Enhancing efficacy of anticancer vaccines by targeted delivery to tumor-draining lymph nodes.

The sentinel or tumor-draining lymph node (tdLN) serves as a metastatic niche for many solid tumors and is altered via tumor-derived factors that support tumor progression and metastasis. tdLNs are often removed surgically, and therapeutic vaccines against tumor antigens are typically administered systemically or in non-tumor-associated sites. Although the tdLN is immune-suppressed, it is also antigen experienced through drainage of tumor-associated antigens (TAA), so we asked whether therapeutic vaccines targeting the tdLN would be more or less effective than those targeting the non-tdLN. Using LN-targeting nanoparticle (NP)-conjugate vaccines consisting of TAA-NP and CpG-NP, we compared delivery to the tdLN versus non-tdLN in two different cancer models, E.G7-OVA lymphoma (expressing the nonendogenous TAA ovalbumin) and B16-F10 melanoma. Surprisingly, despite the immune-suppressed state of the tdLN, tdLN-targeting vaccination induced substantially stronger cytotoxic CD8+ T-cell responses, both locally and systemically, than non-tdLN-targeting vaccination, leading to enhanced tumor regression and host survival. This improved tumor regression correlated with a shift in the tumor-infiltrating leukocyte repertoire toward a less suppressive and more immunogenic balance. Nanoparticle coupling of adjuvant and antigen was required for effective tdLN targeting, as nanoparticle coupling dramatically increased the delivery of antigen and adjuvant to LN-resident antigen-presenting cells, thereby increasing therapeutic efficacy. This work highlights the tdLN as a target for cancer immunotherapy and shows how its antigen-experienced but immune-suppressed state can be reprogrammed with a targeted vaccine yielding antitumor immunity.

Use of drugs with more than a twenty-four-hour duration of action

AIM: To assess compliance with a drug regimen of two doses a day compared with one a day. PATIENTS AND METHODS: A prospective crossover study was set up in a general practice environment to compare compliance on a drug regimen of once a day versus twice a day. Data were collected by electronic monitoring in 113 patients with hypertension or angina pectoris. All patients were prescribed slow-release nifedipine twice a day during the first month and then crossed to a single daily dose of amlodipine for another month. RESULTS: Compliance, defined as the proportion of days on which the correct dose was taken, improved in 30% of patients (95% confidence interval 19-41%; P < 0.001) when the patients were switched from twice a day to once a day, but at the same time there was a 15% increase (95% confidence interval 5-25%; P < 0.02) in the number of patients with one or more no-dose days. Approximately 8% of patients displayed low compliance, irrespective of the dose regimen. Actual dose intervals were used to estimate the extent and timing of periods with unsatisfactory drug activity for various hypothetical drug durations of action. CONCLUSIONS: The apparent advantage of a single daily dose in terms of compliance appears to be clinically meaningful only when the duration of activity extends beyond the dose interval in all patients.

Forensic intelligence framework. Part II: study of the main generic building blocks and challenges through the examples of illicit drugs and false identity documents monitoring

The development of forensic intelligence relies on the expression of suitable models that better represent the contribution of forensic intelligence in relation to the criminal justice system, policing and security. Such models assist in comparing and evaluating methods and new technologies, provide transparency and foster the development of new applications. Interestingly, strong similarities between two separate projects focusing on specific forensic science areas were recently observed. These observations have led to the induction of a general model (Part I) that could guide the use of any forensic science case data in an intelligence perspective. The present article builds upon this general approach by focusing on decisional and organisational issues. The article investigates the comparison process and evaluation system that lay at the heart of the forensic intelligence framework, advocating scientific decision criteria and a structured but flexible and dynamic architecture. These building blocks are crucial and clearly lay within the expertise of forensic scientists. However, it is only part of the problem. Forensic intelligence includes other blocks with their respective interactions, decision points and tensions (e.g. regarding how to guide detection and how to integrate forensic information with other information). Formalising these blocks identifies many questions and potential answers. Addressing these questions is essential for the progress of the discipline. Such a process requires clarifying the role and place of the forensic scientist within the whole process and their relationship to other stakeholders.

