Arsenite toxicity is regulated by queuine availability and oxidation-induced reprogramming of the human tRNA epitranscriptome.

Cells respond to environmental stress by regulating gene expression at the level of both transcription and translation. The ∼50 modified ribonucleotides of the human epitranscriptome contribute to the latter, with mounting evidence that dynamic regulation of transfer RNA (tRNA) wobble modifications leads to selective translation of stress response proteins from codon-biased genes. Here we show that the response of human hepatocellular carcinoma cells to arsenite exposure is regulated by the availability of queuine, a micronutrient and essential precursor to the wobble modification queuosine (Q) on tRNAs reading GUN codons. Among oxidizing and alkylating agents at equitoxic concentrations, arsenite exposure caused an oxidant-specific increase in Q that correlated with up-regulation of proteins from codon-biased genes involved in energy metabolism. Limiting queuine increased arsenite-induced cell death, altered translation, increased reactive oxygen species levels, and caused mitochondrial dysfunction. In addition to demonstrating an epitranscriptomic facet of arsenite toxicity and response, our results highlight the links between environmental exposures, stress tolerance, RNA modifications, and micronutrients.

Rapid recruitment of p53 to DNA damage sites directs DNA repair choice and integrity.

SignificanceOur work focuses on the critical longstanding question of the nontranscriptional role of p53 in tumor suppression. We demonstrate here that poly(ADP-ribose) polymerase (PARP)-dependent modification of p53 enables rapid recruitment of p53 to damage sites, where it in turn directs early repair pathway selection. Specifically, p53-mediated recruitment of 53BP1 at early time points promotes nonhomologous end joining over the more error-prone microhomology end-joining. Similarly, p53 directs nucleotide excision repair by mediating DDB1 recruitment. This property of p53 also correlates with tumor suppression in vivo. Our study provides mechanistic insight into how certain transcriptionally deficient p53 mutants may retain tumor-suppressive functions through regulating the DNA damage response.

Incorporating low haemoglobin into a risk prediction model for conversion in minimally invasive gynaecologic oncology surgeries.

BACKGROUND: A well-known complication of laparoscopic management of gynaecologic masses and cancers is the need to perform an intraoperative conversion to laparotomy. The purpose of this study was to identify novel patient risk factors for conversion from minimally invasive to open surgeries for gynaecologic oncology operations. METHODS: This was a retrospective cohort study of 1356 patients ≥18 years of age who underwent surgeries for gynaecologic masses or malignancies between February 2015 and May 2020 at a single academic medical centre. Multivariable logistic regression was used to study the effects of older age, higher body mass index (BMI), higher American Society of Anaesthesiologist (ASA) physical status, and lower preoperative haemoglobin (Hb) on odds of converting from minimally invasive to open surgery. Receiver operating characteristic (ROC) curve analysis assessed the discriminatory ability of a risk prediction model for conversion. RESULTS: A total of 704 planned minimally invasive surgeries were included with an overall conversion rate of 6.1% (43/704). Preoperative Hb was lowest for conversion cases, compared to minimally invasive and open cases (11.6 ± 1.9 vs 12.8 ± 1.5 vs 11.8 ± 1.9 g/dL, p<.001). Patients with preoperative Hb <10 g/dL had an adjusted odds ratio (OR) of 3.94 (CI: 1.65-9.41, p=.002) for conversion while patients with BMI ≥30 kg/m2 had an adjusted OR of 2.86 (CI: 1.50-5.46, p=.001) for conversion. ROC curve analysis using predictive variables of age >50 years, BMI ≥30 kg/m2, ASA physical status >2, and preoperative haemoglobin <10 g/dL resulted in an area under the ROC curve of 0.71. Patients with 2 or more risk factors were at highest risk of requiring an intraoperative conversion (12.0%). CONCLUSIONS: Lower preoperative haemoglobin is a novel risk factor for conversion from minimally invasive to open gynaecologic oncology surgeries and stratifying patients based on conversion risk may be helpful for preoperative planning.

