Distinct cytokine profiles across trajectories of self-perceived cognitive impairment among early-stage breast cancer survivors.

The aim of the current study is to identify distinct cytokine profiles in relation to self-perceived cognitive trajectories. In our study cohort (n = 128), early-stage breast cancer patients were categorized into no impairment reported, acute, delayed, persistent and intermittent cognitive decline respectively. Pro-inflammatory cytokines were elevated compared to baseline; with TNF-α implicated in the acute cognitive trajectory while IL-6 and IL-8 were involved in the persistent cognitive trajectory. Our findings help to further our understanding of cytokine profiles implicated in cancer-related cognitive impairment (CRCI) and support the use of cytokine levels as biomarkers of cognitive decline over time

Prechemotherapy Levels of Plasma Dehydroepiandrosterone and Its Sulfated Form as Predictors of Cancer-Related Cognitive Impairment in Patients with Breast Cancer Receiving Chemotherapy.

Study objectiveDehydroepiandrosterone (DHEA) and its sulfated form (DHEAS)-jointly referred to as DHEA(S)-are neurosteroids known to regulate brain development and function that have been found to be positively correlated with cognitive function. It is unknown whether prechemotherapy plasma DHEA(S) levels are associated with the onset of cancer-related cognitive impairment (CRCI). The objective of this study was to evaluate whether an association exists between prechemotherapy plasma DHEA(S) levels and onset of CRCI in patients with breast cancer receiving chemotherapy.DesignMulticenter, prospective cohort study.SettingTwo specialized cancer centers in Singapore.PatientsEighty-one patients with early-stage breast cancer (stages I-III) who had no prior exposure to chemotherapy and/or radiotherapy and were scheduled to receive anthracycline-based or taxane-based chemotherapy treatment with curative intent.Measurements and main resultsPatients completed assessments for self-perceived and objective cognitive function at three time points: prechemotherapy (T1), during chemotherapy (T2), and after chemotherapy (T3). Plasma samples were collected prior to chemotherapy, and DHEA(S) levels were quantified by using ultra-high-performance liquid chromatography-tandem mass spectrometry. Multivariable logistic regression was used to adjust for clinically important factors and to evaluate the association between prechemotherapy plasma DHEA(S) levels and CRCI. Mean ± SD age was 48.9 ± 9.3 years, with 27.8% of patients experiencing clinically significant cognitive impairment based on global Functional Assessment of Cancer Therapy-Cognitive Function scores. The mean ± SD prechemotherapy plasma DHEAS and DHEA levels were 1.61 ± 0.91 μmol/L and 19.21 ± 13.13 nmol/L, respectively. Prechemotherapy DHEAS levels were found to be associated with impairment in the self-perceived cognitive domains of verbal fluency (adjusted odds ratio [OR] 0.27, 95% confidence interval [CI] 0.08-0.96) and mental acuity (adjusted OR 0.25, 95% CI 0.08-0.74). Conversely, DHEA levels were not associated with impairment in any cognitive subdomains.ConclusionOur findings suggest that patients with higher prechemotherapy DHEAS levels had lower odds of developing self-perceived cognitive impairment. Future studies are required to further investigate the effect of DHEA(S) on specific cognitive domains and to validate our findings in independent cohorts

Replication and Meta-analysis of the Association between BDNF Val66Met Polymorphism and Cognitive Impairment in Patients Receiving Chemotherapy.

Cancer-related cognitive impairment (CRCI) adversely affects cancer patients. We had previously demonstrated that the BDNF Val66Met genetic polymorphism is associated with lower odds of subjective CRCI in the multitasking and verbal ability domains among breast cancer patients receiving chemotherapy. To further assess our previous findings, we evaluated the association of BDNF Val66Met polymorphism with subjective and objective CRCI in a temporally separate cohort of patients and pooled findings from both the original (n = 145) and current (n = 193) cohorts in a meta-analysis. Subjective CRCI was assessed using FACT-Cog. Objective CRCI was evaluated using computerized neuropsychological tests. Genotyping was carried out using Sanger sequencing. The association of BDNF Val66Met genotypes and CRCI was examined with logistic regression. A fixed-effect meta-analysis was conducted using the inverse variance method. In the meta-analysis (n = 338), significantly lower odds of CRCI were associated with Met allele carriers based on the global FACT-Cog score (OR = 0.52, 95% CI 0.29-0.94). Furthermore, Met allele carriers were at lower odds of developing impairment in the domains of memory (OR = 0.34, 95% CI: 0.17-0.70), multitasking (OR = 0.33, 95% CI: 0.18-0.59), and verbal ability (OR = 0.46, 95% CI: 0.24-0.88). Consistent with the previous study, lower odds of subjective CRCI among patients with the BDNF Met allele was observed after adjusting for potential confounders in the multitasking (OR = 0.30, 95% CI: 0.14-0.67) domain. In conclusion, carriers of the BDNF Met allele were protected against global subjective CRCI, particularly in the domains of memory, multitasking, and verbal ability. Our findings further contribute to the understanding of CRCI pathophysiology

The spotted gar genome illuminates vertebrate evolution and facilitates human-teleost comparisons

To connect human biology to fish biomedical models, we sequenced the genome of spotted gar (Lepisosteus oculatus), whose lineage diverged from teleosts before teleost genome duplication (TGD). The slowly evolving gar genome has conserved in content and size many entire chromosomes from bony vertebrate ancestors. Gar bridges teleosts to tetrapods by illuminating the evolution of immunity, mineralization and development (mediated, for example, by Hox, ParaHox and microRNA genes). Numerous conserved noncoding elements (CNEs; often cis regulatory) undetectable in direct human-teleost comparisons become apparent using gar: functional studies uncovered conserved roles for such cryptic CNEs, facilitating annotation of sequences identified in human genome-wide association studies. Transcriptomic analyses showed that the sums of expression domains and expression levels for duplicated teleost genes often approximate the patterns and levels of expression for gar genes, consistent with subfunctionalization. The gar genome provides a resource for understanding evolution after genome duplication, the origin of vertebrate genomes and the function of human regulatory sequences

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

EVALUATING ASSOCIATION OF BIOMARKERS WITH POST-CANCER TREATMENT SIDE EFFECTS

Ph.DDOCTOR OF PHILOSOPHY (FOS