Drugs, schizotypy and cognition: Cognitive attenuations seem more consistently associated with substance use than schizotypal symptoms

Psychosis is a debilitating disease, causing harm to the individual and society. Since early detection of the disease is associated with a more benign course, factors are warranted that enable the early detection of psychosis. In the present thesis we will be focusing on two potential risk factors, namely schizotypy and drug use. The schizotypy concept, originally developed by Meehl (1962), states that schizophrenia symptoms exist on a spectrum, with symptoms ranging from the most severe in patients with schizophrenia to the least affected individual in the general population. Along the schizophrenia spectrum cognitive impairments are commonly found, for instance reduced hemispheric asymmetry or frontal lobe functions. The second risk factor (drug use), affects similar cognitive functions as those attenuated along the schizophrenia spectrum, and drug use is elevated in schizophrenia and people scoring high on schizotypy. Therefore, we set out to investigate whether cognitive attenuations formerly allocated to schizotypal symptoms could have been influenced by elevated substance use in this population. To test this idea, we assessed various drugs (nicotine, cannabis, mephedrone, general substance dependence) and schizotypy symptoms (O-LIFE), and measured either hemispheric asymmetry of function (left hemisphere dominance for language, and right hemisphere dominance for facial processing) or functions largely relying on the frontal lobes (such as cognitive flexibility, working memory, verbal short-term memory, verbal learning and verbal fluency). Results of all studies suggest that it is mostly drugs, and not schizotypy in general that predict cognitive functioning. Therefore, cognitive attenuations subscribed to schizotypy dimensions are likely to have been affected by enhanced drug use. Future studies should extend the list of potential risk factors (e.g. depression and IQ) to acquire a comprehensive overview of the most reliable predictors of disadvantageous cognitive profiles.

Early investigational drugs that target epidermal growth factor receptors for the treatment of head and neck cancer.

INTRODUCTION: Squamous-cell carcinoma of the head and neck (SCCHN) remains a challenging clinical problem, due to the persistent high rate of local and distant failures and the occurrence of secondary primaries. For locally advanced SCCHN, a combination of chemotherapy (CT), radiation or surgery is often used, but there are limitations, which may reduce compliance. Molecular targeted therapies, namely anti-EGFR treatments, are in development with the aim of improving clinical outcomes and mitigating treatment-related toxicities. AREAS COVERED: This review provides an overview of early investigational drugs that target EGFR for the treatment of SCCHN and discusses the ongoing trials in this domain. EXPERT OPINION: Targeted therapies are increasingly used in oncology, especially in SCCHN. Cetuximab has demonstrated a significant improvement in the treatment outcome, both as a curative treatment in combination with radiation therapy and as a palliative treatment in combination with CT; however, it failed to show any benefit in combination with concomitant chemoradiotherapy. Presently, there are many new agents, including monoclonal antibodies and small-molecule tyrosine kinase inhibitors, which are either currently under investigation for or which warrant further investigation for treating SCCHN. The discovery of predictive factors that help to identify patients most likely to respond to EGFR inhibitors as well as patient-customized therapies would help to improve patient outcomes in the future.

Wipe sampling procedure coupled to LC-MS/MS analysis for the simultaneous determination of 10 cytotoxic drugs on different surfaces.

A simple wipe sampling procedure was developed for the surface contamination determination of ten cytotoxic drugs: cytarabine, gemcitabine, methotrexate, etoposide phosphate, cyclophosphamide, ifosfamide, irinotecan, doxorubicin, epirubicin and vincristine. Wiping was performed using Whatman filter paper on different surfaces such as stainless steel, polypropylene, polystyrol, glass, latex gloves, computer mouse and coated paperboard. Wiping and desorption procedures were investigated: The same solution containing 20% acetonitrile and 0.1% formic acid in water gave the best results. After ultrasonic desorption and then centrifugation, samples were analysed by a validated liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in selected reaction monitoring mode. The whole analytical strategy from wipe sampling to LC-MS/MS analysis was evaluated to determine quantitative performance. The lowest limit of quantification of 10 ng per wiping sample (i.e. 0.1 ng cm(-2)) was determined for the ten investigated cytotoxic drugs. Relative standard deviation for intermediate precision was always inferior to 20%. As recovery was dependent on the tested surface for each drug, a correction factor was determined and applied for real samples. The method was then successfully applied at the cytotoxic production unit of the Geneva University Hospitals pharmacy.