Minimally invasive surgery for management of gynaecologic masses (masses that affect the female reproductive organs) is often preferred over more invasive surgery, because it involves smaller surgical incisions and can have overall better recovery time. However, one unwanted complication of minimally invasive surgery is the need to unexpectedly convert the surgery to an open surgery, which entails a larger incision and is a higher risk procedure. In our study, we aimed to find patient characteristics that are associated with higher risk of converting a minimally invasive surgery to an open surgery. Our study identified that lower levels of preoperative haemoglobin, the protein that carries oxygen within red blood cells, is correlated with higher risk for conversion. This new risk factor was used with other known risk factors, including having higher age, higher body mass index, and higher baseline medical complexity to create a model to help surgical teams identify high risk patients for conversion. This model may be useful for surgical planning before and during the operation to improve patient outcomes.

Efficacy and safety of rucaparib treatment in patients with BRCA-mutated, relapsed ovarian cancer: final results from Study 10.

BACKGROUND: Study 10, a four-part Phase 1/2 study, evaluated oral rucaparib monotherapy in patients with advanced solid tumours. Here we report the final efficacy and safety results in heavily pretreated patients with ovarian cancer who received rucaparib in Study 10 Parts 2A and 2B. METHODS: Parts 2A and 2B (Phase 2 portions) enrolled patients with relapsed, high-grade, platinum-sensitive or platinum-resistant, BRCA-mutated ovarian cancer who had received 2-4 (Part 2A) or 3-4 (Part 2B) prior chemotherapies. Patients received oral rucaparib 600 mg twice daily (starting dose). The primary endpoint was the investigator-assessed objective response rate (ORR) by RECIST v1.1. RESULTS: Fifty-four patients were enrolled: 42 in Part 2A (all had platinum-sensitive disease) and 12 in Part 2B (4 with platinum-sensitive disease; 8 with platinum-resistant disease). ORR was 59.3% (95% CI 45.0-72.4%). The median time to onset of the most common nonhaematological treatment-emergent adverse events (TEAEs) was typically early (<56 days) and was later for haematological TEAEs (53-84 days). The median duration of grade ≥3 TEAEs was ≤13 days. CONCLUSIONS: In patients with relapsed, platinum-sensitive or platinum-resistant germline BRCA-mutant high-grade ovarian cancer who had received ≥2 prior chemotherapies, rucaparib had robust antitumour activity with a safety profile consistent with prior reports. CLINICAL TRIAL REGISTRATION: NCT01482715.

Combination of GWAS and FST-based approaches identified loci associated with economic traits in sugarcane.

Sugarcane is a globally important plant for both sugar and biofuel production. Although conventional breeding has played an important role in increasing the productivity of sugarcane, it takes a long time to achieve breeding goals such as high yield and resistant to diseases. Molecular breeding, including marker-assisted breeding and genomic selection, can accelerate genetic improvement by selecting elites at the seedling stage with DNA markers. However, only a few DNA markers associated with important traits were identified in sugarcane. The purpose of this study was to identify DNA markers associated with sugar content, stalk diameter, and sugarcane top borer resistance. The sugarcane samples with trait records were genotyped using the restriction site-associated DNA sequencing (RADseq) technology. Using FST analysis and genome-wide association study (GWAS), a total of 9, 23 and 9 DNA variants (single nucleotide polymorphisms (SNPs)/insertions and deletions (indels)) were associated with sugar content, stalk diameter, and sugarcane top borer resistance, respectively. The identified genetic variants were on different chromosomes, suggesting that these traits are complex and determined by multiple genetic factors. These DNA markers identified by both approaches have the potential to be used in selecting elite clones at the seeding stage in our sugarcane breeding program to accelerate genetic improvement. Certainly, it is essential to verify the reliability of the identified DNA markers associated with traits before they are used in molecular breeding in other populations.

A Runx1-enhancer Element eR1 Identified Lineage Restricted Mammary Luminal Stem Cells.

Mammary gland homeostasis is maintained by adult tissue stem-progenitor cells residing within the luminal and basal epithelia. Dysregulation of mammary stem cells is a key mechanism for cancer development. However, stem cell characterization is challenging because reporter models using cell-specific promoters do not fully recapitulate the mammary stem cell populations. We previously found that a 270-basepair Runx1 enhancer element, named eR1, marked stem cells in the blood and stomach. Here, we identified eR1 activity in a rare subpopulation of the ERα-negative luminal epithelium in mouse mammary glands. Lineage-tracing using an eR1-CreERT2 mouse model revealed that eR1+ luminal cells generated the entire luminal lineage and milk-secreting alveoli-eR1 therefore specifically marks lineage-restricted luminal stem cells. eR1-targeted-conditional knockout of Runx1 led to the expansion of luminal epithelial cells, accompanied by elevated ERα expression. Our findings demonstrate a definitive role for Runx1 in the regulation of the eR1-positive luminal stem cell proliferation during mammary homeostasis. Our findings identify a mechanistic link for Runx1 in stem cell proliferation and its dysregulation in breast cancer. Runx1 inactivation is therefore likely to be an early hit in the cell-of-origin of ERα+ luminal type breast cancer.

