Structure-based design of 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines as inhibitors of myeloid cell leukemia-1 (Mcl-1).

Mcl-1 has recently emerged as an attractive target to expand the armamentarium in the war on cancer. Using structure-based design, 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines were developed as a new chemotype to inhibit the Mcl-1 oncoprotein. The most potent compound inhibited Mcl-1 with a Ki of 120 nM, as determined by a fluorescence polarization competition assay. Direct binding was confirmed by 2D (1)H-(15)N HSQC NMR spectroscopy with (15)N-Mcl-1, which indicated that interactions with R263 and T266, and occupation of the p2 pocket are likely responsible for the potent binding affinity. The short and facile synthetic chemistry to access target molecules is expected to mediate lead optimization.

A simulation of food-web interactions leading to rainbow smelt Osmerus mordax dominance in Sparkling Lake, Wisconsin.

A process-based simulation model was used to examine the nature and intensity of food-web interactions that allow Osmerus mordax to dominate invaded lakes. The model simulates food-web interactions among linked populations of O. mordax, Coregonus artedi and Sander vitreus. Simulations indicated that O. mordax dominate where: (1) adult O. mordax prey on young-of-the-year (YOY) C. artedi, (2) YOY O. mordax negatively affect YOY S. vitreus through competition and (3) adult S. vitreus experience moderate fishing mortality. Osmerus mordax dominated simulations across a broad range of variable values that regulated competition and predation, and displayed threshold responses to increasing angler harvest. Consequently, angler harvest should be carefully managed in lakes susceptible to O. mordax invasions because the alternative could lead to fishery collapse.

BNCT for skin melanoma in extremities: updated Argentine clinical results.

As part of phase I/II melanoma BNCT clinical trial conducted in Argentina in a cooperative effort of the Argentine Atomic Energy Commission (CNEA) and the Oncology Institute Angel H. Roffo (IOAHR), 7 patients (6 female-1 male) received eight treatment sessions covering ten anatomical areas located in extremities. Mean age of the patients was 64 years (51-74). The treatments were performed between October 2003 and June 2007. All patients presented multiple subcutaneous skin metastases of melanoma and received an infusion containing approximately 14 gr/m(2) of (10)borophenyl-alanine (BPA) followed by the exposition of the area to a mixed thermal-epithermal neutron beam at the RA-6 reactor. The maximum prescribed dose to normal skin ranged from 16.5 to 24 Gy-Eq and normal tissue administered dose varied from 15.8 to 27.5 Gy-Eq. Considering evaluable nodules, 69.3% of overall response and 30.7% of no changes were seen. The toxicity was acceptable, with 3 out of 10 evaluable areas showing ulceration (30% toxicity grade 3).

Tumor control and normal tissue complications in BNCT treatment of nodular melanoma: a search for predictive quantities.

A previous work concerning tumor control and skin damage in cutaneous melanoma treatments with BNCT has been extended to include doses, volumes and responses of 104 subcutaneous lesions from all patients treated in Argentina. Acute skin reactions were also scored for these patients, and cumulative dose-area histograms and dose-based figures of merit for skin were calculated. Broadening the tumor response analysis with the latest data showed that the (minimum or mean) tumor dose is not a good predictor of the observed clinical outcome by itself. However, when the tumor volume was included in the model as second explicative variable, the dose increases its significance and becomes a critical variable jointly with the volume (p-values<0.05). A preliminary analysis to estimate control doses for two groups of tumor sizes revealed that for small tumor volumes (< 0.1cm(3)) doses greater than 20 Gy-Eq produce a high tumor control (> 80%). However, when tumor volumes are larger than 0.1cm(3), control is moderate (< 40%) even for minimum doses up to 40 Gy-Eq. Some quantities based on skin doses, areas and complication probabilities were proposed as candidates for predicting the severity of the early skin reactions. With the current data, all the evaluated figures of merit derived similar results: ulceration is present among the cases for which these quantities take the highest values.

Dynamic infrared imaging of cutaneous melanoma and normal skin in patients treated with BNCT.