Study of common database feeding with results coming from different analytical methods in the framework of illicit drugs chemical profiling

Analytical results harmonisation is investigated in this study to provide an alternative to the restrictive approach of analytical methods harmonisation which is recommended nowadays for making possible the exchange of information and then for supporting the fight against illicit drugs trafficking. Indeed, the main goal of this study is to demonstrate that a common database can be fed by a range of different analytical methods, whatever the differences in levels of analytical parameters between these latter ones. For this purpose, a methodology making possible the estimation and even the optimisation of results similarity coming from different analytical methods was then developed. In particular, the possibility to introduce chemical profiles obtained with Fast GC-FID in a GC-MS database is studied in this paper. By the use of the methodology, the similarity of results coming from different analytical methods can be objectively assessed and the utility in practice of database sharing by these methods can be evaluated, depending on profiling purposes (evidential vs. operational perspective tool). This methodology can be regarded as a relevant approach for database feeding by different analytical methods and puts in doubt the necessity to analyse all illicit drugs seizures in one single laboratory or to implement analytical methods harmonisation in each participating laboratory.

Population PK-guided simulation study in children exposed to drugs in human milk

Risks of significant infant drug exposure through human milk arepoorly defined due to lack of large-scale PK data. We propose to useBayesian approach based on population PK (popPK)-guided modelingand simulation for risk prediction. As a proof-of-principle study, weexploited fluoxetine milk concentration data from 25 women. popPKparameters including milk-to-plasma ratio (MP ratio) were estimatedfrom the best model. The dose of fluoxetine the breastfed infant wouldreceive through mother's milk, and infant plasma concentrations wereestimated from 1000 simulated mother-infant pairs, using randomassignment of feeding times and milk volume. A conservative estimateof CYP2D6 activity of 20% of the allometrically-adjusted adult valuewas assumed. Derived model parameters, including MP ratio were consistentwith those reported in the literature. Visual predictive check andother model diagnostics showed no signs of model misspecifications.The model simulation predicted that infant exposure levels to fluoxetinevia mother's milk were below 10% of weight-adjusted maternal therapeuticdoses in >99% of simulated infants. Predicted median ratio ofinfant-mother serum levels at steady state was 0.093 (range 0.033-0.31),consistent with literature reported values (mean=0.07; range 0-0.59).Predicted incidence of relatively high infant-mother ratio (>0.2) ofsteady-state serum fluoxetine concentrations was <1.3%. Overall, ourpredictions are consistent with clinical observations. Our approach maybe valid for other drugs, allowing in silico prediction of infant drugexposure risks through human milk. We will discuss application of thisapproach to another drug used in lactating women.

Catalytic and anticancer activities of sawhorse-type diruthenium tetracarbonyl complexes derived from fluorinated fatty acids

The reaction of fluorinated fatty acids, perfluorobutyric acid (C3F7CO2H), and perfluorododecanoic acid (C11F23CO2H), with dodecacarbonyltriruthenium (Ru-3(CO)(12)) under reflux in tetrahydrofuran, followed by addition of two-electron donors (L) such as pyridine, 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane, or triphenylphosphine, gives stable diruthenium complexes Ru-2(CO)(4)((2)-(2)-O2CC3F7)(2)(L)(2) (1a, L=C5H5N; 1b, L=PTA; 1c, L=PPh3) and Ru-2(CO)(4)((2)-(2)-O2CC11F23)(2)(L)(2) (2a, L=C5H5N; 2b, L=PTA; 2c, L=PPh3). The catalytic activity of the complexes for hydrogenation of styrene under supercritical carbon dioxide has been assessed and compared to the analogous triphenylphosphine complexes with non-fluorinated carboxylato groups Ru-2(CO)(4)((2)-(2)-O2CC3H7)(2)(PPh3)(2) (3) and Ru-2(CO)(4)((2)-(2)-O2CC11H23)(2)(PPh3)(2) (4). In addition, the cytotoxicities of the fluorinated complexes 1 were also evaluated on several human cancer cell lines (A2780, A549, Me300, HeLa). The complexes appear to be moderately cytotoxic, showing greater activity on the Me300 melanoma cells. Single-crystal X-ray structure analyses of 1a and 3 show the typical sawhorse-type arrangement of the diruthenium tetracarbonyl backbone with two bridging carboxylates and two terminal ligands occupying the axial positions.

Effects of immunosuppressive drugs on HIV infection: implications for solid-organ transplantation.