Integrative multi-omics landscape of fluoxetine action across 27 brain regions reveals global increase in energy metabolism and region-specific chromatin remodelling.

Depression and anxiety are major global health burdens. Although SSRIs targeting the serotonergic system are prescribed over 200 million times annually, they have variable therapeutic efficacy and side effects, and mechanisms of action remain incompletely understood. Here, we comprehensively characterise the molecular landscape of gene regulatory changes associated with fluoxetine, a widely-used SSRI. We performed multimodal analysis of SSRI response in 27 mammalian brain regions using 310 bulk RNA-seq and H3K27ac ChIP-seq datasets, followed by in-depth characterisation of two hippocampal regions using single-cell RNA-seq (20 datasets). Remarkably, fluoxetine induced profound region-specific shifts in gene expression and chromatin state, including in the nucleus accumbens shell, locus coeruleus and septal areas, as well as in more well-studied regions such as the raphe and hippocampal dentate gyrus. Expression changes were strongly enriched at GWAS loci for depression and antidepressant drug response, stressing the relevance to human phenotypes. We observed differential expression at dozens of signalling receptors and pathways, many of which are previously unknown. Single-cell analysis revealed stark differences in fluoxetine response between the dorsal and ventral hippocampal dentate gyri, particularly in oligodendrocytes, mossy cells and inhibitory neurons. Across diverse brain regions, integrative omics analysis consistently suggested increased energy metabolism via oxidative phosphorylation and mitochondrial changes, which we corroborated in vitro; this may thus constitute a shared mechanism of action of fluoxetine. Similarly, we observed pervasive chromatin remodelling signatures across the brain. Our study reveals unexpected regional and cell type-specific heterogeneity in SSRI action, highlights under-studied brain regions that may play a major role in antidepressant response, and provides a rich resource of candidate cell types, genes, gene regulatory elements and pathways for mechanistic analysis and identifying new therapeutic targets for depression and anxiety.

Same day service: A genetic testing station model to improve germline genetic testing in patients with ovarian cancer.

OBJECTIVE: Genetic testing for ovarian cancer (OC) patients is essential to consideration of PARP inhibitor therapy. To improve access, we piloted a Genetic Testing Station (GTS) allowing patients to have a same-day genetic testing visit facilitated by Genetic Counselor Assistants (GCAs) under the supervision of Genetic Counselors (GCs). METHODS: The GTS was implemented December 2018 and operated through February 2020. Gynecologic Oncologists offered ovarian cancer patients a same-day GTS visit with a GCA. The patient received education via videos designed by GCs and then provided consent, a brief family history, and a sample for a standardized 133-gene panel. Results were provided by a GC. Patients were retrospectively identified by querying the medical record for OC patients seen 12 months prior to and 18 months after GTS implementation. RESULTS: A total of 482 patients pre-GTS were compared to 625 patients post-GTS. Genetic testing increased from 68.5% to 75.4% (p = 0.012) after implementation, primarily in patients with epithelial histologies (80% vs 89% in pre-GTS vs post-GTS, p = 0.005). Time from referral for genetic testing to obtaining results was evaluated in the post-GTS cohort, comparing patients who had traditional counseling to those who utilized the GTS. Time to obtaining results was 21 days in the GTS group (95% CI [10, 34]) compared to 56 days (95% CI [41,76]) in the traditional genetic counseling group. CONCLUSIONS: The GTS reduces barriers to care and facilitates discussion of precision treatment within a timely fashion while optimizing GC clinic time. Access improvement remains integral to improving uptake of genetic testing.

Identification of distinct symptom profiles in patients with gynecologic cancers using a pre-specified symptom cluster.

