The influence of modes of action and physicochemical properties of chemicals on the correlation between in vitro and acute fish toxicity data

New EU legislation is providing an impetus for research aimed at replacing acute fish toxicity testing with in vitro alternatives. In line with such research, the objective of this study was to determine what factors influence the correlation between in vitro and fish toxicity data. Basal cytotoxicity (IC₅₀) and acute toxicity data from fathead minnow (LC₅₀) of 82 industrial organic chemicals were obtained from the Halle Registry of Cytotoxicity and the US EPA Fathead Minnow Database. A good correlation between IC₅₀ with LC₅₀ data was found (r 0.84). Yet, IC₅₀ data were less sensitive than LC₅₀ data by an order of magnitude. Using multiple regression analysis, the octanol–water partition coefficient (K_OW) and the Henry’s Law Constant (H) were found to significantly explain the low absolute sensitivity. The mode of action (MOA) of the chemical was found to significantly explain the general variation in the log IC₅₀/log LC₅₀ regression line. These results support the notion that (a) the bioavailability of hydrophobic (high K_OW) and volatile (high H) chemicals is significantly lower in in vitro assays than in the fish bioassay and (b) multiple cell types and endpoints should be included to mimic the modes of action possible in the whole organism.     

Immunization with a P53 synthetic long peptide vaccine induces P53‐specific immune responses in ovarian cancer patients,a phase II trial

The prognosis of ovarian cancer, the primary cause of death from gynecological malignancies, has only modestly improved over the last decades. Immunotherapy is one of the new treatment modalities explored for this disease. To investigate safety, tolerability, immunogenicity and obtain an impression of clinical activity of a p53 synthetic long peptide (p53‐SLP) vaccine, twenty patients with recurrent elevation of CA‐125 were included, eighteen of whom were immunized 4 times with 10 overlapping p53‐SLP in Montanide ISA51. The first 5 patients were extensively monitored for toxicity, but showed no ≥ grade 3 toxicity, thus accrual was continued. Overall, toxicity was limited to grade 1 and 2, mostly locoregional, inflammatory reactions. IFN‐γ producing p53‐specific T‐cell responses were induced in all patients who received all 4 immunizations as measured by IFN‐γ ELISPOT. An IFN‐γ secretion assay showed that vaccine‐induced p53‐specific T‐cells were CD4⁺, produced both Th1 and Th2 cytokines as analyzed by cytokine bead array. Notably, Th2 cytokines dominated the p53‐specific response. P53‐specific T‐cells were present in a biopsy of the last immunization site of at least 9/17 (53%) patients, reflecting the migratory capacity of p53‐specific T‐cells. As best clinical response, stable disease evaluated by CA‐125 levels and CT‐scans, was observed in 2/20 (10%) patients, but no relationship was found with vaccine‐induced immunity. This study shows that the p53‐SLP vaccine is safe, well tolerated and induces p53‐specific T‐cell responses in ovarian cancer patients. Upcoming trials will focus on improving T helper‐1 polarization and clinical efficacy. © 2009 UICC     

Anti-ischaemic efficacy of L-propionylcarnitine -- a promising novel metabolic approach to ischaemia?