With the advent of highly active antiretroviral therapy (HAART), HIV infection has become a chronic disease. Various end-stage organ failures have now become common co-morbidities and are primary causes of mortality in HIV-infected patients. Solid-organ transplantation therefore has been proposed to these patients, as HIV infection is not anymore considered an absolute contraindication. The initial results of organ transplantation in HIV-infected patients are encouraging with no differences in patient and graft survival compared with non-HIV-infected patients. The use of immunosuppressive drug therapy in HIV-infected patients has so far not shown major detrimental effects, and some drugs in combination with HAART have even demonstrated possible beneficial effects for specific HIV settings. Nevertheless, organ transplantation in HIV-infected patients remains a complex intervention, and more studies will be required to clarify open questions such as long-term effects of drug interactions between antiretroviral and immunosuppressive drugs, outcome of recurrent HCV infection in HIV-infected patients, incidence of graft rejection, or long-term graft and patient survival. In this article, we first review the immunological pathogenesis of HIV infection and the rationale for using immunosuppression combined with HAART. We then discuss the most recent results of solid-organ transplantation in HIV-infected patients.

Antitumor activities of ATP-competitive inhibitors of mTOR in colon cancer cells.

BACKGROUND: The mammalian target of rapamycin (mTOR) is frequently activated in colon cancers due to mutations in the phosphatidylinositol 3-kinase (PI3K) pathway. Targeting mTOR with allosteric inhibitors of mTOR such as rapamycin reduces colon cancer progression in several experimental models. Recently, a new class of mTOR inhibitors that act as ATP-competitive inhibitors of mTOR, has been developed. The effectiveness of these drugs in colon cancer cells has however not been fully characterized. METHODS: LS174T, SW480 and DLD-1 colon cancer cell lines were treated with PP242 an ATP-competitive inhibitor of mTOR, NVP-BEZ235, a dual PI3K/mTOR inhibitor or rapamycin. Tumor cell growth, proliferation and survival were assessed by MTS assay, 5-bromo-2'-deoxyuridine (BrDU) incorporation or by quantification of DNA fragmentation respectively. In vivo, the anticancer activity of mTOR inhibitors was evaluated on nude mice bearing colon cancer xenografts. RESULTS: PP242 and NVP-BEZ235 reduced the growth, proliferation and survival of LS174T and DLD-1 colon cancer cells more efficiently than rapamycin. Similarly, PP242 and NVP-BEZ235 also decreased significantly the proliferation and survival of SW480 cells which were resistant to the effects of rapamycin. In vivo, PP242 and NVP-BEZ235 reduced the growth of xenografts generated from LS174T and SW480 cells. Finally, we also observed that the efficacy of ATP-competitive inhibitors of mTOR was enhanced by U0126, a MEK inhibitor. CONCLUSIONS: Taken together, these results show that ATP-competitive inhibitors of mTOR are effective in blocking colon cancer cell growth in vitro and in vivo and thus represent a therapeutic option in colon cancer either alone or in combination with MEK inhibitors.

A new look at atrial fibrillation: lessons learned from drugs, pacing, and ablation therapies.

Atrial fibrillation (AF) is the most common arrhythmia and among the leading causes of stroke and heart failure in Western populations. Despite the increasing size of clinical trials assessing the efficacy and safety of AF therapies, achieved outcomes have not always matched expectations. Considering that AF is a symptom of many possible underlying diseases, clinical research for this arrhythmia should take into account their respective pathophysiology. Accordingly, the definition of the study populations to be included should rely on the established as well as on the new classifications of AF and take advantage from a differentiated look at the AF-electrocardiogram and from increasingly large spectrum of biomarkers. Such an integrated approach could bring researchers and treating physicians one step closer to the ultimate vision of personalized therapy, which, in this case, means an AF therapy based on refined diagnostic elements in accordance with scientific evidence gathered from clinical trials. By applying clear-cut patient inclusion criteria, future studies will be of smaller size and thus of lower cost. In addition, the findings from such studies will be of greater predictive value at the individual patient level, allowing for pinpointed therapeutic decisions in daily practice.

Effects of thyromimetic drugs on aldosterone-dependent sodium transport in the toad bladder.

