Category: Nevin Manimala

J Natl Cancer Inst. 2021 May 28:djab111. doi: 10.1093/jnci/djab111. Online ahead of print.

ABSTRACT

BACKGROUND: Loss of ovarian function is a recognized adverse effect of chemotherapy for breast cancer, and of great importance to patients. Little is known about the ovarian toxicity of newer cancer treatments. This study examined whether breast cancer clinical trials include assessment of the impact of trial interventions on ovarian function.

METHODS: Eligible trials were phase 3 (neo)adjuvant trials of pharmacologic treatments for breast cancer recruiting between June 2008-October 2019, which included premenopausal women. MEDLINE, EMBASE, Clinicaltrials.gov, EudraCT were searched. Data were extracted from trial publications, protocols, databases, and a survey sent to all trial chairs. Tests of statistical significance were two-sided. PROSPERO registration CRD42019134551.

RESULTS: Of 2,354 records identified, 141 trials were eligible. Investigational treatments included chemotherapy (36.9%), HER2-targeted (24.8%), endocrine (12.8%), immunotherapy (7.8%), CDK4/6-inhibitors (5.0%), PARP-inhibitors (2.8%). Ovarian function was a pre-specified endpoint in 13 (9.2%) trials. Forty-five (31.9%) trials collected ovarian function data, but only 33 (23.4%) collected post-trial-intervention data. Common post-intervention data collected included menstruation (15.6%), pregnancy (13.5%), estradiol (9.9%) and follicle-stimulating hormone levels (8.5%). Only four (2.8%) trials collected post-intervention anti-mullerian hormone levels and three (2.1%) trials collected antral follicle count. Of 22 trials investigating immunotherapy, CDK4/6-inhibitors or PARP-inhibitors, none specified ovarian function as an endpoint, but four (18.2%) collected post-intervention ovarian function data.

CONCLUSIONS: The impact of pharmacologic interventions on ovarian function is infrequently assessed in phase 3 breast cancer (neo)adjuvant trials that include premenopausal women. Trialists should consider inclusion of ovarian function endpoints when designing clinical trials, given its importance for informed decision-making.

PMID:34048575 | DOI:10.1093/jnci/djab111

Nucleic Acids Res. 2021 May 28:gkab405. doi: 10.1093/nar/gkab405. Online ahead of print.

ABSTRACT

The Mergeomics web server is a flexible online tool for multi-omics data integration to derive biological pathways, networks, and key drivers important to disease pathogenesis and is based on the open source Mergeomics R package. The web server takes summary statistics of multi-omics disease association studies (GWAS, EWAS, TWAS, PWAS, etc.) as input and features four functions: Marker Dependency Filtering (MDF) to correct for known dependency between omics markers, Marker Set Enrichment Analysis (MSEA) to detect disease relevant biological processes, Meta-MSEA to examine the consistency of biological processes informed by various omics datasets, and Key Driver Analysis (KDA) to identify essential regulators of disease-associated pathways and networks. The web server has been extensively updated and streamlined in version 2.0 including an overhauled user interface, improved tutorials and results interpretation for each analytical step, inclusion of numerous disease GWAS, functional genomics datasets, and molecular networks to allow for comprehensive omics integrations, increased functionality to decrease user workload, and increased flexibility to cater to user-specific needs. Finally, we have incorporated our newly developed drug repositioning pipeline PharmOmics for prediction of potential drugs targeting disease processes that were identified by Mergeomics. Mergeomics is freely accessible at http://mergeomics.research.idre.ucla.edu and does not require login.

PMID:34048577 | DOI:10.1093/nar/gkab405

Genome Biol Evol. 2021 May 28:evab121. doi: 10.1093/gbe/evab121. Online ahead of print.

