The Crk adapter protein is essential for Drosophila embryogenesis, where it regulates multiple actin-dependent morphogenic events.

Small Src homology domain 2 (SH2) and 3 (SH3) adapter proteins regulate cell fate and behavior by mediating interactions between cell surface receptors and downstream signaling effectors in many signal transduction pathways. The CT10 regulator of kinase (Crk) family has tissue-specific roles in phagocytosis, cell migration, and neuronal development and mediates oncogenic signaling in pathways like that of Abelson kinase. However, redundancy among the two mammalian family members and the position of the Drosophila gene on the fourth chromosome precluded assessment of Crk's full role in embryogenesis. We circumvented these limitations with short hairpin RNA and CRISPR technology to assess Crk's function in Drosophila morphogenesis. We found that Crk is essential beginning in the first few hours of development, where it ensures accurate mitosis by regulating orchestrated dynamics of the actin cytoskeleton to keep mitotic spindles in syncytial embryos from colliding. In this role, it positively regulates cortical localization of the actin-related protein 2/3 complex (Arp2/3), its regulator suppressor of cAMP receptor (SCAR), and filamentous actin to actin caps and pseudocleavage furrows. Crk loss leads to the loss of nuclei and formation of multinucleate cells. We also found roles for Crk in embryonic wound healing and in axon patterning in the nervous system, where it localizes to the axons and midline glia. Thus, Crk regulates diverse events in embryogenesis that require orchestrated cytoskeletal dynamics.

[Prevalence of Malaria, Intestinal and Urinary parasite infections in Kalifabougou, Mali]. / Prevalences du Paludisme, des Parasitoses Intestinales et Urinaires a Kalifabougou, Mali.

Soil transmitted helminthiasis and schistosomiasis are neglected tropical diseases (NTD), affecting the health status of endemic Malian populations. Mali has a national NTD elimination program using the mass drug administration (MDA) strategy combining Albendazole, Ivermectinand Praziquantel. Malaria still remains a public health problem in Mali. The Community health Center (CSCOM) in Kalifabougouvillage in the Kati health district has benefited from such MDA program since 2010. AIM: To evaluate the prevalence rate of malaria, intestinal and urinary parasite infections in the local population. MATERIEL AND METHODS: We conducted a nested cross sectional and cohort study in May 2011 on volunteers aged three months old to 25 years old. Blood smear (blood), Kato-Katz (Stools) and urine filtration techniques were used to evaluate parasite prevalence. Informed consent and assentment were obtained from the volunteers before their inclusion. All volunteers received treatment against the parasite diseases of interest according to the guidelines of national disease control programs. RESULTS: A total of 688 volunteers were included. The prevalence rates of parasitic infections were 22.1% [95% CI= 22.06 - 22.12] for Plasmodium falciparum, 9% [95% CI: 8.9-9.034] for Schistosoma haematobium; 3.5% [95% CI: 3.48-3.513] for Hymenolepis nana and 0.1% [95% CI : 0.093-0.107] for Schistoso mamansoni. The prevalence rate of the co-infection Plasmodium falciparum - Schistosoma haematobium was 2.18% [95% CI= 2.17 - 2.19] in Kalifabougou. CONCLUSION: Praziquantel and Albendazole-based MDA and Artemisinin based combined therapy (ACTs) could explain theobserved low prevalence of helminthiasis and malaria in Kalifabougou, Mali.

