Treatment patterns and outcomes in metastatic castration-resistant prostate cancer patients with and without somatic or germline alterations in homologous recombination repair genes.

BACKGROUND: Although germline BRCA mutations have been associated with adverse outcomes in prostate cancer (PC), understanding of the association between somatic/germline alterations in homologous recombination repair (HRR) genes and treatment outcomes in metastatic castration-resistant PC (mCRPC) is limited. The aim of this study was to investigate the prevalence and outcomes associated with somatic/germline HRR alterations, particularly BRCA1/2, in patients initiating first-line (1L) mCRPC treatment with androgen receptor signalling inhibitors (ARSi) or taxanes. PATIENTS AND METHODS: Data from 729 mCRPC patients were pooled for CAPTURE from four multicentre observational studies. Eligibility required 1L treatment with ARSi or taxanes, adequate tumour samples and biomarker panel results. Patients underwent paired normal and tumour DNA analyses by next-generation sequencing using a custom gene panel including ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2, RAD51B and RAD54L. Patients were divided into subgroups based on somatic/germline alteration(s): with BRCA1/2 mutations (BRCA); with HRR mutations except BRCA1/2 (HRR non-BRCA); and without HRR alterations (non-HRR). Patients without BRCA1/2 mutations were classified as non-BRCA. Radiographic progression-free survival (rPFS), progression-free survival 2 (PFS2) and overall survival (OS) were assessed. RESULTS: Of 729 patients, 96 (13.2%), 127 (17.4%) and 506 (69.4%) were in the BRCA, HRR non-BRCA and non-HRR subgroups, respectively. BRCA patients performed significantly worse for all outcomes than non-HRR or non-BRCA patients (P < 0.05), while PFS2 and OS were significantly shorter for BRCA than HRR non-BRCA patients (P < 0.05). HRR non-BRCA patients also had significantly worse rPFS, PFS2 and OS than non-HRR patients. Exploratory analyses suggested that for BRCA patients, there were no significant differences in outcomes associated with 1L treatment choice (ARSi or taxanes) or with the somatic/germline origin of the alterations. CONCLUSIONS: Worse outcomes were observed for mCRPC patients in the BRCA subgroup compared with non-BRCA subgroups, either HRR non-BRCA or non-HRR. Despite its heterogeneity, the HRR non-BRCA subgroup presented worse outcomes than the non-HRR subgroup. Screening early for HRR mutations, especially BRCA1/2, is crucial in improving mCRPC patient prognosis.

A mean-field approach to the dynamics of networks of complex neurons, from nonlinear Integrate-and-Fire to Hodgkin-Huxley models.

We present a mean-field formalism able to predict the collective dynamics of large networks of conductance-based interacting spiking neurons. We apply this formalism to several neuronal models, from the simplest Adaptive Exponential Integrate-and-Fire model to the more complex Hodgkin-Huxley and Morris-Lecar models. We show that the resulting mean-field models are capable of predicting the correct spontaneous activity of both excitatory and inhibitory neurons in asynchronous irregular regimes, typical of cortical dynamics. Moreover, it is possible to quantitatively predict the population response to external stimuli in the form of external spike trains. This mean-field formalism therefore provides a paradigm to bridge the scale between population dynamics and the microscopic complexity of the individual cells physiology.NEW & NOTEWORTHY Population models are a powerful mathematical tool to study the dynamics of neuronal networks and to simulate the brain at macroscopic scales. We present a mean-field model capable of quantitatively predicting the temporal dynamics of a network of complex spiking neuronal models, from Integrate-and-Fire to Hodgkin-Huxley, thus linking population models to neurons electrophysiology. This opens a perspective on generating biologically realistic mean-field models from electrophysiological recordings.

Note: Background Oriented Schlieren as a diagnostics for airflow control by plasma actuators.

Background Oriented Schlieren (BOS) is an optical technique sensitive to the first spatial derivative of the refractive index inside a light-transmitting medium. Compared to other Schlieren-like techniques, BOS is more versatile and allows to capture bi-dimensional gradients rather than just one spatial component. We propose to adopt BOS for studying the capabilities of surface dielectric barrier discharges to work like plasma actuators in flow control applications. The characteristics of the BOS we implemented at this purpose are discussed, together with few results concerning the ionic wind produced by the discharge in absence of an external airflow.