Aldosterone increases transepithelial Na+ transport in the urinary bladder of Bufo marinus. The response is characterized by 3 distinct phases: 1) a lag period of about 60 min, ii) an initial phase (early response) of about 2 hr during which Na+ transport increases rapidly and transepithelial electrical resistance falls, and iii) a late phase (late response) of about 4 to 6 hr during which Na+ transport still increases significantly but with very little change in resistance. Triiodothyronine (T3, 6 nM) added either 2 or 18 hr before aldosterone selectively antagonizes the late response. T3 per se (up to 6 nM) has no effect on base-line Na+ transport. The antagonist activity of T3 is only apparent after a latent period of about 6 to 8 hr. It is not rapidly reversible after a 4-hr washout of the hormone. The effects appear to be selective for thyromimetic drugs since reverse T3 (rT3) is inactive and isopropyldiiodothyronine (isoT2) is more active than T3. The relative activity of these analogs corresponds to their relative affinity for T3 nuclear binding sites which we have previously described. Our data suggest that T3 might control the expression of aldosterone by regulating gene expression, e.g. by the induction of specific proteins, which in turn will inhibit the late mineralocorticoid response, without interaction with the early response.

Efficacy and Safety of Canakinumab Vs Triamcinolone Acetonide in Patients with Gouty Arthritis Unable to Use Nonsteroidal Anti-Inflammatory Drugs and Colchicine, and On Stable Urate Lowering Therapy (ULT) or Unable to Use ULT

Background/Purpose: The primary treatment goals for gouty arthritis (GA) are rapid relief of pain and inflammation during acute attacks, and long-term hyperuricemia management. A post-hoc analysis of 2 pivotal trials was performed to assess efficacy and safety of canakinumab (CAN), a fully human monoclonal anti-IL-1_ antibody, vs triamcinolone acetonide (TA) in GA patients unable to use NSAIDs and colchicine, and who were on stable urate lowering therapy (ULT) or unable to use ULT. Methods: In these 12-week, randomized, multicenter, double-blind, double-dummy, active-controlled studies (_-RELIEVED and _-RELIEVED II), patients had to have frequent attacks (_3 attacks in previous year) meeting preliminary GA ACR 1977 criteria, and were unresponsive, intolerant, or contraindicated to NSAIDs and/or colchicine, and if on ULT, ULT was stable. Patients were randomized during an acute attack to single dose CAN 150 mg s.c. or TA 40 mg i.m. and were redosed "on demand" for each new attack. Patients completing the core studies were enrolled into blinded 12-week extension studies to further investigate on-demand use of CAN vs TA for new attacks. The subpopulation selected for this post-hoc analysis was (a) unable to use NSAIDs and colchicine due to contraindication, intolerance or lack of efficacy for these drugs, and (b) currently on ULT, or contraindication or previous failure of ULT, as determined by investigators. Subpopulation comprised 101 patients (51 CAN; 50 TA) out of 454 total. Results: Several co-morbidities, including hypertension (56%), obesity (56%), diabetes (18%), and ischemic heart disease (13%) were reported in 90% of this subpopulation. Pain intensity (VAS 100 mm scale) was comparable between CAN and TA treatment groups at baseline (least-square [LS] mean 74.6 and 74.4 mm, respectively). A significantly lower pain score was reported with CAN vs TA at 72 hours post dose (1st co-primary endpoint on baseline flare; LS mean, 23.5 vs 33.6 mm; difference _10.2 mm; 95% CI, _19.9, _0.4; P_0.0208 [1-sided]). CAN significantly reduced risk for their first new attacks by 61% vs TA (HR 0.39; 95% CI, 0.17-0.91, P_0.0151 [1-sided]) for the first 12 weeks (2nd co-primary endpoint), and by 61% vs TA (HR 0.39; 95% CI, 0.19-0.79, P_0.0047 [1-sided]) over 24 weeks. Serum urate levels increased for CAN vs TA with mean change from baseline reaching a maximum of _0.7 _ 2.0 vs _0.1 _ 1.8 mg/dL at 8 weeks, and _0.3 _ 2.0 vs _0.2 _ 1.4 mg/dL at end of study (all had GA attack at baseline). Adverse Events (AEs) were reported in 33 (66%) CAN and 24 (47.1%) TA patients. Infections and infestations were the most common AEs, reported in 10 (20%) and 5 (10%) patients treated with CAN and TA respectively. Incidence of SAEs was comparable between CAN (gastritis, gastroenteritis, chronic renal failure) and TA (aortic valve incompetence, cardiomyopathy, aortic stenosis, diarrohea, nausea, vomiting, bicuspid aortic valve) groups (2 [4.0%] vs 2 [3.9%]). Conclusion: CAN provided superior pain relief and reduced risk of new attack in highly-comorbid GA patients unable to use NSAIDs and colchicine, and who were currently on stable ULT or unable to use ULT. The safety profile in this post-hoc subpopulation was consistent with the overall _-RELIEVED and _-RELIEVED II population.