PURPOSE: Pain, fatigue, sleep disturbance, and depression are four of the most common symptoms in patients with gynecologic cancer. The purposes were to identify subgroups of patients with distinct co-occurring pain, fatigue, sleep disturbance, and depression profiles (i.e., pre-specified symptom cluster) in a sample of patients with gynecologic cancer receiving chemotherapy and assess for differences in demographic and clinical characteristics, as well as the severity of other common symptoms and QOL outcomes among these subgroups. METHODS: Patients completed symptom questionnaires prior to their second or third cycle of chemotherapy. Latent profile analysis was used to identify subgroups of patients using the pre-specified symptom cluster. Parametric and nonparametric tests were used to evaluate for differences between the subgroups. RESULTS: In the sample of 233 patients, two distinct latent classes were identified (i.e., low (64.8%) and high (35.2%)) indicating lower and higher levels of symptom burden. Patients in high class were younger, had child care responsibilities, were unemployed, and had a lower annual income. In addition, these women had a higher body mass index, a higher comorbidity burden, and a lower functional status. Patients in the high class reported higher levels of anxiety, as well as lower levels of energy and cognitive function and poorer quality of life scores. CONCLUSIONS: This study identified a number of modifiable and non-modifiable risk factors associated with membership in the high class. Clinicians can use this information to refer patients to dieticians and physical therapists for tailored interventions.

Up-regulated cytotrophoblast DOCK4 contributes to over-invasion in placenta accreta spectrum.

In humans, a subset of placental cytotrophoblasts (CTBs) invades the uterus and its vasculature, anchoring the pregnancy and ensuring adequate blood flow to the fetus. Appropriate depth is critical. Shallow invasion increases the risk of pregnancy complications, e.g., severe preeclampsia. Overly deep invasion, the hallmark of placenta accreta spectrum (PAS), increases the risk of preterm delivery, hemorrhage, and death. Previously a rare condition, the incidence of PAS has increased to 1:731 pregnancies, likely due to the rise in uterine surgeries (e.g., Cesarean sections). CTBs track along scars deep into the myometrium and beyond. Here we compared the global gene expression patterns of CTBs from PAS cases to gestational age-matched control cells that invaded to the normal depth from preterm birth (PTB) deliveries. The messenger RNA (mRNA) encoding the guanine nucleotide exchange factor, DOCK4, mutations of which promote cancer cell invasion and angiogenesis, was the most highly up-regulated molecule in PAS samples. Overexpression of DOCK4 increased CTB invasiveness, consistent with the PAS phenotype. Also, this analysis identified other genes with significantly altered expression in this disorder, potential biomarkers. These data suggest that CTBs from PAS cases up-regulate a cancer-like proinvasion mechanism, suggesting molecular as well as phenotypic similarities in the two pathologies.

Transposon-induced epigenetic silencing in the X chromosome as a novel form of dmrt1 expression regulation during sex determination in the fighting fish.

BACKGROUND: Fishes are the one of the most diverse groups of animals with respect to their modes of sex determination, providing unique models for uncovering the evolutionary and molecular mechanisms underlying sex determination and reversal. Here, we have investigated how sex is determined in a species of both commercial and ecological importance, the Siamese fighting fish Betta splendens. RESULTS: We conducted association mapping on four commercial and two wild populations of B. splendens. In three of the four commercial populations, the master sex determining (MSD) locus was found to be located in a region of ~ 80 kb on LG2 which harbours five protein coding genes, including dmrt1, a gene involved in male sex determination in different animal taxa. In these fish, dmrt1 shows a male-biased gonadal expression from undifferentiated stages to adult organs and the knockout of this gene resulted in ovarian development in XY genotypes. Genome sequencing of XX and YY genotypes identified a transposon, drbx1, inserted into the fourth intron of the X-linked dmrt1 allele. Methylation assays revealed that epigenetic changes induced by drbx1 spread out to the promoter region of dmrt1. In addition, drbx1 being inserted between two closely linked cis-regulatory elements reduced their enhancer activities. Thus, epigenetic changes, induced by drbx1, contribute to the reduced expression of the X-linked dmrt1 allele, leading to female development. This represents a previously undescribed solution in animals relying on dmrt1 function for sex determination. Differentiation between the X and Y chromosomes is limited to a small region of ~ 200 kb surrounding the MSD gene. Recombination suppression spread slightly out of the SD locus. However, this mechanism was not found in the fourth commercial stock we studied, or in the two wild populations analysed, suggesting that it originated recently during domestication. CONCLUSIONS: Taken together, our data provide novel insights into the role of epigenetic regulation of dmrt1 in sex determination and turnover of SD systems and suggest that fighting fish are a suitable model to study the initial stages of sex chromosome evolution.