ABSTRACT

Sex chromosomes are generally derived from a pair of autosomes that have acquired a locus controlling sex. Sex chromosomes may evolve reduced recombination around this locus and undergo a long process of molecular divergence. At that point, the original loci controlling sex may be difficult to pinpoint. This difficulty has affected many model species from mammals to birds to flies, which present highly diverged sex chromosomes. Identifying sex-controlling loci is easier in species with molecularly similar sex chromosomes. Here we aimed at pinpointing the sex-determining region (SDR) of Armadillidium vulgare, a terrestrial isopod with female heterogamety (ZW females and ZZ males) and whose sex chromosomes appear to show low genetic divergence. To locate the SDR, we assessed SNP allele frequencies in F1 daughters and sons sequenced in pools (pool-seq) in several families. We developed a Bayesian method that uses the SNP genotypes of individually sequenced parents and poolseq data from F1 siblings to estimate the genetic distance between a given genomic region (contig) and the SDR. This allowed us to assign more than 43 Megabases of contigs to sex chromosomes, and to demonstrate extensive recombination and very low divergence between these chromosomes. By taking advantage of multiple F1 families, we delineated a very short genomic region (∼65 kilobases) that presented no evidence of recombination with the SDR. In this short genomic region, the comparison of sequencing depths between sexes highlighted female-specific genes that have undergone recent duplication, and which may be involved in sex determination in A. vulgare.

PMID:34048551 | DOI:10.1093/gbe/evab121

Nucleic Acids Res. 2021 May 28:gkab410. doi: 10.1093/nar/gkab410. Online ahead of print.

ABSTRACT

Genetic association studies are frequently used to study the genetic basis of numerous human phenotypes. However, the rapid interrogation of how well a certain genomic region associates across traits as well as the interpretation of genetic associations is often complex and requires the integration of multiple sources of annotation, which involves advanced bioinformatic skills. We developed snpXplorer, an easy-to-use web-server application for exploring Single Nucleotide Polymorphisms (SNP) association statistics and to functionally annotate sets of SNPs. snpXplorer can superimpose association statistics from multiple studies, and displays regional information including SNP associations, structural variations, recombination rates, eQTL, linkage disequilibrium patterns, genes and gene-expressions per tissue. By overlaying multiple GWAS studies, snpXplorer can be used to compare levels of association across different traits, which may help the interpretation of variant consequences. Given a list of SNPs, snpXplorer can also be used to perform variant-to-gene mapping and gene-set enrichment analysis to identify molecular pathways that are overrepresented in the list of input SNPs. snpXplorer is freely available at https://snpxplorer.net. Source code, documentation, example files and tutorial videos are available within the Help section of snpXplorer and at https://github.com/TesiNicco/snpXplorer.

PMID:34048563 | DOI:10.1093/nar/gkab410

Bioinformatics. 2021 May 28:btab414. doi: 10.1093/bioinformatics/btab414. Online ahead of print.

ABSTRACT

MOTIVATION: The classic multispecies coalescent (MSC) model provides the means for theoretical justification of incomplete lineage sorting-aware species tree inference methods. This has motivated an extensive body of work on phylogenetic methods that are statistically consistent under MSC. One such particularly popular method is ASTRAL, a quartet-based species tree inference method. Novel studies suggest that ASTRAL also performs well when given multi-locus gene trees in simulation studies. Further, Legried et al. recently demonstrated that ASTRAL is statistically consistent under the gene duplication and loss model (GDL). GDL is prevalent in evolutionary histories and is the first core process in the powerful duplication-loss-coalescence evolutionary model (DLCoal) by Rasmussen and Kellis.

RESULTS: In this work we prove that ASTRAL is statistically consistent under the general DLCoal model. Therefore, our result supports the empirical evidence from the simulation-based studies. More broadly, we prove that the quartet-based inference approach is statistically consistent under DLCoal.

PMID:34048529 | DOI:10.1093/bioinformatics/btab414

Database (Oxford). 2021 May 28;2021:baab034. doi: 10.1093/database/baab034.

