The BRCA1/2 proteins are involved in regulation of cellular proliferation by DNA damage repair via homologous recombination. Therefore, BRCA1/2 mutation carriers with pancreatic cancer may have ...distinct biologic outcomes.
Patients with BRCA1/2-associated pancreatic ductal adenocarcinoma (PDAC) diagnosed between January 1994 and December 2012 were identified from databases at three participating institutions. Clinical data were collected. Disease-free survival and overall survival (OS) were analysed.
Overall, 71 patients with PDAC and BRCA1 (n=21), BRCA2 (n=49) or both (n=1) mutations were identified. Mean age at diagnosis was 60.3 years (range 33-83), 81.7% (n=58) had any family history of malignancy; 30% (n=21) underwent primary resection. Out of 71 participants, 12 received experimental therapy; one patient had missing data, these 13 cases were excluded from OS analysis. Median OS for 58 patients was 14 months (95% CI 10-23 months). Median OS for patients with stage 1/2 disease has not been reached with 52% still alive at 60 months. Median OS for stage 3/4 was 12 months (95% CI 6-15). Superior OS was observed for patients with stage 3/4 treated with platinum vs those treated with non-platinum chemotherapies (22 vs 9 months; P=0.039).
Superior OS was observed for advanced-disease BRCA-associated PDAC with platinum exposure.
Iron is required for microbial growth and proliferation. To survive in low-iron environments, some microorganisms secrete ferric iron chelators called siderophores. Siderophore biosynthesis occurs ...via two pathways: the non-ribosomal peptide synthetase (NRPS) pathway and the NRPS-independent siderophore (NIS) synthetase pathway. NIS enzymes function by adenylating a carboxylic acid substrate, typically citrate, or a derivative, followed by nucleophilic capture of an amine or alcohol and displacement of a citryl intermediate. In this review, we summarize recent advances in NIS biochemistry with a particular focus on structural biology and confirm the classification of NIS enzymes into Types A, A', B, and C based on substrate specificity. Based on a phylogenetic analysis, we also propose a new subclass of NIS enzymes, Type C', responsible for dimerization and macrocyclization of complex and substituted amine or amide intermediates. Finally, we describe the role of NIS enzymes in virulence of pathogenic microbes and discuss NIS inhibitors as potential anti-microbial agents.
COVID-19 pandemic is a global calamity posing an unprecedented opportunity to study resilience. We developed a brief resilience survey probing self-reliance, emotion-regulation, ...interpersonal-relationship patterns and neighborhood-environment, and applied it online during the acute COVID-19 outbreak (April 6-15, 2020), on a crowdsourcing research website ( www.covid19resilience.org ) advertised through social media. We evaluated level of stress (worries) regarding COVID-19: (1) contracting, (2) dying from, (3) currently having, (4) family member contracting, (5) unknowingly infecting others with (6) experiencing significant financial burden following. Anxiety (GAD7) and depression (PHQ2) were measured. Totally, 3042 participants (n = 1964 females, age range 18-79, mean age = 39) completed the resilience and COVID-19-related stress survey and 1350 of them (mean age = 41, SD = 13; n = 997 females) completed GAD7 and PHQ2. Participants significantly endorsed more distress about family contracting COVID-19 (48.5%) and unknowingly infecting others (36%), than getting COVID-19 themselves (19.9%), p < 0.0005 covarying for demographics and proxy COVID-19 exposures like getting tested and knowing infected individuals. Patterns of COVID-19 related worries, rates of anxiety (GAD7 > 10, 22.2%) and depression (PHQ2 > 2, 16.1%) did not differ between healthcare providers and non-healthcare providers. Higher resilience scores were associated with lower COVID-19 related worries (main effect F
= 134.9; p < 0.00001, covarying for confounders). Increase in 1 SD on resilience score was associated with reduced rate of anxiety (65%) and depression (69%), across healthcare and non-healthcare professionals. Findings provide empirical evidence on mental health associated with COVID-19 outbreak in a large convenience sample, setting a stage for longitudinal studies evaluating mental health trajectories following COVID-19 pandemic.