Transcriptomic Responses of Salvia hispanica to the Infestation of Red Spider Mites (Tetranychus neocaledonicus).

Salvia hispanica (chia) is a highly nutritious food source and has gained popularity due to its high omega-3 fatty acid content. Red spider mites are a serious problem in the production of S. hispanica. However, no study has been conducted to analyze the defensive response to the infestation of red spider mites in S. hispanica. To elucidate the molecular mechanisms of the defensive response of S. hispanica to red spider mites, we performed a transcriptomic analysis of S. hispanica when infested by red spider mites. In the comparative assessment of leaf transcriptomes, a total of 1743 differentially expressed genes (DEGs) were identified between control and mite-infested S. hispanica. From these, 1208 (69%) transcripts were upregulated and 535 (31%) were downregulated. The DEGs included transcription factors, defense hormones, and secondary metabolites that were either suppressed or activated in response to spider mite herbivory. Gene Ontology (GO) enrichment analysis revealed that plant secondary metabolites, such as glucosinolates, and signaling pathways, including the jasmonic acid signaling pathway, may play an important role in the defense against red spider mites. This study provides novel insights into the defense response of S. hispanica to insect herbivory and could be a resource for the improvement of pest resistance in the chia.

IgE-mediated fish allergy in Singaporean children.

BACKGROUND: Fish is one of the common causes of food allergy and there is limited literature about fish allergy in Singapore. OBJECTIVE: We aimed to describe the demographics, clinical features, and natural history of children with IgE-mediated fish allergy. METHODS: A retrospective review was conducted for children diagnosed with fish allergy in a tertiary pediatric hospital in Singapore between 2015 and 2020. RESULTS: The diagnosis of fish allergy was made in 108 patients based on a convincing history of IgE-mediated allergic reaction and a positive skin prick test. The median age at first reaction was 12 months (range 6-168) with most reacting on first ingestion (62.0%). The most common fish causing reactions were threadfin (48.1%), salmon (33.3%) and cod (31.5%). Majority presented with cutaneous symptoms (97.2%). Anaphylaxis occurred in 6.5%. Five were mono-sensitized (4.6%), 77 were oligo-sensitized (71.3%) and 26 were polysensitized (24.1%). Most can tolerate another species of fish (75.9%), most commonly salmon (37.0%), tuna (24.1%) and cod (22.2%). Median duration of follow up was 24 months (range 0-176). Twenty-eight out of 108 children (25.9%) acquired natural tolerance to index fish at a median age of 60 months (range 18-159). CONCLUSIONS: Most children with fish allergy can tolerate at least one other species of fish and resolution of fish allergy is possible. Thus, it is important to follow-up with an allergist to evaluate which fish species can be included in their diet to avoid unnecessary dietary restrictions.

Genomic Basis of Striking Fin Shapes and Colors in the Fighting Fish.

Resolving the genomic basis underlying phenotypic variations is a question of great importance in evolutionary biology. However, understanding how genotypes determine the phenotypes is still challenging. Centuries of artificial selective breeding for beauty and aggression resulted in a plethora of colors, long-fin varieties, and hyper-aggressive behavior in the air-breathing Siamese fighting fish (Betta splendens), supplying an excellent system for studying the genomic basis of phenotypic variations. Combining whole-genome sequencing, quantitative trait loci mapping, genome-wide association studies, and genome editing, we investigated the genomic basis of huge morphological variation in fins and striking differences in coloration in the fighting fish. Results revealed that the double tail, elephant ear, albino, and fin spot mutants each were determined by single major-effect loci. The elephant ear phenotype was likely related to differential expression of a potassium ion channel gene, kcnh8. The albinotic phenotype was likely linked to a cis-regulatory element acting on the mitfa gene and the double-tail mutant was suggested to be caused by a deletion in a zic1/zic4 coenhancer. Our data highlight that major loci and cis-regulatory elements play important roles in bringing about phenotypic innovations and establish Bettas as new powerful model to study the genomic basis of evolved changes.

The role of adjuvant radiation therapy in older patients with node-positive vulvar cancer: A national cancer database analysis.