We recently initiated a program aimed to investigate the suitability of dynamic infrared imaging for following-up nodular melanoma patients treated with BNCT. The reason that makes infrared imaging attractive is the fact that it constitutes a functional and non-invasive imaging method, providing information on the normal and abnormal physiologic response of the nervous and vascular systems, as well as the local metabolic rate and inflammatory processes that ultimately appear as differences in the skin temperature. An infrared camera, with a focal plane array of 320 x 240 uncooled ferroelectric detectors is employed, which provides a video stream of the infrared emission in the 7-14 microm wavelength band. A double blackbody is used as reference for absolute temperature calibration. After following a protocol for patient preparation and acclimatization, a basal study is performed. Subsequently, the anatomic region of interest is subjected to a provocation test (a cold stimulus), which induces an autonomic vasoconstriction reflex in normal structures, thus enhancing the thermal contrast due to the differences in the vasculature of the different skin regions. Radiation erythema reactions and melanoma nodules possess typically a faster temperature recovery than healthy, non-irradiated skin. However, some other non-pathological structures are also detectable by infrared imaging, (e.g. scars, vessels, arteriovenous anastomoses and injuries), thus requiring a multi-study comparison in order to discriminate the tumor signal. Besides the superficial nodules, which are readily noticeable by infrared imaging, we have detected thermal signals that are coincident with the location of non-palpable nodules, which are observable by CT and ultrasound. Diffuse regions of fast temperature recovery after a cold stimulus were observed between the third and sixth weeks post-BNCT, concurrent with the clinical manifestation of radiation erythema. The location of the erythematous visible and infrared regions is consistent with the 3D dosimetry calculations.

Biodistribution studies of boronophenylalanine-fructose in melanoma and brain tumor patients in Argentina.

A study of the (10)B-enriched p-boronophenylalanine-fructose complex ((10)BPA-F) infusion procedure in potential BNCT patients, including four melanoma of extremities and two high-grade gliomas (glioblastoma and ganglioglioma) was performed. T/B and S/B ratios for (10)B concentrations in tumor (T), blood (B) and skin (S) were determined. The T/B ratio for the glioblastoma was in the 1.8-3.4 range. The ganglioglioma did not show any significant boron uptake. For the nodular metastasic melanoma T/B values were between 1.5 and 2.6 (average 2.1+/-0.4), corresponding to the lower limit of the mean values reported for different melanoma categories. This result might suggest a lower boron uptake for nodular metastasic melanomas. S/B was 1.5+/-0.4. An open two-compartment pharmacokinetic model was applied to predict the boron concentration during the course and at the end of a BNCT irradiation.

First BNCT treatment of a skin melanoma in Argentina: dosimetric analysis and clinical outcome.

A Phase I/II protocol for treating cutaneuos melanomas with BNCT was designed in Argentina by the Comisión Nacional de Energía Atómica and the medical center Instituto Roffo. The first of a cohort of thirty planned patients was treated on October 9, 2003. This article depicts the protocol-based procedure and describes the first clinical case, treatment regime and planning, patient irradiation, retrospective dosimetric analysis and clinical outcome. Considering the low acute skin toxicity and the complete response in 21 of the 25 subcutaneous melanoma nodules treated, a second irradiation was performed in a different location of the extremity of the same patient. The corresponding clinical outcome is still under evaluation.

Boron neutron capture therapy of skin melanomas at the RA-6 reactor: a procedural approach to beam set up and performance evaluation for upcoming clinical trials.

This article reports on the progress of the modeling and experimental characterization of the RA-6 reactor neutron beam, designed for the upcoming BNCT clinical trials of skin melanoma, and presents the first theoretical analysis of such beam performance. The aspects relating to surface source modeling and assessment, beam dosimetry, treatment planning system calibration, and treatment planning optimization are presented herein. Several methods and criteria were established in order to provide guidance for future clinical studies conducted in this facility. Following a realistic model, the theoretical analysis was based on a clinical case of malignant melanoma in extremities. Owing to the complex geometry of the tumor, this particular clinical case represents one of the most difficult lesions to be treated. This article discusses the thorough evaluation stage that has led to the optimization of the treatment planning procedure. Two candidate plans were proposed, and dose-volume distributions in the target volume were evaluated on the basis of the application of a series of criteria that define the critical normal structures which limit the dose delivered. In spite of the complexity of the clinical case under review, results showed that only 4% of the tumor volume is underdosed in cases of mean blood 10B concentration values, even in the most unfavorable analysis. The overall results suggest that this BNCT facility is prepared to rigorously explore the clinical efficacy of the RA-6 beam and the BNCT treatment modality for peripheral melanomas.