Accumulation of copy number alterations and clinical progression across advanced prostate cancer.

BACKGROUND: Genomic copy number alterations commonly occur in prostate cancer and are one measure of genomic instability. The clinical implication of copy number change in advanced prostate cancer, which defines a wide spectrum of disease from high-risk localised to metastatic, is unknown. METHODS: We performed copy number profiling on 688 tumour regions from 300 patients, who presented with advanced prostate cancer prior to the start of long-term androgen deprivation therapy (ADT), in the control arm of the prospective randomised STAMPEDE trial. Patients were categorised into metastatic states as follows; high-risk non-metastatic with or without local lymph node involvement, or metastatic low/high volume. We followed up patients for a median of 7 years. Univariable and multivariable Cox survival models were fitted to estimate the association between the burden of copy number alteration as a continuous variable and the hazard of death or disease progression. RESULTS: The burden of copy number alterations positively associated with radiologically evident distant metastases at diagnosis (P=0.00006) and showed a non-linear relationship with clinical outcome on univariable and multivariable analysis, characterised by a sharp increase in the relative risk of progression (P=0.003) and death (P=0.045) for each unit increase, stabilising into more modest increases with higher copy number burdens. This association between copy number burden and outcome was similar in each metastatic state. Copy number loss occurred significantly more frequently than gain at the lowest copy number burden quartile (q=4.1 × 10-6). Loss of segments in chromosome 5q21-22 and gains at 8q21-24, respectively including CHD1 and cMYC occurred more frequently in cases with higher copy number alteration (for either region: Kolmogorov-Smirnov distance, 0.5; adjusted P<0.0001). Copy number alterations showed variability across tumour regions in the same prostate. This variance associated with increased risk of distant metastases (Kruskal-Wallis test P=0.037). CONCLUSIONS: Copy number alteration in advanced prostate cancer associates with increased risk of metastases at diagnosis. Accumulation of a limited number of copy number alterations associates with most of the increased risk of disease progression and death. The increased likelihood of involvement of specific segments in high copy number alteration burden cancers may suggest an order underlying the accumulation of copy number changes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00268476 , registered on December 22, 2005. EudraCT  2004-000193-31 , registered on October 4, 2004.

Clinically Applicable Assessment of Tisagenlecleucel CAR T Cell Treatment by Digital Droplet PCR for Copy Number Variant Assessment.

Chimeric antigen receptor (CAR) T cell therapy is an innovative immunotherapy for treating cancers in both children and adults with proven utility in numerous clinical trials. Significantly, some CAR T cell therapies have now been approved by relevant national regulatory bodies across numerous countries for clinical therapeutic use outside of clinical trials. One such recently licensed product is tisagenlecleucel, a CAR T therapy approved for the treatment of B-cell acute lymphoblastic leukemia (B-ALL) using autologous T cells from the patient. The genetically engineered T cells target a protein called CD19, common to B cells, through a CAR incorporating a 4-1BB costimulatory domain to improve response. Since tisagenlecleucel is now a standard of care treatment for B-ALL, it is clinically essential to be able to accurately monitor these CAR T cells in patients. Assessment of the copy number variant (CNV) of the CAR T cell products allows this within a clinically acceptable timeframe for optimal patient benefit. However, no standardized method with high reproducibility and efficiency has been described within a routine clinical laboratory setting. Here, we demonstrated a novel digital droplet PCR (ddPCR)-based methodology for the study of CNV (ddPCR-CNV) in 4-1BB CD19-specific CAR T cells with universal applicability across clinical diagnostic laboratories.

Ten simple rules for improving communication among scientists.

Communication is a fundamental part of scientific development and methodology. With the advancement of the internet and social networks, communication has become rapid and sometimes overwhelming, especially in science. It is important to provide scientists with useful, effective, and dynamic tools to establish and build a fluid communication framework that allows for scientific advancement. Therefore, in this article, we present advice and recommendations that can help promote and improve science communication while respecting an adequate balance in the degree of commitment toward collaborative work. We have developed 10 rules shown in increasing order of commitment that are grouped into 3 key categories: (1) speak (based on active participation); (2) join (based on joining scientific groups); and (3) assess (based on the analysis and retrospective consideration of the weaknesses and strengths). We include examples and resources that provide actionable strategies for involvement and engagement with science communication, from basic steps to more advanced, introspective, and long-term commitments. Overall, we aim to help spread science from within and encourage and engage scientists to become involved in science communication effectively and dynamically.

Interspecific hybrids show a reduced adaptive potential under DNA damaging conditions.

Hybridization may increase the probability of adaptation to extreme stresses. This advantage could be caused by an increased genome plasticity in hybrids, which could accelerate the search for adaptive mutations. High ultraviolet (UV) radiation is a particular challenge in terms of adaptation because it affects the viability of organisms by directly damaging DNA, while also challenging future generations by increasing mutation rate. Here we test whether hybridization accelerates adaptive evolution in response to DNA damage, using yeast as a model. We exposed 180 populations of hybrids between species (Saccharomyces cerevisiae and Saccharomyces paradoxus) and their parental strains to UV mimetic and control conditions for approximately 100 generations. Although we found that adaptation occurs in both hybrids and parents, hybrids achieved a lower rate of adaptation, contrary to our expectations. Adaptation to DNA damage conditions comes with a large and similar cost for parents and hybrids, suggesting that this cost is not responsible for the lower adaptability of hybrids. We suggest that the lower adaptive potential of hybrids in this condition may result from the interaction between DNA damage and the inherent genetic instability of hybrids.

