Long term activity of vemurafenib in cancers with BRAF mutations: the ACSE basket study for advanced cancers other than BRAFV600-mutated melanoma.

BACKGROUND: BRAF inhibitors are approved in BRAFV600-mutated metastatic melanoma, non-small-cell lung cancer (NSCLC), Erdheim-Chester disease (ECD), and thyroid cancer. We report here the efficacy, safety, and long-term results of single-agent vemurafenib given in the AcSé vemurafenib basket study to patients with various BRAF-mutated advanced tumours other than BRAFV600-mutated melanoma and NSCLC. PATIENTS AND METHODS: Patients with advanced tumours other than BRAFV600E melanoma and progressing after standard treatment were eligible for inclusion in nine cohorts (including a miscellaneous cohort) and received oral vemurafenib 960 mg two times daily. The primary endpoint was the objective response rate (ORR) estimated with a Bayesian design. The secondary outcomes were disease control rate, duration of response, progression-free survival (PFS), overall survival (OS), and vemurafenib safety. RESULTS: A total of 98 advanced patients with various solid or haematological cancers, 88 with BRAFV600 mutations and 10 with BRAFnonV600 mutations, were included. The median follow-up duration was 47.7 months. The Bayesian estimate of ORR was 89.7% in hairy cell leukaemias (HCLs), 33.3% in the glioblastomas cohort, 18.2% in cholangiocarcinomas, 80.0% in ECD, 50.0% in ovarian cancers, 50.0% in xanthoastrocytomas, 66.7% in gangliogliomas, and 60.0% in sarcomas. The median PFS of the whole series was 8.8 months. The 12-, 24-, and 36-month PFS rates were 42.2%, 23.8%, and 17.9%, respectively. Overall, 54 patients died with a median OS of 25.9 months, with a projected 4-year OS of 40%. Adverse events were similar to those previously reported with vemurafenib. CONCLUSION: Responses and prolonged PFS were observed in many tumours with BRAF mutations, including HCL, ECD, ovarian carcinoma, gliomas, ganglioglioma, and sarcomas. Although not all cancer types responded, vemurafenib is an agnostic oncogene therapy of cancers.

Spine apparatus modulates Ca 2+ in spines through spatial localization of sources and sinks.

Dendritic spines are small protrusions on dendrites in neurons and serve as sites of postsynaptic activity. Some of these spines contain smooth endoplasmic reticulum (SER), and sometimes an even further specialized SER known as the spine apparatus (SA). In this work, we developed a stochastic spatial model to investigate the role of the SER and the SA in modulating Ca 2+ dynamics. Using this model, we investigated how ryanodine receptor (RyR) localization, spine membrane geometry, and SER geometry can impact Ca 2+ transients in the spine and in the dendrite. Our simulations found that RyR opening is dependent on where it is localized in the SER and on the SER geometry. In order to maximize Ca 2+ in the dendrites (for activating clusters of spines and spine-spine communication), a laminar SA was favorable with RyRs localized in the neck region, closer to the dendrite. We also found that the presence of the SER without the laminar structure, coupled with RyR localization at the head, leads to higher Ca 2+ presence in the spine. These predictions serve as design principles for understanding how spines with an ER can regulate Ca 2+ dynamics differently from spines without ER through a combination of geometry and receptor localization. Highlights: 1RyR opening in dendritic spine ER is location dependent and spine geometry dependent. Ca 2+ buffers and SERCA can buffer against runaway potentiation of spines even when CICR is activated. RyRs located towards the ER neck allow for more Ca 2+ to reach the dendrites. RyRs located towards the spine head are favorable for increased Ca 2+ in spines.

The relationship between an athlete's maximal aerobic speed determined in a laboratory and their final speed reached during a field test (UNCa Test).

AIM: The main purpose of this study was to apply a field test to predict the maximal aerobic speed (MAS) of an athlete using the same protocol done in a laboratory. METHODS: Fourteen male subjects volunteered to participate in this study and were evaluated on four separate occasions. First, an anthropometric evaluation was carried out. Secondly, an aerobic test was done on the treadmill with a gass analyzer to measure the maximum oxygen consumption (VO2máx) and to calculate the MAS. Third, Unca test was evaluated again to confirm the reliability of the test. Finally, the participants were evaluated on field using the National University of Catamarca test (UNCa test). RESULTS: The MAS reached on a treadmill 15.6±1.0 km·h-1 was significantly higher than that found during the field test 13,6 ± 1,1 km·h-1 (P=0.0001). However the relationship between the treadmill and the field test were highly correlated in all variables: speed: r=0.83, distance covered r= 0,81, test duration r=0.83. CONCLUSION: If MAS found on a treadmill is considered to be "the gold-standard" to validate MAS on field, it can be said that the UNCa test underestimates speed.

Functional identification of an osmotic response element (ORE) in the promoter region of the killifish deiodinase 2 gene (FhDio2).