OBJECTIVE: We sought to evaluate whether the survival benefit of adjuvant radiotherapy in patients with node-positive vulvar cancer is maintained in older patients, who comprise a large subgroup of patients with vulvar cancer. METHODS: The National Cancer Database (NCDB) was queried for patients aged 65 years or older, who were diagnosed with vulvar squamous cell carcinoma from 2004 to 2017 and underwent surgery with confirmed node-positive disease. Statistical analysis was performed with propensity-score matching, chi-square test, log-rank test, Kaplan-Meier, and multivariable Cox proportional regression. RESULTS: A total of 2396 patients were analyzed, and 1517 (63.3%) received adjuvant radiotherapy. Median follow-up was 73 months. Median age at diagnosis was 77 years (range 65-90). In the propensity score-matched cohort, five-year overall survival (OS) was 29%. Five-year OS was 33% in patients who received surgery followed by adjuvant radiotherapy and 26% in patients who received surgery alone (p < 0.0001). Multivariable analysis continued to demonstrate a survival benefit associated with the addition of adjuvant radiotherapy (OR 0.77 [95% CI 0.69-00.87], p < 0.001). Adjuvant radiotherapy was associated with improved OS among patients aged 65-84 (5-year OS 35% vs 29%, p = 0.0004), but not in patients aged 85 years and older (5-year OS 20% vs 19%, p = 0.32). CONCLUSION: This NCDB study suggests that in older patients with node-positive vulvar cancer, radiotherapy continues to be a vital component of multimodality therapy. However, a comprehensive and geriatrics-specific approach is crucial for treating older adults with node-positive vulvar cancer, as the benefit of adjuvant radiotherapy may be compromised by treatment-related morbidity/toxicity.

Better late than never: Brachytherapy is more important than timing in treatment of locally advanced cervical cancer.

PURPOSE: To evaluate the utilization of brachytherapy and duration of treatment on overall survival for locally advanced cervical cancer. METHODS: The National Cancer Database (NCDB) was queried to identify stage II-IVA cervical cancer patients diagnosed in the United States between 2004 and 2015 who were treated with definitive chemoradiation therapy. We defined standard of care (SOC) treatment as receiving external beam radiation therapy (EBRT) and concurrent chemotherapy, brachytherapy (BT), and completing treatment within 8 weeks, and compared SOC treatment to non-SOC. The primary outcome was overall survival (OS). We also evaluated the effect of sociodemographic and clinical variables on receiving SOC. RESULTS: We identified 10,172 women with locally advanced cervical cancer primarily treated with chemotherapy and concurrent EBRT of which 6047 (59.4%) patients received brachytherapy, and only 2978 (29.3%) completed treatment within 8 weeks (SOC). Receipt of SOC was associated with significantly improved overall survival (median OS 131.0 mos vs 95.5 mos, 78.1 mos, 49.2 mos; p < 0.0001). Furthemore, in patients whose treatment extended beyond 8 weeks, brachytherapy was still associated with an improved survival (median OS 95.5 vs 49.2 mos, p < 0.0001). More advanced stage, Non-Hispanic Black race, lower income, lack of insurance or government insurance, less education, and rural residence were associated with decreased likelihood of receiving SOC. CONCLUSIONS: Completing standard of care concurrent chemoradiation therapy and brachytherapy in the recommended 8 weeks was associated with a superior overall survival. Patients who received brachytherapy boost show superior survival to patients receiving EBRT alone, regardless of treatment duration. Disparities in care for vulnerable populations highlight the challenges and importance of care coordination for patients with cervical cancer.

Epigenomes of Human Hearts Reveal New Genetic Variants Relevant for Cardiac Disease and Phenotype.