L-propionylcarnitine, a naturally occurring derivative of L-Carnitine,essential for mitochondrial fatty acid transport and high-energyphosphate exchange, acutely reduces myocardial ischaemia andimproves ischaemia-induced cardiac dysfunction following intravenousadministration. This randomized, crossover study was designedto compare the long-term anti-ischaemic effects of oral L-propionylcarnitinewith diltiazem in patients with stable, exercise-induced angina.After a 2-week washout phase of anti-anginal medication anda 2-week single-blind placebo period, 46 patients were includedin the study, 23 of whom received 1500 mg L-propionylcarnitinedaily for 6 weeks, and 23 diltiazem (180 mg daily for 3 weeks,followed by 360 mg daily for 3 weeks), crossing over to theother treatment after a 1-week washout period. Three patientson L-propionylcarnitine and two on diltiazem discontinued. Bothtreatments resulted in comparable exercise duration (582 ±35 s and 588 ± 33s, x ± SEM), time to 0·1mV ST depression (436 ± 38 s and 465 ± 36 s),and increase in time to 0·1 mV ST depression from baseline(20% and 28%), L-propionylcarnitine and diltiazem, respectively. Diltiazem decreased the rate-pressure product at rest and exercise,L-prOpionylcarnitine did not. Both compounds significantly reducedST depression at maximal exercise [23% (L-propionylcarnitine)vs 35% (diltiazem), P<0·05 diltiazem vs L-propionylcarnitine].Diltiazem increased the time to onset of angina by 22%. In contrast,no significant changes occurred with L-propionylcarnitine. Duringthe study, anginal attacks were reduced by 70% and 57%, andnitroglycerin consumption decreased by 57% and 70%, L-proplonylcarnitineand diltiazem, respectively. Thus, both L-propionylcarnitineand (high-dose) diltiazem result in anti-ischaemic effects anddecrease angina attacks in daily life. Although the effect ofdiltiazem on exerciseinduced ischaemia appears more pronouncedthan that of L-propionylcarnitine, this novel metabolic approachto ischaemia warrants further development. (Eur Heart J 1996; 17: 414–420)     

Sublingual nitroglycerin used in routine tilt testing provokes a cardiac output-mediated vasovagal response

OBJECTIVES: We set out to determine the effect of sublingual nitroglycerin (NTG), as used during routine tilt testing in patients with unexplained syncope, on hemodynamic characteristics and baroreflex control of heart rate (HR) and systemic vascular resistance (SVR). BACKGROUND: Nitroglycerin is used in tilt testing to elicit a vasovagal response. It is known to induce venous dilation and enhance pooling. Also, NTG is lipophilic and readily passes cell membranes, and animal studies suggest a sympatho-inhibitory effect of NTG on circulatory control. METHODS: Routine tilt testing was conducted in 39 patients with suspected vasovagal syncope (age 36 +/- 16 years, 18 females). Patients were otherwise healthy and free of medication. Before a loss of consciousness set in, oncoming syncope was cut short by tilt-back or counter-maneuvers. Finger arterial pressure was monitored continuously (Finapres). Left ventricular stroke volume (SV) was computed from the pressure pulsations (Modelflow). Spontaneous baroreflex control of HR was estimated in the time and frequency domains. RESULTS: During tilt testing, 22 patients developed presyncope. After NTG administration but before presyncope, SV and cardiac output (CO) decreased (p < 0.001), whereas SVR and HR increased (p < 0.001) in all patients. Arterial pressure was initially maintained. Baroreflex sensitivity decreased after NTG. On Cox regression analysis, the occurrence of a vasovagal response was related to a drop in SV after NTG (hazard ratio 0.86, p = 0.005). CONCLUSIONS: The cardiovascular response to NTG is similar in vasovagal and non-vasovagal patients, but more pronounced in those with tilt-positive results. The NTG-facilitated presyncope appears to be CO-mediated, and there is no evidence of NTG-induced sympathetic inhibition.     

Emerging Intraoperative Imaging Modalities to Improve Surgical Precision

Intraoperative imaging (IOI) is performed to guide delineation and localization of regions of surgical interest. While oncological surgical planning predominantly utilizes x-ray computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound (US), intraoperative guidance mainly remains on surgeon interpretation and pathology for confirmation. Over the past decades however, intraoperative guidance has evolved significantly with the emergence of several novel imaging technologies, including fluorescence-, Raman, photoacoustic-, and radio-guided approaches. These modalities have demonstrated the potential to further optimize precision in surgical resection and improve clinical outcomes for patients. Not only can these technologies enhance our understanding of the disease, they can also yield large imaging datasets intraoperatively that can be analyzed by deep learning approaches for more rapid and accurate pathological diagnosis. Unfortunately, many of these novel technologies are still under preclinical or early clinical evaluation. Organizations like the Intra-Operative Imaging Study Group of the European Society for Molecular Imaging (ESMI) support interdisciplinary interactions with the aim to improve technical capabilities in the field, an approach that can succeed only if scientists, engineers, and physicians work closely together with industry and regulatory bodies to resolve roadblocks to clinical translation. In this review, we provide an overview of a variety of novel IOI technologies, discuss their challenges, and present future perspectives on the enormous potential of IOI for oncological surgical navigation.