Les géohelminthes et les schistosomoses sont des maladies tropicales négligées, impactant sur l'état de santé des populations maliennes endémiques. Le Mali dispose d'un programme national d'élimination qui utilise la stratégie du Traitement de Masse à base Communautaire (TMC) combinant l'Albendazole, Ivermectine et le Praziquantel (PZQ). Quant au paludisme, il reste un problème majeur de santé publique au Mali. L'aire de santé du Centre de Santé Communautaire (CSCOM) de Kalifabougou, dans le district sanitaire de Kati, bénéficie de tel programme TMC depuis 2010. OBJECTIF: Evaluer les taux de prévalences du paludisme infestation, des parasitoses intestinales et urinaires dans la population du village de Kalifabougou, Mali. MATERIELS ET MÉTHODES: Nous avons réalisé une étude transversale en mai 2011 nichée dans une cohorte de volontaires âgés de 3 mois à 25 ans. Les techniques de la goutte épaisse (sang), de Kato-Katz, (selles), et de la filtration des urines; ont été utilisées pour l'évaluation des prévalences parasitaires. Le consentement éclairé et libre ainsi l'assentiment ont été obtenus de tous les volontaires avant leur inclusion. Tous les volontaires ont reçu des traitements contre les parasitoses selon les recommandations des programmes nationaux de lutte contre ces maladies. RÉSULTATS: Un total de 688 volontaires a été inclus dans notre étude. Les taux de prévalences des infections parasitaires étaient de 22,1%[95% CI: 22,06­22,12] pour le Plasmodium falciparum, 9%[95% CI: 8,9­9,034] pour Schistosomahaematobium, 3,5%[95% CI:3,48­3,513] pour Hymenolepis nana et 0,1%[95% CI : 0,093­0,107] pour Schistosomamansoni. Le taux de prévalence de la co-infection Plasmodium falciparum - Schistosomahaematobium était de 2,18%[95% CI :2,17­2,19] a Kalifabougou. CONCLUSION: Le traitement de masse à base de Praziquantel (PZQ) et d'Albendazole et le traitement systématique des cas de fièvres par les combinaisons thérapeutiques à base d'artemisinine (CTAs), auraient pu contribuer à la baisse de la prévalence des helminthes et du paludisme à Kalifabougou, Mali.

Bevacizumab safety in patients with central nervous system metastases.

PURPOSE: Patients with central nervous system (CNS) metastases were excluded from bevacizumab trials following a case of fatal cerebral hemorrhage in a patient with hepatocellular carcinoma in 1997. Safety information for bevacizumab-treated patients with CNS metastases was reviewed to determine whether general exclusion of these patients from bevacizumab treatment is still justified. EXPERIMENTAL DESIGN: A retrospective exploratory analysis was conducted using datasets from 13 randomized controlled phase II/III trials (dataset A), two open-label single-arm safety trials (dataset B), and two prospective studies including patients with treated CNS metastases (dataset C). In datasets A and B, known CNS metastasis was an exclusion criterion; patients with CNS metastasis had unrecognized CNS metastases at study entry or developed them during the trial. All reported cerebral hemorrhage grades in patients with CNS metastases were quantified. RESULTS: In dataset A, occult brain metastases were identified in 187 of 8,443 patients (91 in bevacizumab arms and 96 in non-bevacizumab arms). Three bevacizumab-treated patients (3.3%) developed grade 4 cerebral hemorrhage, whereas one control-arm patient (1.0%) developed grade 5 cerebral hemorrhage. In dataset B, 321 of 4,382 patients had initially occult CNS metastases, in whom two grade 1 and one grade 3 cerebral hemorrhage (0.9%) were reported. In 131 patients with treated CNS metastases in dataset C, one bevacizumab-treated patient (0.8%) developed grade 2 cerebral hemorrhage. CONCLUSIONS: In this selected population, patients with CNS metastases are at similar risk of developing cerebral hemorrhage, independent of bevacizumab therapy. Consequently, such patients with CNS metastases from advanced/metastatic breast cancer, non-small cell lung carcinoma, and renal and colorectal cancer should not be generally excluded from bevacizumab therapy or clinical trials.

Safety of bevacizumab in patients with non-small-cell lung cancer and brain metastases.

PURPOSE: Patients with non-small-cell lung cancer (NSCLC) and brain metastases have previously been excluded from trials of bevacizumab because of suspected risk of CNS hemorrhage. This phase II trial, AVF3752g (PASSPORT), specifically addressed bevacizumab safety (incidence of grade > or = 2 CNS hemorrhage) in patients with NSCLC and previously treated brain metastases. PATIENTS AND METHODS: This open-label multicenter trial for first- and second-line treatment of nonsquamous NSCLC enrolled patients with treated brain metastases. First-line patients received bevacizumab (15 mg/kg) every 3 weeks with platinum-based doublet therapy or erlotinib (at physician's decision), and second-line patients received bevacizumab with single-agent chemotherapy or erlotinib, until disease progression or death. RESULTS: Of the 115 enrolled patients, 66 of 76 first-line patients received carboplatin-based chemotherapy; 22 of 39 second-line patients received pemetrexed, and nine of 39 received erlotinib. As of the June 23, 2008 data cut, among 106 safety-evaluable patients, median on-study duration was 6.3 months (range, 0 to 22 months), with a median of five bevacizumab cycles (range, one to 17), and no reported episodes of grade > or = 2 CNS hemorrhage (95% CI, 0.0% to 3.3%). Of the bevacizumab-targeted adverse events reported, two were grade 5. Both were pulmonary hemorrhages, one occurring during treatment and the other occurring 6 weeks after the data cut; there was also one grade 4, nonpulmonary/non-CNS hemorrhage. Twenty-six patients (24.5%) discontinued study treatment as a result of an adverse event, and 37 (34.9%) discontinued because of disease progression. CONCLUSION: Addition of bevacizumab to various chemotherapy agents or erlotinib in patients with NSCLC and treated brain metastases seems to be safe and is associated with a low incidence of CNS hemorrhage.