ABSTRACT

Oral cancer is highly prevalent in India and is the most frequent cancer type among Indian males. It is also very common in southeast Asia. India has participated in the International Cancer Genome Consortium (ICGC) and some national initiatives to generate large-scale genomic data on oral cancer patients and analyze to identify associations and systematically catalog the associated variants. We have now created an open, web-accessible database of these variants found significantly associated with Indian oral cancer patients, with a user-friendly interface to enable easy mining. We have value added to this database by including relevant data collated from various sources on other global populations, thereby providing opportunities of comparative geographical and/or ethnic analyses. Currently, no other database of similar nature is available on oral cancer. We have developed Database of GENomic Variants of Oral Cancer, a browsable online database framework for storage, retrieval and analysis of large-scale data on genomic variants and make it freely accessible to the scientific community. Presently, the web-accessible database allows potential users to mine data on ∼24 million clinically relevant somatic and germline variants derived from exomes (n = 100) and whole genomes (n = 5) of Indian oral cancer patients; all generated by us. Variant data from The Cancer Genome Atlas and data manually curated from peer-reviewed publications were also incorporated into the database for comparative analyses. It allows users to query the database by a single gene, multiple genes, multiple variant sites, genomic region, patient ID and pathway identities. Database URL: http://research.nibmg.ac.in/dbcares/dbgenvoc/.

PMID:34048545 | DOI:10.1093/database/baab034

J Med Entomol. 2021 May 28:tjab084. doi: 10.1093/jme/tjab084. Online ahead of print.

ABSTRACT

Container Aedes mosquitoes are the most important vectors of human arboviruses (i.e., dengue, chikungunya, Zika, or yellow fever). Invasive and native container Aedes spp. potentially utilize natural and artificial containers in specific environments for oviposition. Several container Aedes spp. display ‘skip-oviposition’ behavior, which describes the distribution of eggs among multiple containers during a single gonotrophic cycle. In this study, we compared individual skip-oviposition behavior using identical eight-cup testing arenas with three container Aedes species: Aedes aegypti (Linnaeus), Aedes albopictus (Skuse), and Aedes triseriatus (Say). We applied the index of dispersion, an aggregation statistic, to individual mosquitoes’ oviposition patterns to assess skip-oviposition behavior. Aedes aegypti and Ae. albopictus utilized more cups and distributed eggs more evenly among cups than Ae. triseriatus under nutritionally enriched oviposition media (oak leaf infusion) conditions. When presented with a nutritionally unenriched (tap water) oviposition media, both Ae. aegypti and Ae. albopictus increased egg spreading behavior. Aedes albopictus did not modify skip-oviposition behavior when reared and assessed under fall-like environmental conditions, which induce diapause egg production. This study indicates specific oviposition site conditions influence skip-oviposition behavior with ‘preferred’ sites receiving higher amounts of eggs from any given individual and ‘non-preferred’ sites receive a limited contribution of eggs. A further understanding of skip-oviposition behavior is needed to make the best use of autodissemination trap technology in which skip-ovipositing females spread a potent larvicide among oviposition sites within the environment.

PMID:34048548 | DOI:10.1093/jme/tjab084

Integr Comp Biol. 2021 May 28:icab110. doi: 10.1093/icb/icab110. Online ahead of print.

ABSTRACT

One key evolutionary innovation that separates vertebrates from invertebrates is the notochord, a central element that provides the stiffness needed for powerful movements. Later, the notochord was further stiffened by the vertebrae, cartilaginous and bony elements, surrounding the notochord. The ancestral notochord is retained in modern vertebrates as intervertebral material, but we know little about its mechanical interactions with surrounding vertebrae. In this study, the internal shape of the vertebrae-where this material is found-was quantified in sixteen species of fishes with various body shapes, swimming modes, and habitats. We used micro-computed tomography to measure the internal shape. We then created and mechanically tested physical models of intervertebral joints. We also mechanically tested actual vertebrae of five species. Material testing shows that internal morphology of the centrum significantly affects bending and torsional stiffness. Finally, we performed swimming trials to gather kinematic data. Combining these data, we created a model that uses internal vertebral morphology to make predictions about swimming kinematics and mechanics. We used linear discriminant analysis (LDA) to assess the relationship between vertebral shape and our categorical traits. The analysis revealed that internal vertebral morphology is sufficient to predict habitat, body shape, and swimming mode in our fishes. This model can also be used to make predictions about swimming in fishes not easily studied in the lab, such as deep sea and extinct species, allowing the development of hypotheses about their natural behavior.

