Solanidine is a sensitive and specific dietary biomarker for CYP2D6 activity.

BACKGROUND: Individual assessment of CYP enzyme activities can be challenging. Recently, the potato alkaloid solanidine was suggested as a biomarker for CYP2D6 activity. Here, we aimed to characterize the sensitivity and specificity of solanidine as a CYP2D6 biomarker among Finnish volunteers with known CYP2D6 genotypes. RESULTS: Using non-targeted metabolomics analysis, we identified 9152 metabolite features in the fasting plasma samples of 356 healthy volunteers. Machine learning models suggested strong association between CYP2D6 genotype-based phenotype classes with a metabolite feature identified as solanidine. Plasma solanidine concentration was 1887% higher in genetically poor CYP2D6 metabolizers (gPM) (n = 9; 95% confidence interval 755%, 4515%; P = 1.88 × 10-11), 74% higher in intermediate CYP2D6 metabolizers (gIM) (n = 89; 27%, 138%; P = 6.40 × 10-4), and 35% lower in ultrarapid CYP2D6 metabolizers (gUM) (n = 20; 64%, - 17%; P = 0.151) than in genetically normal CYP2D6 metabolizers (gNM; n = 196). The solanidine metabolites m/z 444 and 430 to solanidine concentration ratios showed even stronger associations with CYP2D6 phenotypes. Furthermore, the areas under the receiver operating characteristic and precision-recall curves for these metabolic ratios showed equal or better performances for identifying the gPM, gIM, and gUM phenotype groups than the other metabolites, their ratios to solanidine, or solanidine alone. In vitro studies with human recombinant CYP enzymes showed that solanidine was metabolized mainly by CYP2D6, with a minor contribution from CYP3A4/5. In human liver microsomes, the CYP2D6 inhibitor paroxetine nearly completely (95%) inhibited the metabolism of solanidine. In a genome-wide association study, several variants near the CYP2D6 gene associated with plasma solanidine metabolite ratios. CONCLUSIONS: These results are in line with earlier studies and further indicate that solanidine and its metabolites are sensitive and specific biomarkers for measuring CYP2D6 activity. Since potato consumption is common worldwide, this biomarker could be useful for evaluating CYP2D6-mediated drug-drug interactions and to improve prediction of CYP2D6 activity in addition to genotyping.

Microbial nanotechnology for agriculture, food, and environmental sustainability: Current status and future perspective.

The field of nanotechnology has the mysterious capacity to reform every subject it touches. Nanotechnology advancements have already altered a variety of scientific and industrial fields. Nanoparticles (NPs) with sizes ranging from 1 to 100 nm (nm) are of great scientific and commercial interest. Their functions and characteristics differ significantly from those of bulk metal. Commercial quantities of NPs are synthesized using chemical or physical methods. The use of the physical and chemical approaches remained popular for many years; however, the recognition of their hazardous effects on human well-being and conditions influenced serious world perspectives for the researchers. There is a growing need in this field for simple, non-toxic, clean, and environmentally safe nanoparticle production methods to reduce environmental impact and waste and increase energy productivity. Microbial nanotechnology is relatively a new field. Using various microorganisms, a wide range of nanoparticles with well-defined chemical composition, morphology, and size have been synthesized, and their applications in a wide range of cutting-edge technological areas have been investigated. Green synthesis of the nanoparticles is cost-efficient and requires low maintenance. The present review highlights the synthesis of the nanoparticles by different microbes, their characterization, and their biotechnological potential. It further deals with the applications in biomedical, food, and textile industries as well as its role in biosensing, waste recycling, and biofuel production.

Factors Impacting Follow-Up Care in Allergic Fungal Rhinosinusitis.

