PSMA PET/CT to evaluate response to SBRT for prostate cancer bone metastases

BackgroundIn the current study we evaluated ⁶⁸Ga PSMA PET/ CT to measure local control of bone metastasis in oligometastatic prostate cancer patients treated with SBRT.Materials and methodsAfter the institutional review board approval, a retrospective review of medical records of consecutive prostate cancer patients treated between 2014 and 2018 was conducted. Only medical records of patients that were treated with SBRT for bone metastasis and had pre-and post-SBRT ⁶⁸Ga PSMA PET/CT scans were included in our study. Data extracted from the medical files included patient-related (age), disease-related (Gleason score, site of metastasis), and treatment-related factors and outcomes.ResultsDuring the study period, a total of 12 patients (15 lesions) were included, with a median age of 73 years. The median follow-up was 26.5 months (range 13–45 months). Median time of ⁶⁸Ga PSMA PET/ CT follow up was 17.0 months (range 3–39 months). The median pre-treatment PSA was 2 ng/mL (range 0.56–44 ng/mL) vs. post treatment PSA nadir of 0.01 ng/mL (0.01–4.32) with a median time to nadir of 7 months (range, 2–12). Local control was 93% during the follow up period and there was correlation with PS MA avidity on PE T. None patients developed recurrences in the treated bone. None of the patients had grade 3 or more toxicities during follow-up.ConclusionsSBRT is a highly effective and safe method for treatment of prostate cancer bone metastases. More studies are required to determine if SBRT provides greater clinical benefit than standard fractionation for oligometastatic prostate cancer patients. ⁶⁸Ga PSMA PET/CT should be further investigated for delineation and follow-up.     

Infantile cerebellar-retinal degeneration associated with a mutation in mitochondrial aconitase, ACO2

Degeneration of the cerebrum, cerebellum, and retina in infancy is part of the clinical spectrum of lysosomal storage disorders, mitochondrial respiratory chain defects, carbohydrate glycosylation defects, and infantile neuroaxonal dystrophy. We studied eight individuals from two unrelated families who presented at 2-6 months of age with truncal hypotonia and athetosis, seizure disorder, and ophthalmologic abnormalities. Their course was characterized by failure to acquire developmental milestones and culminated in profound psychomotor retardation and progressive visual loss, including optic nerve and retinal atrophy. Despite their debilitating state, the disease was compatible with survival of up to 18 years. Laboratory investigations were normal, but the oxidation of glutamate by muscle mitochondria was slightly reduced. Serial brain MRI displayed progressive, prominent cerebellar atrophy accompanied by thinning of the corpus callosum, dysmyelination, and frontal and temporal cortical atrophy. Homozygosity mapping followed by whole-exome sequencing disclosed a Ser112Arg mutation in ACO2, encoding mitochondrial aconitase, a component of the Krebs cycle. Specific aconitase activity in the individuals' lymphoblasts was severely reduced. Under restrictive conditions, the mutant human ACO2 failed to complement a yeast ACO1 deletion strain, whereas the wild-type human ACO2 succeeded, indicating that this mutation is pathogenic. Thus, a defect in mitochondrial aconitase is associated with an infantile neurodegenerative disorder affecting mainly the cerebellum and retina. In the absence of noninvasive biomarkers, determination of the ACO2 sequence or of aconitase activity in lymphoblasts are warranted in similarly affected individuals, based on clinical and neuroradiologic grounds.     

Fast coding of orientation in primary visual cortex

Understanding how populations of neurons encode sensory information is a major goal of systems neuroscience. Attempts to answer this question have focused on responses measured over several hundred milliseconds, a duration much longer than that frequently used by animals to make decisions about the environment. How reliably sensory information is encoded on briefer time scales, and how best to extract this information, is unknown. Although it has been proposed that neuronal response latency provides a major cue for fast decisions in the visual system, this hypothesis has not been tested systematically and in a quantitative manner. Here we use a simple 'race to threshold' readout mechanism to quantify the information content of spike time latency of primary visual (V1) cortical cells to stimulus orientation. We find that many V1 cells show pronounced tuning of their spike latency to stimulus orientation and that almost as much information can be extracted from spike latencies as from firing rates measured over much longer durations. To extract this information, stimulus onset must be estimated accurately. We show that the responses of cells with weak tuning of spike latency can provide a reliable onset detector. We find that spike latency information can be pooled from a large neuronal population, provided that the decision threshold is scaled linearly with the population size, yielding a processing time of the order of a few tens of milliseconds. Our results provide a novel mechanism for extracting information from neuronal populations over the very brief time scales in which behavioral judgments must sometimes be made.     