Favorable neurodevelopmental outcome in a hypothyroid neonate following intracordal amiodarone for cardioversion of refractory supraventricular tachycardia in a fetus.

Fetal supraventricular tachycardia (SVT), characterized by a fetal ventricular heart rate faster than 200 beats per minute (bpm), is often diagnosed during routine fetal heart monitoring or prenatal ultrasound examinations. Clinical guidelines for management of fetal SVT have not been determined in standardized trials, nor do we have a clear sense regarding the long-term developmental outcomes and side effects of in utero antiarrhythmic therapy. We describe our approach to the treatment of refractory SVT in a fetus with hydrops using direct umbilical vein treatment with amiodarone coupled with effusion evacuation. We successfully achieved in utero resolution of SVT. There was transient amiodarone-induced hypothyroidism, which we screened for early and treated with Synthroid. Ultimately our patient had normal long-term growth and development as measured by modified Denver office checklists and Ages and Stages questionnaires. Our experience advocates for vigilant screening and management of hypothyroidism in fetuses exposed to in utero amiodarone and suggests that it is possible to achieve good outcomes in high-acuity refractory cases of SVT.

Reconstruction of artery wall in experimental giant aneurysms.

AIM: This study describes five experimental techniques for the surgical treatment of giant aneurysms based on the resection of the aneurysm sac and reconstruction of the arterial wall. METHODS: The aneurysm was realized with a venous graft implanted with end-to-side anastomosis on the common carotid artery on 50 rabbits (with each technique realized in 10 rabbits). The first two experimental techniques (A and B) involve the reconstruction of the artery wall by a synthetic dural patch and by direct suture reinforced by a venous patch, respectively. In the model C a collateral branch arising from the aneurysm is resected and reimplanted on the parent artery after aneurysm resection. In the experimental model D the arterial defect is closed by a venous patch surrounding the whole arterial wall and sutured with the aid of fibrin glue. In the model E clamping of the parent artery proximal to the aneurysm site and termino-lateral anastomosis with the contralateral artery lead to the thrombosis of the aneurysm fulled only by refluent flow. RESULTS AND CONCLUSION: The venous pouch experimental models are useful to realize giant aneurysms. The above described techniques allow to realize the reconstruction of the arterial wall without stenosis and shortening the clamping time.

The neurovascular dysfunction induced by angiotensin II in the mouse neocortex is sexually dimorphic.

Women are less susceptible to the cerebrovascular complications of hypertension, such as a stroke and vascular dementia. The mechanism of such protection may be related to a reduced vulnerability of women to the cerebrovascular actions of hypertension. To test this hypothesis, we used a model of hypertension based on infusion of angiotensin II (ANG II), an octapeptide that plays a key role in hypertension and produces cerebrovascular dysregulation. Cerebral blood flow (CBF) was monitored by laser-Doppler flowmetry in anesthetized (urethane-chloralose) C57BL/6J male and female mice equipped with a cranial window. ANG II administration (0.25 mug.kg(-1).min(-1) iv x 30-45 min) elevated arterial pressure equally in both sexes but attenuated the CBF increase induced by whisker stimulation or by the endothelium-dependent vasodilator acetylcholine (ACh) in male but not in female mice. The administration of ANG II for 7 days (2.74 mg.kg(-1).day(-1)), using osmotic minipumps, also attenuated these cerebrovascular responses in male, but not female, mice. The reduced susceptibility to the effect of ANG II in female mice was abolished by ovariectomy and reinstated by estrogen administration to ovariectomized mice. Administration of estrogen to male mice abolished the ANG II-induced attenuation of CBF responses. We conclude that female mice are less susceptible to the cerebrovascular dysregulation induced by ANG II, an effect related to estrogen. Such protection from the deleterious cerebrovascular effects of hypertension may play a role in the reduced vulnerability to the cerebrovascular complications of hypertension observed in women.