Cardiac radiotherapy (RT) may be effective in treating heart failure (HF) patients with refractory ventricular tachycardia (VT). The previously proposed mechanism of radiation-induced fibrosis does ...not explain the rapidity and magnitude with which VT reduction occurs clinically. Here, we demonstrate in hearts from RT patients that radiation does not achieve transmural fibrosis within the timeframe of VT reduction. Electrophysiologic assessment of irradiated murine hearts reveals a persistent supraphysiologic electrical phenotype, mediated by increases in Na
1.5 and Cx43. By sequencing and transgenic approaches, we identify Notch signaling as a mechanistic contributor to Na
1.5 upregulation after RT. Clinically, RT was associated with increased Na
1.5 expression in 1 of 1 explanted heart. On electrocardiogram (ECG), post-RT QRS durations were shortened in 13 of 19 patients and lengthened in 5 patients. Collectively, this study provides evidence for radiation-induced reprogramming of cardiac conduction as a potential treatment strategy for arrhythmia management in VT patients.
A hypothalamic pulse generator located in the arcuate nucleus controls episodic release of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) and is essential for reproduction. Recent ...evidence suggests this generator is composed of arcuate "KNDy" cells, the abbreviation based on coexpression of kisspeptin, neurokinin B, and dynorphin. However, direct visual evidence of KNDy neuron activity at a single-cell level during a pulse is lacking. Here, we use in vivo calcium imaging in freely moving female mice to show that individual KNDy neurons are synchronously activated in an episodic manner, and these synchronized episodes always precede LH pulses. Furthermore, synchronization among KNDy cells occurs in a temporal order, with some subsets of KNDy cells serving as "leaders" and others as "followers" during each synchronized episode. These results reveal an unsuspected temporal organization of activation and synchronization within the GnRH pulse generator, suggesting that different subsets of KNDy neurons are activated at pulse onset than afterward during maintenance and eventual termination of each pulse. Further studies to distinguish KNDy "leader" from "follower" cells is likely to have important clinical significance, since regulation of pulsatile GnRH secretion is essential for normal reproduction and disrupted in pathological conditions such as polycystic ovary syndrome and hypothalamic amenorrhea.
The Net Effect of Functional Traits on Fitness Laughlin, Daniel C.; Gremer, Jennifer R.; Adler, Peter B. ...
Trends in ecology & evolution (Amsterdam),
November 2020, 2020-11-00, 20201101, Letnik:
35, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Generalizing the effect of traits on performance across species may be achievable if traits explain variation in population fitness. However, testing relationships between traits and vital rates to ...infer effects on fitness can be misleading. Demographic trade-offs can generate variation in vital rates that yield equal population growth rates, thereby obscuring the net effect of traits on fitness. To address this problem, we describe a diversity of approaches to quantify intrinsic growth rates of plant populations, including experiments beyond range boundaries, density-dependent population models built from long-term demographic data, theoretical models, and methods that leverage widely available monitoring data. Linking plant traits directly to intrinsic growth rates is a fundamental step toward rigorous predictions of population dynamics and community assembly.
Community ecology seeks to generalize the effects of traits on performance across species, which may be possible if traits explain variation in population fitness.Linking traits to a specific demographic rate, such as survival or reproduction, is an important step but can be misleading because trade-offs among demographic rates obscure the net effect on fitness.Integrating demographic rates (survival, growth, and reproduction) and computing low density population growth rates incorporates these trade-offs into measures of fitness.Several approaches can be used to quantify the net effect of traits on fitness, and these approaches span a trade-off of empirical rigor and logistical ease.The adaptive value of traits is evident when intrinsic growth rates are explained by trait–environment interactions across multiple coexisting species spanning an environmental gradient.
Neurons in the hypothalamic arcuate nucleus (ARC) that co-express kisspeptin, neurokinin B and dynorphin (KNDy cells) are essential for mammalian reproduction as key regulators of ...gonadotropin-releasing hormone (GnRH) secretion. Although multiple endogenous and exogenous signals act indirectly via KNDy neurons to regulate GnRH, the identity of upstream neurons that provide synaptic input to this subpopulation is unclear. We used rabies-mediated tract-tracing in transgenic Kiss1-Cre mice combined with whole-brain optical clearing and multiple-label immunofluorescence to create a comprehensive and quantitative brain-wide map of neurons providing monosynaptic input to KNDy cells, as well as identify the estrogen receptor content and peptidergic phenotype of afferents. Over 90% of monosynaptic input to KNDy neurons originated from hypothalamic nuclei in both male and female mice. The greatest input arose from non-KNDy ARC neurons, including proopiomelanocortin-expressing cells. Significant female-dominant sex differences in afferent input were detected from estrogen-sensitive hypothalamic nuclei critical for reproductive endocrine function and sexual behavior in mice, indicating KNDy cells may provide a unique site for the coordination of sex-specific behavior and gonadotropin release. These data provide key insight into the structural framework underlying the ability of KNDy neurons to integrate endogenous and environmental signals important for the regulation of reproductive function.
