Neoadjuvant chemoradiotherapy with or without panitumumab in patients with wild-type KRAS, locally advanced rectal cancer (LARC): a randomized, multicenter, phase II trial SAKK 41/07.

BACKGROUND: We conducted a randomized, phase II, multicenter study to evaluate the anti-epidermal growth factor receptor (EGFR) mAb panitumumab (P) in combination with chemoradiotherapy (CRT) with standard-dose capecitabine as neoadjuvant treatment for wild-type KRAS locally advanced rectal cancer (LARC). PATIENTS AND METHODS: Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). RESULTS: Forty of 68 patients were randomly assigned to P + CRT and 28 to CRT. pNC/CR was achieved in 21 patients (53%) treated with P + CRT [95% confidence interval (CI) 36%-69%] versus 9 patients (32%) treated with CRT alone (95% CI: 16%-52%). pCR was achieved in 4 (10%) and 5 (18%) patients, and pNCR in 17 (43%) and 4 (14%) patients. In immunohistochemical analysis, most DC 3 cells were not apoptotic. The most common grade ≥3 toxic effects in the P + CRT/CRT arm were diarrhea (10%/6%) and anastomotic leakage (15%/4%). CONCLUSIONS: The addition of panitumumab to neoadjuvant CRT in patients with KRAS wild-type LARC resulted in a high pNC/CR rate, mostly grade 3 DC. The results of both treatment arms exceeded prespecified thresholds. The addition of panitumumab increased toxicity.

MART-1 peptide vaccination plus IMP321 (LAG-3Ig fusion protein) in patients receiving autologous PBMCs after lymphodepletion: results of a Phase I trial.

BACKGROUND: Immunotherapy offers a promising novel approach for the treatment of cancer and both adoptive T-cell transfer and immune modulation lead to regression of advanced melanoma. However, the potential synergy between these two strategies remains unclear. METHODS: We investigated in 12 patients with advanced stage IV melanoma the effect of multiple MART-1 analog peptide vaccinations with (n = 6) or without (n = 6) IMP321 (LAG-3Ig fusion protein) as an adjuvant in combination with lymphodepleting chemotherapy and adoptive transfer of autologous PBMCs at day (D) 0 (Trial registration No: NCT00324623). All patients were selected on the basis of ex vivo detectable MART-1-specific CD8 T-cell responses and immunized at D0, 8, 15, 22, 28, 52, and 74 post-reinfusion. RESULTS: After immunization, a significant expansion of MART-1-specific CD8 T cells was measured in 83% (n = 5/6) and 17% (n = 1/6) of patients from the IMP321 and control groups, respectively (P < 0.02). Compared to the control group, the mean fold increase of MART-1-specific CD8 T cells in the IMP321 group was respectively >2-, >4- and >6-fold higher at D15, D30 and D60 (P < 0.02). Long-lasting MART-1-specific CD8 T-cell responses were significantly associated with IMP321 (P < 0.02). At the peak of the response, MART-1-specific CD8 T cells contained higher proportions of effector (CCR7⁻ CD45RA⁺/⁻) cells in the IMP321 group (P < 0.02) and showed no sign of exhaustion (i.e. were mostly PD1⁻CD160⁻TIM3⁻LAG3⁻2B4⁺/⁻). Moreover, IMP321 was associated with a significantly reduced expansion of regulatory T cells (P < 0.04); consistently, we observed a negative correlation between the relative expansion of MART-1-specific CD8 T cells and of regulatory T cells. Finally, although there were no confirmed responses as per RECIST criteria, a transient, 30-day partial response was observed in a patient from the IMP321 group. CONCLUSIONS: Vaccination with IMP321 as an adjuvant in combination with lymphodepleting chemotherapy and adoptive transfer of autologous PBMCs induced more robust and durable cellular antitumor immune responses, supporting further development of IMP321 as an adjuvant for future immunotherapeutic strategies.

A phase I dose-escalation study of the immunocytokine EMD 521873 (Selectikine) in patients with advanced solid tumours.