Similarities in biological processes can be used to bridge ecology and molecular biology.

Much of the research in biology aims to understand the origin of diversity. Naturally, ecological diversity was the first object of study, but we now have the necessary tools to probe diversity at molecular scales. The inherent differences in how we study diversity at different scales caused the disciplines of biology to be organized around these levels, from molecular biology to ecology. Here, we illustrate that there are key properties of each scale that emerge from the interactions of simpler components and that these properties are often shared across different levels of organization. This means that ideas from one level of organization can be an inspiration for novel hypotheses to study phenomena at another level. We illustrate this concept with examples of events at the molecular level that have analogs at the organismal or ecological level and vice versa. Through these examples, we illustrate that biological processes at different organization levels are governed by general rules. The study of the same phenomena at different scales could enrich our work through a multidisciplinary approach, which should be a staple in the training of future scientists.

Catechol-O-methyltransferase val158met genotype determines effect of reboxetine on emotional memory in healthy male volunteers.

BACKGROUND: Catechol-O-methyltransferase (COMT) metabolizes catecholamines in the prefrontal cortex (PFC). A common polymorphism in the COMT gene (COMT val158met) has pleiotropic effects on cognitive and emotional processing. The met allele has been associated with enhanced cognitive processing but impaired emotional processing relative to the val allele. METHODS: We genotyped healthy, white men in relation to the COMT val158met polymorphism. They were given a single 4 mg dose of the selective noradrenaline reuptake inhibitor (NRI) reboxetine or placebo in a randomized, double-blind between-subjects model and then completed an emotional memory task 2 hours later. RESULTS: We included 75 men in the study; 41 received reboxetine and 34 received placebo. In the placebo group, met/met carriers did not demonstrate the usual memory advantage for emotional stimuli that was observed in val carriers. Reboxetine restored this emotional enhancement of memory in met/met carriers, but had no significant effect in val carriers. LIMITATIONS: We studied only men, thus limiting the generalizability of our findings. We also relied on self-reported responses to screening questions to establish healthy volunteer status, and in spite of the double-blind design, participants were significantly better than chance at identifying their intervention allocation. CONCLUSION: Emotional memory is impaired in healthy met homozygotes and selectively improved in this group by reboxetine. This has potential translational implications for the use of reboxetine, which is currently licensed as an antidepressant in several countries, and edivoxetine, a new selective NRI currently in development.

Alpha 2B adrenoceptor genotype moderates effect of reboxetine on negative emotional memory bias in healthy volunteers.

Evidence suggests that emotional memory plays a role in the pathophysiology of depression/anxiety disorders. Noradrenaline crucially modulates emotional memory. Genetic variants involved in noradrenergic signaling contribute to individual differences in emotional memory and vulnerability to psychopathology. A functional deletion polymorphism in the α-2B adrenoceptor gene (ADRA2B) has been linked to emotional memory and post-traumatic stress disorder. The noradrenaline reuptake inhibitor reboxetine attenuates enhanced memory for negative stimuli in healthy and depressed individuals. We examined whether the effect of reboxetine on emotional memory in healthy individuals would be moderated by ADRA2B genotype. ADRA2B deletion carriers demonstrated enhanced emotional memory for negative stimuli compared with deletion noncarriers, consistent with prior studies. Reboxetine attenuated enhanced memory for negative stimuli in deletion noncarriers but had no significant effect in deletion carriers. This is the first demonstration of genetic variation influencing antidepressant drug effects on emotional processing in healthy humans.

Transporte intraabdominal y endovaginal de paquetes de droga (body packer y body pusher) / Intra-abdominal and endovaginal transport of drug packets (body packer and body pusher)

El transporte endovaginal de paquetes de droga (body pusher) es una variedad poco frecuente de tráfico intracorporal de sustancias ilegales (body packer). Presentamos 2 casos de transporte simultáneo intraabdominal (body packer) y endovaginal (body pusher) de envoltorios de droga. El manejo conservador, basado en la administración de medicación laxante, extracción cuidadosa de los paquetes intravaginales y observación clínica estrecha -junto a pruebas radiológicas de confirmación- representa una aproximación terapéutica segura y eficaz para este tipo de pacientes. La sospecha y tratamiento tempranos de los body pusher, con importantes complicaciones potenciales -principalmente, intoxicación grave por cocaína-resultan esenciales(AU)

Vaginal smuggling of drug containers (body pusher) is a relatively uncommon subtype of intraabdominal trafficking of illicit substances (body packer). We report two cases of drug smuggling by simultaneous internal (body packer) and vaginal (body pusher) concealment of drug packages. Conservative management, based on laxative treatment, careful extraction of endovaginal packets and close clinical observation -with radiological tests for confirmation- is a safe and useful therapeutic approach for these patients. Early suspicion and treatment of body pusher, with severe potential complications -mainly, acute cocaine intoxication-, remains essential(AU)