OBJECTIVE: The purpose of this study was to analyze barriers to medical care and follow-up in patients with allergic fungal rhinosinusitis (AFRS). STUDY DESIGN: Cross-sectional questionnaire-based study with retrospective chart review. SETTING: Tertiary Medical Center. METHODS: Subjects with AFRS and chronic rhinosinusitis with nasal polyps (CRSwNP) were prospectively recruited for completion of the Barriers to Care Questionnaire (BCQ) and formal chart review. RESULTS: Fifty-nine AFRS and 51 CRSwNP patients participated. AFRS patients were more likely to be lost to follow-up within 6 months of surgery (35.6% vs 17.7%, P = 0.04) and no-show at least 1 appointment (20.3% vs 5.9%, P = 0.03) compared to CRSwNP patients. Men with AFRS were more likely to have only a single follow-up visit (37.0% vs 3.1%, P < 0.001) and be lost to follow-up (66.7% vs 9.4%, P < 0.001) than women. There were no significant differences in the BCQ between groups; however, rate of questionnaire completion was lower in the AFRS group than the CRS group (62.7% vs 80.4%, P = 0.042). AFRS patients who did not complete the BCQ were more likely to be male (63.6% vs 35.1%, P = 0.034), lost to follow-up (77.3% vs 10.8%, P < 0.0001), and have a single follow-up visit (40.9% vs 5.4%, P < 0.0001). Younger age was associated with increased likelihood of having a single follow-up visit (odds ratio 1.143, 95% CI 1.022-1.276). CONCLUSION: Young, male AFRS patients are more frequently lost to follow-up after surgery and less likely to complete questionnaires assessing barriers to care. Further investigation is needed to assess barriers to follow-up in these at-risk groups.

The readability of online patient education materials on maxillomandibular advancement surgery.

STUDY OBJECTIVES: Maxillomandibular advancement (MMA) is an effective surgical option for patients suffering from obstructive sleep apnea (OSA). As a relatively new treatment option, patients may turn to the Internet to learn more. However, online patient education materials (OPEMs) on MMA may be written at a higher literacy level than recommended for patients. The aim of this study was to analyze the readability of OPEMs on MMA. METHODS: A Google search of "maxillomandibular advancement" was performed, and the first 100 results were screened. Websites that met eligibility criteria were analyzed for their readability using the Automated Readability Index (ARI), Coleman-Liau Index (CLI), Flesch-Kincaid Grade Level (FKGL), Gunning Fog (GF), and Simple Measure of Gobbledygook (SMOG) and compared to the recommended sixth-grade reading level using one-tailed t tests. Readability scores were compared based on the type of website, including hospitals/universities or physician clinics, using ANOVA tests. RESULTS: The mean (SD) for ARI, CLI, FKGL, GF, and SMOG was 11.91 (2.43), 13.42 (1.81), 11.91 (2.06), 14.32 (2.34), and 13.99 (1.56), respectively. All readability scores were significantly higher than a sixth-grade reading level (p < 0.001). After comparing readability scores between different website types (university/hospital, clinic, and other), there was no statistical difference found. CONCLUSIONS: The available OPEMs on MMA surgery for OSA are above the recommended sixth-grade reading level. Identifying and reducing the gap between the reading levels of OPEMs and the reading level of the patient are needed to encourage a more active role, informed decisions, and better patient satisfaction.

Harnessing fungal endophytes for natural management: a biocontrol perspective.

In the ever-evolving realm of agriculture, the convoluted interaction between plants and microorganisms have assumed paramount significance. Fungal endophytes, once perceived as mere bystanders within plant tissues, have now emerged as dynamic defenders of plant health. This comprehensive review delves into the captivating world of fungal endophytes and their multifaceted biocontrol mechanisms. Exploring their unique ability to coexist with their plant hosts, fungal endophytes have unlocked a treasure trove of biological weaponry to fend off pathogens and enhance plant resilience. From the synthesis of bioactive secondary metabolites to intricate signaling pathways these silent allies are masters of biological warfare. The world of fungal endophytes is quite fascinating as they engage in a delicate dance with the plant immune system, orchestrating a symphony of defense that challenges traditional notions of plant-pathogen interactions. The journey through the various mechanisms employed by these enigmatic endophytes to combat diseases, will lead to revelational understanding of sustainable agriculture. The review delves into cutting-edge research and promising prospects, shedding light on how fungal endophytes hold the key to biocontrol and the reduction of chemical inputs in agriculture. Their ecological significance, potential for bioprospecting and avenues for future research are also explored. This exploration of the biocontrol mechanisms of fungal endophytes promise not only to enrich our comprehension of plant-microbe relationships but also, to shape the future of sustainable and ecofriendly agricultural practices. In this intricate web of life, fungal endophytes are indeed the unsung heroes, silently guarding our crops and illuminating a path towards a greener, healthier tomorrow.