Safety of efalizumab therapy in patients with moderate to severe psoriasis: an open-label extension of a phase IIIb trial.

BACKGROUND: Psoriasis is a chronic autoimmune disease characterized by infiltration of the dermis and epidermis by activated T cells and the hyperproliferation and abnormal differentiation of keratinocytes. It is a life-long disease with alternating periods of remission and recurrence. Efalizumab is a humanized, recombinant, T-cell targeting monoclonal antibody, approved for use in adults with chronic moderate to severe plaque psoriasis. OBJECTIVE: To assess the safety of continued or newly initiated treatment with efalizumab for up to 48 weeks in patients with psoriasis who were treated previously with efalizumab or placebo. METHODS: This study was an open-label, 48-week extension of a previously published 12-week, randomized, double-blind, parallel-group, placebo-controlled, multicentre, phase IIIb study, carried out in the US and Canada between 24 October 2002 and 2 July 2004. Patients were followed and treated at the study clinic in an outpatient setting and also were trained to self-administer the drug at home. Patients comprising individuals with chronic moderate to severe plaque psoriasis who had completed the 12-week, placebo-controlled segment of the study were eligible for enrolment in the extension phase. Of the 686 patients enrolled in the study, 636 (92.7%) enrolled in the open-label extension of the study, 418 of whom had received 12 weeks of efalizumab therapy and 218 of whom had received 12 weeks of placebo. All patients entering the open-label phase of the study received efalizumab 1 mg/kg/wk for an additional 48 weeks, for a maximum exposure of up to 60 weeks. Safety was evaluated by an assessment of adverse events, including infections and serious adverse events. RESULTS: The rate of withdrawal due to adverse events remained low throughout the trial, ranging from 1.2% to 6.6% during the 12-week segments of the open-label extension phase of the trial. The incidence of adverse events decreased with increased exposure to efalizumab; the incidence during the initial 12 weeks of exposure to efalizumab was 79.0% compared with 72.9% for patients exposed to placebo. Patients treated with efalizumab for 13-24 weeks, 25-36 weeks, 37-48 weeks and 49-60 weeks experienced adverse events at an incidence of 66.8%, 54.3%, 49.6% and 48.5%, respectively. The incidence of serious adverse events ranged from 1.6% to 3.5% during the 12-week segments of efalizumab therapy, compared with an incidence of 3.4% for placebo-treated patients. The incidence of infection ranged from 9.9% to 14.7% during the 12-week segments of efalizumab therapy, compared with an incidence of 19.1% for placebo-treated patients. Malignancies were reported with an incidence of

A review of malignancies observed during efalizumab (Raptiva) clinical trials for plaque psoriasis.

BACKGROUND: Psoriasis is a chronic, incurable immune-mediated disease. Most therapies used for moderate to severe psoriasis are immunosuppressive. Agents that depress immune function, including traditional psoriasis therapies, have been associated with an increased incidence of malignancies. Efalizumab is a recombinant monoclonal immunoglobulin G1 (IgG1) antibody approved for use in psoriasis patients. OBJECTIVES: To evaluate the incidence of malignancy in patients receiving efalizumab during clinical trials compared with placebo-treated patients, psoriasis patients from external cohorts and the general US population. METHODS: Patient data were pooled from multiple phase III placebo-controlled, open-label efalizumab clinical trials, and the incidence rate of reported malignancies was calculated as a function of patient years of observation. The results for the efalizumab-treated patients were compared with the data on psoriasis patients from insurance claims databases and a registry of events in the general population. RESULTS: The efalizumab- and placebo-treated patients had similar incidence rates of malignancy, including lymphoproliferative disease, solid tumor, malignant melanoma and nonmelanoma skin cancer. The incidence of nonmelanoma skin cancers, including basal cell carcinoma and squamous cell carcinoma, in patients receiving efalizumab or placebo was elevated relative to the external databases. CONCLUSIONS: These results suggest that efalizumab treatment does not increase a patient's risk for malignancy. The difference observed with nonmelanoma skin cancer may be due to biases introduced by the clinical trial methodology. Additional patient observation is necessary to ascertain whether a link exists between efalizumab therapy and nonmelanoma skin cancer above that normally observed in psoriasis patients.