The physiological role played by thyroid hormones (TH) in hydro-osmotic homeostasis in fish remains a controversial issue. Previous studies have shown that in Fundulus heteroclitus (killifish) hypo-osmotic stress increases liver iodothyronine deiodinase type 2 (D2) mRNA and D2 activity. In this study we identified two conserved osmotic response element (ORE) motifs in the promoter region of the killifish D2 gene (FhDio2) and examined their possible role in the transcriptional regulation of FhDio2 during hypo-osmotic stress. As assessed by the electrophoretic mobility shift assay, results from in vivo and in vitro experiments demonstrate that exposure to an abrupt hyposmotic challenge triggers in the liver of killifish a strong nuclear recruitment of a putative osmotic response element binding protein (OREBP). This protein-DNA binding is time-dependent, attains a maximum within 2-8 h after the osmotic stress, and is followed by a significant increase in D2 activity. Furthermore, protein-DNA binding and the subsequent elevation in enzyme activity were blocked by the tyrosine kinase inhibitor genistein. Thus, during hypo-osmotic stress, a putative OREBP kinase-activated pathway stimulates FhDio2 transcription and enzymatic activity. These data and the fact that D2 is the major enzyme providing local intracellular T(3) suggest that TH plays a direct role in osmoregulation in fish, possibly by participating in hepatic ammonia metabolism. This study provides important insight into the physiological role of TH in hydro-osmotic homeostasis in fish.

3,5-Diiodothyronine in vivo maintains euthyroidal expression of type 2 iodothyronine deiodinase, growth hormone, and thyroid hormone receptor beta1 in the killifish.

Until recently, 3,5-diiodothyronine (3,5-T(2)) has been considered an inactive by-product of triiodothyronine (T(3)) deiodination. However, studies from several laboratories have shown that 3,5-T(2) has specific, nongenomic effects on mitochondrial oxidative capacity and respiration rate that are distinct from those due to T(3). Nevertheless, little is known about the putative genomic effects of 3,5-T(2). We have previously shown that hyperthyroidism induced by supraphysiological doses of 3,5-T(2) inhibits hepatic iodothyronine deiodinase type 2 (D2) activity and lowers mRNA levels in the killifish in the same manner as T(3) and T(4), suggesting a pretranslational effect of 3,5-T(2) (Garcia-G C, Jeziorski MC, Valverde-R C, Orozco A. Gen Comp Endocrinol 135: 201-209, 2004). The question remains as to whether 3,5-T(2) would have effects under conditions similar to those that are physiological for T(3). To this end, intact killifish were rendered hypothyroid by administering methimazole. Groups of hypothyroid animals simultaneously received 30 nM of either T(3), reverse T(3), or 3,5-T(2). Under these conditions, we expected that, if it were bioactive, 3,5-T(2) would mimic T(3) and thus reverse the compensatory upregulation of D2 and tyroid receptor beta1 and downregulation of growth hormone that characterize hypothyroidism. Our results demonstrate that 3,5-T(2) is indeed bioactive, reversing both hepatic D2 and growth hormone responses during a hypothyroidal state. Furthermore, we observed that 3,5-T(2) and T(3) recruit two distinct populations of transcription factors to typical palindromic and DR4 thyroid hormone response elements. Taken together, these results add further evidence to support the notion that 3,5-T(2) is a bioactive iodothyronine.

Is atherosclerosis increasing in Mexico City?

This report compares quantitative measures of atherosclerosis in aortas and coronaries from autopsies of deceased men from Mexico City collected during 1960 to 1964 and 1986 to 1987. The comparison of lesions in two different time periods provides an opportunity for determining whether the extent of atherosclerosis has changed over time in Mexico City. Three pathologists independently evaluated the extent of fatty streaks (FS), fibrous plaques (FP), calcified plaques (CA), and complicated lesions (CO) in 165 aortas and 120 sets of coronary arteries collected during 1986 to 1987 for comparison with similar gradings of 128 aortas and coronary arteries from the International Atherosclerosis Project in 1960 to 1964. Neither FS nor more advanced lesions differed significantly in either the descending thoracic or abdominal aorta between the two collection periods. In contrast, there were more extensive FP and raised atherosclerotic lesions (RL = FP + CA + CO) in the coronary artery segments evaluated in the younger age groups in 1986 to 1987 versus 1960 to 1964. Additional analyses, based on 75 pairs of aortas and 32 pairs of coronary arteries from age-matched cases, all regraded by the team of pathologists after blind coding, showed more FS in both aortic segments and more extensive involvement with RL in the three main branches of the coronary arteries in the more recent study. An overview of our findings suggests that atherosclerosis, particularly in the coronary arteries, is increasing in Mexico City. This hypothesis merits careful testing in parallel with consideration of possible changes in the risk factors that could be responsible for changes in extent of lesions.

[Prevention of coronary atherosclerosis. II: Topography and morphology of "protruding" lesions. Epidemiologic, diagnostic and therapeutic implications]. / Prevención de la aterosclerosis coronaria. II: Topografía y morfología de lesiones "protruyentes". Implicaciones epidemiológicas, diagnósticas y terapéuticas.

Topographic and morphologic aspects of coronary atherosclerotic "protruding" lesions were investigated in 119 accidental deaths in males living in Mexico City. Morphology and topography varied according to the arterial trunk studied and age. Left anterior descending and circumflex lesions were almost always confined to the initial 5 cms and if a lesion was present after the 3rd cm there was always a proximal lesion. Right coronary lesions occasionally were found distally even in the absence of proximal lesions. Third decade lesions were usually not calcified. Stenosis if present was rarely multivascular. Some fourth decade lesions were calcified; plurivascular stenosis was present in some cases. Fifth decade lesions show sequential stenotic lesions in the same vessel; calcium and plurivascular stenosis were often observed. However the features observed in the 3rd decade could be observed in the older subjects. Reference is made to lesions which are found in both the left main trunk and the left anterior descending. Epidemiological and clinical applications related with preventive programs are mentioned.