BACKGROUND: EMD 521873 (Selectikine), an immunocytokine comprising a DNA-targeting antibody, aimed at tumour necrosis, fused with a genetically modified interleukin-2 (IL-2) moiety, was investigated in this first-in-human phase I study. METHODS: Patients had metastatic or locally advanced solid tumours failing previous standard therapy. Selectikine was administered as a 1-hour intravenous infusion on 3 consecutive days, every 3weeks. A subgroup of patients also received 300mg/m(2) cyclophosphamide on day 1 of each cycle. Escalating doses of Selectikine were investigated with the primary objective of determining the maximum tolerated dose (MTD). RESULTS: Thirty-nine patients were treated with Selectikine alone at dose levels from 0.075 to 0.9mg/kg, and nine were treated at doses of 0.45 and 0.6mg/kg in combination with cyclophosphamide. A dose-dependent linear increase of peak serum concentrations and area under curve was found. The dose-limiting toxicity was grade 3 skin rash at the 0.9mg/kg dose-level; the MTD was 0.6mg/kg. Rash and flu-like symptoms were the most frequent side-effects. No severe cardiovascular side-effects (hypotension or vascular leak) were observed. At all dose-levels, transient increases in total lymphocyte, eosinophil and monocyte counts were recorded. No objective tumour responses, but long periods of disease stabilisation were observed. Transient and non-neutralising Selectikine antibodies were detected in 69% of patients. CONCLUSIONS: The MTD of Selectikine with or without cyclophosphamide administered under this schedule was 0.6mg/kg. The recommended phase II dose was 0.45-0.6mg/kg. Selectikine had a favourable safety profile and induced biological effects typical for IL-2.

Taxation and Total Government Take from the UK Continental Shelf (UKCS) Following Phase 3 of the European Emissions Trading Scheme (EU ETS)

NORTH SEA STUDY OCCASIONAL PAPER No. 117

Solid-phase synthesis and NMR studies of modified oligonucleotides forming triplex helix and of oligonucleopeptides mimicking the topoisomerase I-DNA covalent complex

Report for the scientific sojourn carried out at the Institut de Biologia Molecular de Barcelona of the CSIC –state agency – from april until september 2007. Topoisomerase I is an essential nuclear enzyme that modulates the topological status of DNA, facilitating DNA helix unwinding during replication and transcription. We have prepared the oligonucleotide-peptide conjugate Ac-NLeu-Asn-Tyr(p-3’TTCAGAAGC5’)-LeuC-CONH-(CH2)6-OH as model compound for NMR studies of the Topoisomerase I- DNA complex. Special attention was made on the synthetic aspects for the preparation of this challenging compound especially solid supports and protecting groups. The desired peptide was obtained although we did not achieve the amount of the conjugate needed for NMR studies. Most probably the low yield is due to the intrinsic sensitive to hydrolysis of the phosphate bond between oligonucleotide and tyrosine. We have started the synthesis and the structural characterization of oligonucleotides carrying intercalating compounds. At the present state we have obtained model duplex and quadruplex sequences modified with acridine and NMR studies are underway. In addition to this project we have successfully resolved the structure of a fusion peptide derived from hepatitis C virus envelope synthesized by the group of Dr. Haro and we have synthesized and started the characterization of a modified G-quadruplex.

Efficacy of vitamin D3 as add-on therapy in patients with relapsing-remitting multiple sclerosis receiving subcutaneous interferon β-1a: a Phase II, multicenter, double-blind, randomized, placebo-controlled trial.

Recent studies have demonstrated the immunomodulatory properties of vitamin D, and vitamin D deficiency may be a risk factor for the development of MS. The risk of developing MS has, in fact, been associated with rising latitudes, past exposure to sun and serum vitamin D status. Serum 25-hydroxyvitamin D [25(OH)D] levels have also been associated with relapses and disability progression. The identification of risk factors, such as vitamin D deficiency, in MS may provide an opportunity to improve current treatment strategies, through combination therapy with established MS treatments. Accordingly, vitamin D may play a role in MS therapy. Small clinical studies of vitamin D supplementation in patients with MS have reported positive immunomodulatory effects, reduced relapse rates and a reduction in the number of gadolinium-enhancing lesions. However, large randomized clinical trials of vitamin D supplementation in patients with MS are lacking. SOLAR (Supplementation of VigantOL(®) oil versus placebo as Add-on in patients with relapsing-remitting multiple sclerosis receiving Rebif(®) treatment) is a 96-week, three-arm, multicenter, double-blind, randomized, placebo-controlled, Phase II trial (NCT01285401). SOLAR will evaluate the efficacy of vitamin D(3) as add-on therapy to subcutaneous interferon beta-1a in patients with RRMS. Recruitment began in February 2011 and is aimed to take place over 1 calendar year due to the potential influence of seasonal differences in 25(OH)D levels.