Reversible pegylation prolongs the hypotensive effect of atrial natriuretic peptide

Natriuretic peptides (NP), including atrial natriuretic peptide (ANP), induce potent natriuresis and vasodilation and thereby generate hypotension in vivo. Despite intensive efforts, clinical application of NP as an antihypertensive agent is limited because of their short biological half-life and poor bioavailability. Recently, we have developed a strategy that facilitates slow release of peptides from PEG-peptide inactive conjugates, based on reversible pegylation. Peptides prepared by this approach undergo slow, spontaneous chemical hydrolysis at physiological conditions, releasing the native active peptide/protein drug from the inactive conjugates over prolonged periods. A PEG chain of 30 kDa was linked covalently to the alpha-amino side chain of the hormone via a MAL-Fmoc-NHS spacer, yielding PEG 30-Fmoc-ANP, a prodrug that releases the native hormone upon incubation at physiological conditions. Bolus administration of native ANP to Wistar rats receiving adrenaline yields a short, transitory effect in lowering blood pressure (BP), reaching a maximum at 2 min, and then returning to control values after 12 to 25 min. In contrast, administration of PEG 30-Fmoc-ANP lowered BP following a lag period of 50 min, and maintained low BP for a period exceeding 60 min. Saline or PEG 30-Fmoc-Alanine were not effective in lowering BP in Wistar rats. These results show that the novel compound, PEG 30-Fmoc-ANP, is a reversible pegylated prodrug derivative that facilitates a prolonged BP lowering effect in rats and may be considered as a candidate for development into an antihypertensive drug.     

Does elevated pCO2 affect reef octocorals?

Increasing anthropogenic pCO₂ alters seawater chemistry, with potentially severe consequences for coral reef growth and health. Octocorals are the second most important faunistic component in many reefs, often occupying 50% or more of the available substrate. Three species of octocorals from two families were studied in Eilat (Gulf of Aqaba), comprising the zooxanthellate Ovabunda macrospiculata and Heteroxenia fuscescens (family Xeniidae), and Sarcophyton sp. (family Alcyoniidae). They were maintained under normal (8.2) and reduced (7.6 and 7.3) pH conditions for up to 5 months. Their biolological features, including protein concentration, polyp weight, density of zooxanthellae, and their chlorophyll concentration per cell, as well as polyp pulsation rate, were examined under conditions more acidic than normal, in order to test the hypothesis that rising pCO₂ would affect octocorals. The results indicate no statistically significant difference between the octocorals exposed to reduced pH values compared to the control. It is therefore suggested that the octocorals' tissue may act as a protective barrier against adverse pH conditions, thus maintaining them unharmed at high levels of pCO₂.     

Functional gene groups are concentrated within chromosomes,among chromosomes and in the nuclear space of the human genome

Genomes undergo changes in organization as a result of gene duplications, chromosomal rearrangements and local mutations, among other mechanisms. In contrast to prokaryotes, in which genes of a common function are often organized in operons and reside contiguously along the genome, most eukaryotes show much weaker clustering of genes by function, except for few concrete functional groups. We set out to check systematically if there is a relation between gene function and gene organization in the human genome. We test this question for three types of functional groups: pairs of interacting proteins, complexes and pathways. We find a significant concentration of functional groups both in terms of their distance within the same chromosome and in terms of their dispersal over several chromosomes. Moreover, using Hi-C contact map of the tendency of chromosomal segments to appear close in the 3D space of the nucleus, we show that members of the same functional group that reside on distinct chromosomes tend to co-localize in space. The result holds for all three types of functional groups that we tested. Hence, the human genome shows substantial concentration of functional groups within chromosomes and across chromosomes in space.     

Sensitive In Situ Monitoring of a Recombinant Bioluminescent Yersinia enterocolitica Reporter Mutant in Real Time on Camembert Cheese

Bioluminescent mutants of Yersinia enterocolitica were generated by transposon mutagenesis using a promoterless, complete lux operon (luxCDABE) derived from Photorhabdus luminescens, and their production of light in the cheese environment was monitored. Mutant B94, which had the lux cassette inserted into an open reading frame of unknown function was used for direct monitoring of Y. enterocolitica cells on cheeses stored at 10°C by quantifying bioluminescence using a photon-counting, intensified charge-coupled device camera. The detection limit on cheese was 200 CFU/cm². Bioluminescence of the reporter mutant was significantly regulated by its environment (NaCl, temperature, and cheese), as well as by growth phase, via the promoter the lux operon had acquired upon transposition. At low temperatures, mutant B94 did not exhibit the often-reported decrease of photon emission in older cells. It was not necessary to include either antibiotics or aldehyde in the food matrix in order to gain quantitative, reproducible bioluminescence data. As far as we know, this is the first time a pathogen has been monitored in situ, in real time, in a “real-product” status, and at a low temperature.     

A probabilistic methodology for integrating knowledge and experiments on biological networks.

Biological systems are traditionally studied by focusing on a specific subsystem, building an intuitive model for it, and refining the model using results from carefully designed experiments. Modern experimental techniques provide massive data on the global behavior of biological systems, and systematically using these large datasets for refining existing knowledge is a major challenge. Here we introduce an extended computational framework that combines formalization of existing qualitative models, probabilistic modeling, and integration of high-throughput experimental data. Using our methods, it is possible to interpret genomewide measurements in the context of prior knowledge on the system, to assign statistical meaning to the accuracy of such knowledge, and to learn refined models with improved fit to the experiments. Our model is represented as a probabilistic factor graph, and the framework accommodates partial measurements of diverse biological elements. We study the performance of several probabilistic inference algorithms and show that hidden model variables can be reliably inferred even in the presence of feedback loops and complex logic. We show how to refine prior knowledge on combinatorial regulatory relations using hypothesis testing and derive p-values for learned model features. We test our methodology and algorithms on a simulated model and on two real yeast models. In particular, we use our method to explore uncharacterized relations among regulators in the yeast response to hyper-osmotic shock and in the yeast lysine biosynthesis system. Our integrative approach to the analysis of biological regulation is demonstrated to synergistically combine qualitative and quantitative evidence into concrete biological predictions.