The PRECISION trial was a multicentre randomised study that demonstrated that multiparametric magnetic resonance imaging (mpMRI)–targeted biopsy is superior to standard transrectal ultrasound–guided ...biopsy for the detection of prostate cancer. The outcomes of studies reporting mpMRI-targeted biopsies are dependent on the quality of the mpMRI but there are currently no scoring systems available for evaluating this. We introduced a novel scoring system, the Prostate Imaging Quality (PI-QUAL) score, to assess the quality of scans in the PRECISION trial. PI-QUAL is a score on a Likert scale from 1 to 5, where 1 means that no mpMRI sequences are of diagnostic quality and 5 implies that each sequence is independently of optimal diagnostic quality. Fifty-eight out of 252 (23%) mpMRI scans chosen at random from each of the 22 centres in this trial were evaluated by two experienced radiologists from the coordinating trial centre, in consensus, blinded to pathology results. Overall, the mpMRI quality in the centres participating in PRECISION was good. MpMRI quality was of sufficient diagnostic quality (PI-QUAL ≥3) for 55 scans (95%) and of good or optimal diagnostic quality (PI-QUAL ≥4) for 35 scans (60%). Fifty-five out of 58 (95%) scans were of diagnostic quality for T2WI, followed by DWI (46/58 scans; 79%), and DCE (38/58 scans; 66%). Further validation of this scoring system is warranted.
In this study we developed a scoring system (PI-QUAL) to assess the quality of multiparametric magnetic resonance imaging (mpMRI) in prostate cancer detection. We used scans from 22 centres that participated in the PRECISION trial. Although there was room for improvement in images that used intravenous contrast, we found that mpMRI in the PRECISION trial was of sufficient diagnostic quality (PI-QUAL score ≥3) for 95% of the scans.
PI-QUAL is a novel scoring system based on objective criteria that can be used to assess the quality of multiparametric magnetic resonance imaging (mpMRI) of the prostate. An assessment system can facilitate quality improvements for scanners and centres. The greatest variability in mpMRI quality across centres that participated in the PRECISION trial was for dynamic contrast–enhanced sequences. Further validation of this scoring system is warranted.
A very limited amount of research has examined intermittent fasting (IF) programs, such as time-restricted feeding (TRF), in active populations.
Our objective was to examine the effects of TRF, with ...or without β-hydroxy β-methylbutyrate (HMB) supplementation, during resistance training (RT).
This study employed a randomized, placebo-controlled, reduced factorial design and was double-blind with respect to supplementation in TRF groups. Resistance-trained females were randomly assigned to a control diet (CD), TRF, or TRF plus 3 g/d HMB (TRFHMB). TRF groups consumed all calories between 1200 h and 2000 h, whereas the CD group ate regularly from breakfast until the end of the day. All groups completed 8 wk of supervised RT and consumed supplemental whey protein. Body composition, muscular performance, dietary intake, physical activity, and physiological variables were assessed. Data were analyzed prior to unblinding using mixed models and both intention-to-treat (ITT) and per protocol (PP) frameworks.
Forty participants were included in ITT, and 24 were included in PP. Energy and protein intake (1.6 g/kg/d) did not differ between groups despite different feeding durations (TRF and TRFHMB: ∼7.5 h/d; CD: ∼13 h/d). Comparable fat-free mass (FFM) accretion (+2% to 3% relative to baseline) and skeletal muscle hypertrophy occurred in all groups. Differential effects on fat mass (CD: +2%; TRF: −2% to −4%; TRFHMB: −4% to −7%) were statistically significant in the PP analysis, but not ITT. Muscular performance improved without differences between groups. No changes in physiological variables occurred in any group, and minimal side effects were reported.
IF, in the form of TRF, did not attenuate RT adaptations in resistance-trained females. Similar FFM accretion, skeletal muscle hypertrophy, and muscular performance improvements can be achieved with dramatically different feeding programs that contain similar energy and protein content during RT. Supplemental HMB during fasting periods of TRF did not definitively improve outcomes. This study was prospectively registered at clinicaltrials.gov as NCT03404271.
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