Experimental chagas' disease in rhesus monkeys. I. Clinical parasitological, hematological and anatomo-pathological studies in the acute and indeterminate phase of the disease

Rhesus monkeys (macaca mulatta) were infected subcutaneously with 1.0 x 10**4 to 1.5 x 10**4 metacyclic trypomastigotes of Trypanosoma cruzi (Colombian strain). Parasitological and immunological parameters were evaluated in these animals for periods of 1 month to over 3 years. a chagona was observed between the 3 rd and the 13th day after infection (a.i) and patent parasitaemia between the 13th and 59th day a.i.. Thereafter, parasites were demonstrated only by haemoculture and/or xenodiagnosis. Circulating specifc IgM and IgC antibodies were observed as early as in the 2nd week a. i. IgG levels persisted until the end of the expriment, but IgM antibodies were detectable nine months a. i. Haematological alterations comprised leucocytosis and lymphocytosis. Eletrocardiographic alterations were minor and transient, similar to those observe in non-lethal human acute Chagas' myocarditis. Myocarditis and myositis, characterized by multiple foci of lympho-histiocyte inflammatory infiltrate, were present in monkeys sacrificed on the 41 th, 70th and 76 th day but not in the animal sacrificed 3 years and 3 months a. i.. The results suggest that Chagas' disease in rhesus monkeys reproduces the acute and indeterminate phases of human Chagas' disease.

A computational and geometric approach to phase resetting curves and surfaces

"Vegeu el resum a l'inici del document del fitxer adjunt."

Automatic front-crawl temporal phase detection using adaptive filtering of inertial signals

This study introduces a novel approach for automatic temporal phase detection and inter-arm coordination estimation in front-crawl swimming using inertial measurement units (IMUs). We examined the validity of our method by comparison against a video-based system. Three waterproofed IMUs (composed of 3D accelerometer, 3D gyroscope) were placed on both forearms and the sacrum of the swimmer. We used two underwater video cameras in side and frontal views as our reference system. Two independent operators performed the video analysis. To test our methodology, seven well-trained swimmers performed three 300 m trials in a 50 m indoor pool. Each trial was in a different coordination mode quantified by the index of coordination. We detected different phases of the arm stroke by employing orientation estimation techniques and a new adaptive change detection algorithm on inertial signals. The difference of 0.2 +/- 3.9% between our estimation and video-based system in assessment of the index of coordination was comparable to experienced operators' difference (1.1 +/- 3.6%). The 95% limits of agreement of the difference between the two systems in estimation of the temporal phases were always less than 7.9% of the cycle duration. The inertial system offers an automatic easy-to-use system with timely feedback for the study of swimming.

On a size-structured two-phase population model with infinite states-at-birth

In this work we introduce and analyze a linear size-structured population model with infinite states-at-birth. We model the dynamics of a population in which individuals have two distinct life-stages: an “active” phase when individuals grow, reproduce and die and a second “resting” phase when individuals only grow. Transition between these two phases depends on individuals’ size. First we show that the problem is governed by a positive quasicontractive semigroup on the biologically relevant state space. Then we investigate, in the framework of the spectral theory of linear operators, the asymptotic behavior of solutions of the model. We prove that the associated semigroup has, under biologically plausible assumptions, the property of asynchronous exponential growth.

Mean platelet volume in the early phase of acute ischemic stroke is not associated with severity or functional outcome.