Protective role of MnSOD and redox regulation of neuronal cell survival.

Reactive oxygen species (ROS) play a central role in neuronal pathophysiology and in neurodegenerative disorders. However, recent evidence indicates that these molecules also operate as signaling intermediates in a variety of physiological settings, including cell protection from apoptosis. Data presented here strongly support such a dual role for oxidants in neuronal cell homeostasis. In rat pheocromocytoma cells, cell rescue by the nerve growth factor (NGF) is accompanied by a transient burst of ROS generated in the cytosol by a GTPase-dependent mechanism. Within the NGF signaling cascade, ROS lie upstream and are necessary for activation/phosphorylation of AKT/PKB and of the antiapoptotic transcription factor cAMP-responsive element-binding protein (CREB). Conversely, an increase in mitochondrial oxygen species heralds apoptosis of serum-deprived cells, and these events can be prevented by cell exposure to NGF or by treatment with the mitochondrially targeted antioxidant MitoQ. Importantly, NGF-mediated decrease of mitochondrial ROS is dependent on the transcriptional up-regulation of the manganese superoxide dismutase (MnSOD) by active CREB. These observations therefore outline a circuitry whereby cytosolic redox signaling promotes neuronal cell survival by increasing the mitochondrial antioxidant defenses.

Client variables associated with selection and outcome in a methadone tapering program.

Based on archival information on 36 methadone maintenance patients, indicators of success in a methadone tapering program were investigated. None of the variables selected for study were found to differentiate successful from unsuccessful taperers. However, patients who were offered the opportunity to participate in the tapering program had significantly fewer years of heroin use prior to their admittance to a methadone maintenance program than patients in the general methadone maintenance population. In addition, the racial composition of patients attempting to taper included significantly fewer Black patients than the racial composition of the general methadone maintenance population. Possible explanations are offered.

Biostability of a non-ether polyurethane.

A new type of medical grade polyurethane elastomer, based upon an ether-free macroglycol, has been developed by VASCOR, Inc. Prior research conducted by others has indicated that an ether-free urethane should be inherently immune to biodegradation and environmental stress cracking. Specimens of the experimental polyurethane, along with positive and negative control materials, were formed into tubing, mounted on mandrels, and implanted in rabbits. After being exposed to the in vivo environment for six months, the specimens were explanted and examined with scanning electron microscopy. No indication of degradation was observed in the experimental polymer or negative control specimens, whereas severe microcracking was seen in most of the positive control specimens.

A cognitive-existential analysis of counselor responses to HIV-positive substance misusers in an outpatient methadone program and a residential therapeutic community.

Counselors of HIV-afflicted substance abusers not only must apply counseling strategies directed toward curbing drug use, but also are called upon to assess suicide risk, attend to the promotion of social support, treat adverse affective reactions, and respond to spiritual and existential concerns. The present study attempted to explore systematically the self-reported feelings, thoughts, and behaviors of counselors as they confront such demands. All counselors reported experiencing increased stress as a result of working with HIV-afflicted clients, and cognitive distortions were sometimes noted in counselor responses. However, more generally, thoughts seemed clearly formulated, and planned behaviors appeared directed toward rendering the best treatment possible.

The emergence of the sleep-wake cycle in infancy.

In order to investigate the appearance of a rest-activity periodicity, spontaneous motor behavior of five low-risk preterm infants (gestational age range 27-31 weeks) was monitored for 24 hours at weekly intervals until term. Using a time lapse videorecorder (6.5 fields/sec.) both slow and rapid movements were counted every three minutes; this interval was adopted as basic chronological paradigm in order to evaluate the daily distribution of motor activity. The results of quantitative analysis showed a developmental trend of motor behavior which increased from earliest conceptional ages (C.A.) until 32-33 weeks, and decreased around 36-37 weeks C.A. Prolonged complete rest intervals are rare at low C.A., while in older infants (approx. 40 weeks C.A.) an initial tendency to organize motor activity in ultradian cycle-like periods seems to be more evident, contemporary with consolidated behavioral states.