Efalizumab retreatment in patients with moderate to severe chronic plaque psoriasis.

BACKGROUND: Efalizumab targets T cell-mediated steps important in psoriasis immunopathogenesis. OBJECTIVE: We sought to evaluate the efficacy and safety of efalizumab retreatment in patients with moderate to severe plaque psoriasis. METHODS: In this open-label, phase III study, 365 patients who received efalizumab therapy during an earlier clinical trial were retreated with 12 weeks of subcutaneous efalizumab (1 mg/kg/wk) 35 days or more after their last dose of efalizumab. RESULTS: After 12 weeks of efalizumab retreatment, 56.9% of patients achieved 50% or more improvement from baseline Psoriasis Area and Severity Index (PASI) and 25.3% achieved at least 75% reduction in PASI score. The mean percentage PASI improvement from baseline was 51.2%. Overall, 76.1% of patients surveyed were "very satisfied" or "satisfied" with the efficacy of efalizumab. The safety profile of efalizumab retreatment was similar to that observed in patients receiving efalizumab for the first time. LIMITATIONS: Not all patients received sufficient exposure to efalizumab during their previous efalizumab clinical trial to allow for determination of their initial response to efalizumab. Of 365 patients enrolled in the study, 282 received at least 12 weeks of prior efalizumab therapy; of these patients, 208 (73.8%) achieved a PASI-50 response from their previous therapy. CONCLUSION: These results suggest that retreatment with efalizumab therapy is an efficacious option for patients who have previously discontinued treatment.

Long-term continuous efalizumab therapy in patients with moderate to severe chronic plaque psoriasis: updated results from an ongoing trial.

BACKGROUND: Efalizumab is a T cell-targeted therapy for psoriasis. OBJECTIVE: We sought to evaluate the efficacy and safety of long-term, continuous efalizumab therapy. METHODS: Of 339 patients enrolled in this ongoing, open-label, phase III study, after 3 months 290 qualified for and entered the maintenance treatment phase. RESULTS: Results for the first 27 months of this 36-month continuous therapy trial are available. At month 3, 41% of patients achieved at least a 75% reduction in Psoriasis Area and Severity Index (PASI) score; at month 27, 47% achieved at least a 75% reduction in PASI score (intent to treat, n = 339). Among patients eligible for maintenance therapy (n = 290), 56% achieved at least a 75% reduction in PASI score at month 27. Moreover, the at least 90% reduction in PASI score rate increased through 18 months (33%). The safety profile with efalizumab was sustained throughout 27 months of continuous treatment with no new common events over time. LIMITATIONS: Because the extended treatment period was not a randomized clinical trial, no formal comparative analyses versus placebo were conducted. Three-month placebo data from randomized, parallel, placebo-controlled studies are briefly discussed. CONCLUSIONS: These results suggest that efalizumab maintains, and in some patients continues to improve, efficacy during long-term therapy.

An overview of the pharmacokinetics and pharmacodynamics of efalizumab: a monoclonal antibody approved for use in psoriasis.

Efalizumab is a recombinant humanized monoclonal IgG(1) antibody shown to be efficacious for the treatment of moderate to severe chronic plaque psoriasis. Efalizumab, a targeted inhibitor of T cell interactions, binds to the CD11a subunit of lymphocyte function-associated antigen 1 (LFA-1), thereby preventing LFA-1 binding to intercellular adhesion molecule 1 (ICAM-1). The authors review the pharmacokinetic and pharmacodynamic data from the efalizumab clinical development program and discuss how these data led to selection of the optimal weekly subcutaneous (SC) dose of efalizumab (1.0 mg/kg) in adults. Efalizumab SC dosages of 1.0 mg/kg/wk or greater exerted maximal pharmacodynamic effects for CD11a expression and available CD11a binding sites on T lymphocytes. Dosages greater than 1.0 mg/kg/wk SC did not provide additional benefits; moreover, higher doses did not alter the safety profile. During long-term administration of efalizumab, serum levels were generally stable and pharmacodynamic markers remained maximally affected.

Population pharmacokinetics of efalizumab (humanized monoclonal anti-CD11a antibody) following long-term subcutaneous weekly dosing in psoriasis subjects.

