴ dL/kg[min per μU/mL]; P = 0.02), resulting in a lower disposition index (DI) during exendin-(9,39) infusion (1,118 ± 118 vs. 816 ± 83 vs. 725 ± 127 vs. 955 ± 166 10⁻¹⁴ dL/kg/min² per pmol/L; P = 0.003). Endogenous glucose production and glucose disappearance did not differ significantly among groups. We conclude that exendin-(9,39), but not GLP-1-(9,36)amide, decreases insulin action and DI in healthy humans.The incretin hormone glucagon-like peptide-1 (GLP-1) arises by posttranslational processing of preproglucagon in the enteroendocrine L cells distributed throughout the intestine. GLP-1 secretion occurs within minutes of food ingestion, is a potent insulin secretagogue, and suppresses glucagon (1). However, the active form(s) of GLP-1 are rapidly deactivated by a serine protease dipeptidyl peptidase-4, which cleaves the two NH₂-terminal amino acids necessary for activation of the GLP-1 receptor (GLP-1R). This enzyme is widely distributed so that the half-life of active GLP-1 in the circulation is ∼1 min (2). The resulting metabolite GLP-1-(9,36) has been proposed as a potential antagonist of GLP-1R, although at present there is no evidence of an effect of this peptide on insulin secretion (3).Exendin-(7,39) is a naturally occurring analog of GLP-1-(7,36) and is an agonist of the GLP-1R. This compound binds to GLP-1R with greater affinity than the natural ligand due to a nine–amino acid COOH-terminal sequence absent in native GLP-1 (4). On the other hand, exendin-(9,39), which arises from the removal of the two NH₂-terminal amino acids, is a competitive antagonist of GLP-1 at the GLP-1R (5). It has been used to examine the effects of endogenous GLP-1 secretion on glucose homeostasis (6). Although it is presumed that exendin-(9,39) has no direct effects on glucose metabolism, it alters gastric emptying and capacitance through vagal mechanisms, thereby altering glucose tolerance independent of its ability to inhibit GLP-1-(7,36) effects on insulin and glucagon secretion (7,8). A direct effect of GLP-1-(9,36) signaling on glucose metabolism has been reported (9).The present studies were undertaken to determine whether exendin-(9,39) and GLP-1-(9,36)amide have direct effects on β-cell function, insulin action, glucagon secretion, and glucose metabolism. We did so by infusing glucose in a manner that mimicked the systemic appearance of glucose after ingestion of carbohydrate. Since glucose was infused intravenously, this created a model that resulted in the stimulation of insulin and suppression of glucagon in the absence of a change in endogenous GLP-1 concentrations. Subjects were studied on four occasions: receiving, in random order, saline, exendin-(9,39) infused at 30 pmol/kg/min (Ex 30) and at 300 pmol/kg/min (Ex 300), and GLP-1-(9,36)amide. Glucose turnover was measured on each occasion using [3-³H]glucose; insulin secretion and action were measured using the minimal model.     

Surgical techniques in breast cancer: an overview

Despite significant advances in the medical treatment and chemo-manipulation of breast cancer, surgery with curative intent retains a fundamental mainstay of treatment, with surgeons continuing to play a central and key role within the multidisciplinary team setting.