PMID:34048550 | DOI:10.1093/icb/icab110

J Mater Chem B. 2021 May 28. doi: 10.1039/d1tb00776a. Online ahead of print.

ABSTRACT

Hydrogels are perfectly suited to support cell and tissue growth in advanced tissue engineering applications as well as classical wound treatment scenarios. Ideal hydrogel materials for these applications should be easy to produce, biocompatible, resorbable and antimicrobial. Here we report the fabrication of degradable covalent antimicrobial lysine and tryptophan containing copolypeptide hydrogels, whereby the hydrogel properties can be independently modulated by the copolypeptide monomer ratio and chiral composition. Well-defined statistical copolypeptides comprising different overall molecular weights as well as ratios of l- and d-lysine and tryptophan at ratios of 35 : 15, 70 : 30 and 80 : 20 were obtained by N-carboxyanhydride (NCA) polymerisation and subsequently crosslinked by the selective reaction of bifunctional triazolinedione (TAD) with tryptophan. Real-time rheology was used to monitor the crosslinking reaction recording the fastest increase and overall modulus for copolypeptides with the higher tryptophan ratio. Water uptake of cylindrical hydrogel samples was dependent on crosslinking ratio but found independent of chiral composition, while enzymatic degradation proceeded significantly faster for samples containing more l-amino acids. Antimicrobial activity on a range of hydrogels containing different polypeptide chain lengths, lysine/tryptophan composition and l/d enantiomers was tested against reference laboratory strains of Gram-negative Escherichia coli (E. coli; ATCC25922) and Gram-positive, Staphylococcus aureus (S. aureus; ATCC25923). log reductions of 2.8-3.4 were recorded for the most potent hydrogels. In vitro leachable cytotoxicity tests confirmed non-cytotoxicity as per ISO guidelines.

PMID:34048521 | DOI:10.1039/d1tb00776a

Am J Health Syst Pharm. 2021 May 28:zxab223. doi: 10.1093/ajhp/zxab223. Online ahead of print.

ABSTRACT

PURPOSE: Pharmacists are well positioned to provide transitions of care (TOC) services to patients with heart failure (HF); however, hospitalizations for patients with HF likely exceed the capacity of a TOC pharmacist. We developed and validated a tool to help pharmacists efficiently identify high-risk patients with HF and maximize their potential impact by intervening on patients at the highest risk for 30-day all-cause readmission.

METHODS: We conducted a retrospective cohort study including adults with HF admitted to a health system between October 1, 2016, and October 31, 2019. We randomly divided the cohort into development (n = 2,114) and validation (n = 1,089) subcohorts. Nine models were applied to select the most important predictors of 30-day readmission. The final tool, called the Tool for Pharmacists to Predict 30-day hospital readmission in patients with Heart Failure (ToPP-HF) relied upon multivariable logistic regression. We assessed discriminative ability using the C statistic and calibration using the Hosmer-Lemeshow goodness-of-fit test.

RESULTS: The risk of 30-day all-cause readmission was 15.7% (n = 331) and 18.8% (n = 205) in the development and validation subcohorts, respectively. The ToPP-HF tool included 13 variables: number of hospital admissions in previous 6 months; admission diagnosis of HF; number of scheduled medications; chronic obstructive pulmonary disease diagnosis; number of comorbidities; estimated glomerular filtration rate; hospital length of stay; left ventricular ejection fraction; critical care requirement; renin-angiotensin-aldosterone system inhibitor use; antiarrhythmic use; hypokalemia; and serum sodium. Discriminatory performance (C statistic of 0.69; 95% confidence interval [CI], 0.65-0.73) and calibration (Hosmer-Lemeshow P = 0.28) were good.

CONCLUSIONS: The ToPP-HF performs well and can help pharmacists identify high-risk patients with HF most likely to benefit from TOC services.

PMID:34048528 | DOI:10.1093/ajhp/zxab223