Background: Previous studies reported an increase of mean platelet volume (MPV) in patients with acute ischemic stroke. However, its correlation with stroke severity has not been investigated. Moreover, studies on the association of MPV with functional outcome yielded inconsistent results. Methods: We included all consecutive ischemic stroke patients admitted to CHUV (Centre Hospitalier Universitaire Vaudois) Neurology Service within 24 h after stroke onset who had MPV measured on admission. The association of MPV with stroke severity (NIHSS score at admission and at 24 h) and outcome (Rankin Scale score at 3 and 12 months) was analyzed in univariate analysis. The chi(2) test was performed to compare the frequency of minor strokes (NIHSS score </=4) and good functional outcome (Rankin Scale score </=2) across MPV quartiles. The ANOVA test was used to compare MPV between stroke subtypes according to the TOAST classification. Student's two-tailed unpaired t test was performed to compare MPV between lacunar and nonlacunar strokes. MPV was generated at admission by the Sysmex XE-2100 automated cell counter (Sysmex Corporation, Kobe, Japan) from EDTA blood samples. Results: There was no significant difference in the frequency of minor strokes (p = 0.46) and good functional outcome (p = 0.06) across MPV quartiles. MPV was not associated with stroke severity or outcome in univariate analysis. There was no significant difference in MPV between stroke subtypes according to the TOAST classification (p = 0.173) or between lacunar and nonlacunar strokes (10.50 +/- 0.91 vs. 10.40 +/- 0.81 fl, p = 0.322). Conclusions: MPV, assessed within 24 h after ischemic stroke onset, is not associated with stroke severity or functional outcome.

T cell derived cytokines in lung-phase immunity to Schistosoma mansoni

In C57Bl/6 strain mice vaccinated with radiation-attenuated cercariae of Schistosoma mansoni immune elimination of challenge parasites occurs in the lungs. Leococytes were recovered from the lungs of such mice by bronchoalveolar lavage and cultured in vitro with larval antigen; the profile of cytokines released was then analyzed. From 14 days after vaccination, BAL cultures contained infiltrating lymphocytes wich produced abundant quantitties of IFN-g and IL-3. Challenge of vaccinated mice resulted in a second influx of IFN-g nd IL-3- producing cells, earlier than after vaccination or in the appropriate contropls. Ablation studies revealed that CD4+ T cells were the source of IFN-g. The timing of cytokine production after vaccination, and challenge was coincident with the phases of macrophage activation previously reported. At no time could lymphocytes in BAL cultures to stimulated to proliferate with either larval Ag or mitogen, in contrast to splenocytes from the same mice. Furthermore, T cell growth factor activity was not detected in BAL cultures stimulated with Ag. We suggest that the lymphocytes recruited to the lungs are memory/effector cells, When Ag. released challenge schistosomula is presented to these cells, they respond by secreting cytokines wich mediate the formation of cellular aggregates around the parasites, blocking their onward migration.

Experimental murine schistosomiasis mansoni: estabilishment of the chronic phase of the disease

After the acute hyperergic phase of schistosomal infection, the chronic phase of the disease corresponds to the estabilishment of a relative equilibrium between the host and the parasite. This involves: (1) A shift from the predominance of the TH2 response observed in the acute phase, to the predominance of the TH1 response in the chronic phase of the disease, with modification of lymphokine and immunoglobulin secretions patterns. (2) Redistribution of hosts responses to parasite, with predominance of systemic controls in the acute phase, and a shift towards local tissue responses in the chronic phase. This redistribution relieves the hyperergic responses involving the whole body of the host, and delimits cellular and molecular reactions to parasites to only those tissues that are directly involved by the adult parasites and their eggs. Mobilization of eosinophil granulocytes in schistosomal periovular granulomas is one of examples of this redistribution.

Development of Eosinophilia in dogs intradermically inoculated with sand fly saliva and Leishmania (Leishmania) chagasi stationary-phase promastigotes

Salivary glad lysates of the sand fly Lutzomia longipalpis have been shown to enhance the infectivity of Leishmania in mice. As shown herein, the simultaneous inoculation of Leishmania chagasi stationary-phase promastigotes and L. longipalpis salivary gland by the intradermal route in a group of mongrel dogs induced a statistically significant eosinophilia, in relation to dogs inoculated with Leishmania or with salivary gland lysate only. These dogs had no evidence of infection, in spite of the infectivity of the promastigotes when inoculated by the intravenous route.