RATIONALE: Identifying genetic markers for heterogeneous complex diseases such as heart failure is challenging and requires prohibitively large cohort sizes in genome-wide association studies to meet the stringent threshold of genome-wide statistical significance. On the other hand, chromatin quantitative trait loci, elucidated by direct epigenetic profiling of specific human tissues, may contribute toward prioritizing subthreshold variants for disease association. OBJECTIVE: Here, we captured noncoding genetic variants by performing epigenetic profiling for enhancer H3K27ac chromatin immunoprecipitation followed by sequencing in 70 human control and end-stage failing hearts. METHODS AND RESULTS: We have mapped a comprehensive catalog of 47 321 putative human heart enhancers and promoters. Three thousand eight hundred ninety-seven differential acetylation peaks (FDR [false discovery rate], 5%) pointed to pathways altered in heart failure. To identify cardiac histone acetylation quantitative trait loci (haQTLs), we regressed out confounding factors including heart failure disease status and used the G-SCI (Genotype-independent Signal Correlation and Imbalance) test1 to call out 1680 haQTLs (FDR, 10%). RNA sequencing performed on the same heart samples proved a subset of haQTLs to have significant association also to gene expression (expression quantitative trait loci), either in cis (180) or through long-range interactions (81), identified by Hi-C (high-throughput chromatin conformation assay) and HiChIP (high-throughput protein centric chromatin) performed on a subset of hearts. Furthermore, a concordant relationship between the gain or disruption of TF (transcription factor)-binding motifs, inferred from alternative alleles at the haQTLs, implied a surprising direct association between these specific TF and local histone acetylation in human hearts. Finally, 62 unique loci were identified by colocalization of haQTLs with the subthreshold loci of heart-related genome-wide association studies datasets. CONCLUSIONS: Disease and phenotype association for 62 unique loci are now implicated. These loci may indeed mediate their effect through modification of enhancer H3K27 acetylation enrichment and their corresponding gene expression differences (bioRxiv: https://doi.org/10.1101/536763). Graphical Abstract: A graphical abstract is available for this article.

NCCN Guidelines® Insights: Ovarian Cancer, Version 3.2022.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years following diagnosis. The NCCN Guidelines for Ovarian Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with ovarian, fallopian tube, and primary peritoneal cancers. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised guidance on alternative chemotherapy regimens for patients with advanced age and/or comorbidities, a new algorithm for recurrent low-grade serous carcinoma based on developing research and novel therapeutic agents, and updated language regarding tumor molecular analysis applications in ovarian cancer.

EgSPEECHLESS Responses to Salt Stress by Regulating Stomatal Development in Oil Palm.

Oil palm is the most productive oil producing plant. Salt stress leads to growth damage and a decrease in yield of oil palm. However, the physiological responses of oil palm to salt stress and their underlying mechanisms are not clear. RNA-Seq was conducted on control and leaf samples from young palms challenged under three levels of salts (100, 250, and 500 mM NaCl) for 14 days. All three levels of salt stress activated EgSPCH expression and increased stomatal density of oil palm. Around 41% of differential expressed genes (DEGs) were putative EgSPCH binding target and were involved in multiple bioprocesses related to salt response. Overexpression of EgSPCH in Arabidopsis increased the stomatal production and lowered the salt tolerance. These data indicate that, in oil palm, salt activates EgSPCH to generate more stomata in response to salt stress, which differs from herbaceous plants. Our results might mirror the difference of salt-induced stomatal development between ligneous and herbaceous crops.

Improving critical care patients' sleep quality in a surgical high-dependency unit: An evidence-based practice project.

BACKGROUND: Sleep is an essential basic need. However, patients in critical care often experience poor and fragmented sleep. As such, there is a need to examine strategies to promote sleep in critical care patients. AIM: This project aimed to promote sleep in surgical high-dependency patients through the implementation of evidence-based best practice. METHODS: An evidence-based practice (EBP) project was implemented in May 2015 in a 24-bed surgical high-dependency (progressive care) unit in a public tertiary hospital in Singapore in three phases using the JBI framework. Outcomes measured were sleep quality, using the Richards-Campbell Sleep Questionnaire, and nurses' adherence to sleep promotion activities, using an audit tool adapted from the JBI-Practical Application of Clinical Education System. Data were collected at baseline, 1, 3, 6, and 12 months. Getting Research into Practice analysis was done at each time point. RESULTS: A total of 120 patients were surveyed, and 150 observation audits were conducted over 1 year. Sleep quality was similar between pre-audit (mean 53, SD 19.89) and month 1 (mean 54, SD 24.40), improved at month 3 (mean 64, SD 19.34), and sustained at month 6 (mean 64, SD 24.13) and 12 (mean 64, SD 19.4). The effect size between pre-audit and month 3 was a medium effect size of 0.49, which continued to improve at month 12, with a medium effect size of 0.56. Nurses' adherence to the EBP generally improved, and the thresholds of 80% were exceeded by month 12. LINKING EVIDENCE TO ACTION: Sleep is an essential basic need and can be improved through simple evidence-based interventions. Best practice for promoting sleep includes grouping nursing activities and reducing light and noise at night.