The population pharmacokinetics of efalizumab was characterized in patients with moderate to severe plaque psoriasis. The study included 1088 subjects who received 1 or 2 mg/kg/wk subcutaneous efalizumab for 12 weeks from a phase I (64 subjects) and 3 phase III studies with day 42 and/or day 84 trough levels (1024 patients). Due to the limitation of the data, a 1-compartment model with first-order absorption and elimination was used to fit the data. The population means for V/F, Ka, and CL/F were 9.13 L, 0.191 day(-1), and 1.29 L/d, respectively, for a typical subject receiving a 1-mg/kg dose. Interindividual variability in CL/F was 48.2%. Body weight has the largest influence on CL/F. Other covariates (obesity, baseline lymphocyte counts, Psoriasis Area and Severity Index score, and age) had only modest effects. Subjects in the 2-mg/kg dose group had a 24.0% lower CL/F, consistent with nonlinear pharmacokinetics of efalizumab. The results of this analysis support the current body weight-adjusted dosing strategy.

Extended efalizumab therapy improves chronic plaque psoriasis: results from a randomized phase III trial.

BACKGROUND: Efalizumab inhibits multiple T-cell-mediated processes. OBJECTIVE: To evaluate 12- and 24-week efalizumab therapy for psoriasis. METHODS: In this phase III, randomized, double-blind trial, 498 patients received subcutaneous 1 or 2 mg/kg/wk efalizumab or placebo for 12 weeks. Efalizumab-treated patients who achieved <75% Psoriasis Area and Severity Index improvement (PASI-75) were re-randomized to a second 12-week course of treatment. Results At week 12, 39% and 27% of efalizumab-treated patients (1 and 2 mg/kg, respectively) achieved PASI-75 (vs 2% placebo; P < .001, both dose groups). At week 24, an additional 20% of efalizumab-treated patients achieved PASI-75 (vs placebo 7%, P = .018). Efalizumab was well tolerated. CONCLUSION: Twelve-week efalizumab treatment resulted in significant improvement; extension of therapy to 24 weeks resulted in additional improvement in patients who initially had not achieved PASI-75. There were no significant changes in safety profile during weeks 13-24.

Safety of efalizumab in patients with moderate to severe chronic plaque psoriasis: review of clinical data. part II.

BACKGROUND: The efficacy and safety of efalizumab have been evaluated in multiple clinical trials. OBJECTIVE: The purpose of this review is to provide an overview of the safety profile of efalizumab during the clinical trials. METHODS: Twelve-week data from four placebo-controlled trials were pooled and analyzed. Data from patients receiving 13-60 weeks of efalizumab therapy were pooled to evaluate longer-term safety. RESULTS: The most common adverse events were mild to moderate, self-limiting, flu-like symptoms that were most frequent following the first two efalizumab doses; by the third dose the incidence was comparable to placebo. Serious adverse events were observed in 2.2% and 1.7% of efalizumab- and placebo-treated patients, respectively. Nonserious adverse events leading to withdrawal were infrequent and similar to placebo (2.8% vs 1.8%). There does not appear to be increased risk of end-organ toxicity, infection, or malignancy in efalizumab-treated patients. CONCLUSION: Efalizumab was well tolerated, with a favorable safety profile.

Clinical efficacy of efalizumab in patients with chronic plaque psoriasis: results from three randomized placebo-controlled Phase III trials: part I.

BACKGROUND: Effective psoriasis therapies are needed for long-term symptom control. OBJECTIVE: Assess efalizumab (Raptiva) efficacy in a large cohort of psoriasis patients. METHODS: Data from three Phase III, randomized, double-blind, parallel-group, placebo-controlled, multicenter studies were pooled. Patients (n = 1,651) with moderate to severe plaque psoriasis received 12 weeks of subcutaneous efalizumab 1 or 2 mg/kg/wk or placebo. RESULTS: All efficacy measures reached statistical significance within each of the individual studies (p < 0.001) and overall. More efalizumab-treated patients achieved > or = 75% and > or = 50% Psoriasis Area and Severity Index (PASI) improvement at week 12 than did placebo-treated patients (27.8% vs 3.8% [p < 0.001] and 56.1% vs 14.6% [p < 0.001], respectively). Significant PASI improvements occurred as early as week 2 (12.5% vs 7.9%, p =0.0001). Adverse events were generally mild to moderate. CONCLUSION: Efalizumab resulted in early and significant improvement for all efficacy endpoints and was well tolerated in patients with moderate to severe chronic plaque psoriasis.