NTHL1 is a recessive cancer susceptibility gene.

In search of novel breast cancer (BC) risk variants, we performed a whole-exome sequencing and variant analysis of 69 Finnish BC patients as well as analysed loss-of-function variants identified in DNA repair genes in the Finns from the Genome Aggregation Database. Additionally, we carried out a validation study of SERPINA3 c.918-1G>C, recently suggested for BC predisposition. We estimated the frequencies of 41 rare candidate variants in 38 genes by genotyping them in 2482-4101 BC patients and in 1273-3985 controls. We further evaluated all coding variants in the candidate genes in a dataset of 18,786 BC patients and 182,927 controls from FinnGen. None of the variants associated significantly with cancer risk in the primary BC series; however, in the FinnGen data, NTHL1 c.244C>T p.(Gln82Ter) associated with BC with a high risk for homozygous (OR = 44.7 [95% CI 6.90-290], P = 6.7 × 10-5) and a low risk for heterozygous women (OR = 1.39 [1.18-1.64], P = 7.8 × 10-5). Furthermore, the results suggested a high risk of colorectal, urinary tract, and basal-cell skin cancer for homozygous individuals, supporting NTHL1 as a recessive multi-tumour susceptibility gene. No significant association with BC risk was detected for SERPINA3 or any other evaluated gene.

VarSCAT: A computational tool for sequence context annotations of genomic variants.

The sequence contexts of genomic variants play important roles in understanding biological significances of variants and potential sequencing related variant calling issues. However, methods for assessing the diverse sequence contexts of genomic variants such as tandem repeats and unambiguous annotations have been limited. Herein, we describe the Variant Sequence Context Annotation Tool (VarSCAT) for annotating the sequence contexts of genomic variants, including breakpoint ambiguities, flanking bases of variants, wildtype/mutated DNA sequences, variant nomenclatures, distances between adjacent variants, tandem repeat regions, and custom annotation with user customizable options. Our analyses demonstrate that VarSCAT is more versatile and customizable than the currently available methods or strategies for annotating variants in short tandem repeat (STR) regions or insertions and deletions (indels) with breakpoint ambiguity. Variant sequence context annotations of high-confidence human variant sets with VarSCAT revealed that more than 75% of all human individual germline and clinically relevant indels have breakpoint ambiguities. Moreover, we illustrate that more than 80% of human individual germline small variants in STR regions are indels and that the sizes of these indels correlated with STR motif sizes. VarSCAT is available from https://github.com/elolab/VarSCAT.

All chronic rhinosinusitis endotype clusters demonstrate improvement in patient-reported and clinical outcome measures after endoscopic sinus surgery.

BACKGROUND: It is unclear whether chronic rhinosinusitis (CRS) endotypes show a differential response to endoscopic sinus surgery (ESS). We explored patient mucous inflammatory cytokine expression and associations with patient-reported and clinically measured post-operative outcome measures. METHODS: Patients with CRS were prospectively recruited between 2016 and 2021 into a national multicenter, observational study. Mucus was collected from the olfactory cleft preoperatively and evaluated for 26 biomarkers using cluster analysis. Patient-reported outcome measures included the 22-item Sino-Nasal Outcome Test (SNOT-22) and Questionnaire of Olfactory Dysfunction (QOD). Additional clinical measures of disease severity included threshold, discrimination, and identification (TDI) scores using "Sniffin' Sticks" testing and Lund-Kennedy endoscopic score (LKES). RESULTS: A total of 115 patients were clustered into type 2 inflammatory, non-type 2 inflammatory, noninflammatory, and two indeterminate clusters based on individual protein levels. Overall, the type 2 inflammatory cluster was found to have the highest mean improvement in both SNOT-22 (-28.3 [standard deviation, ±16.2]) and TDI (6.5 [standard deviation, ±7.9]) scores 6 months after ESS. However, on average, all endotype clusters demonstrated improvement in all outcome measures after ESS without statistically significant between-group differences in SNOT-22 (p = 0.738), QOD (p = 0.306), TDI (p = 0.358), or LKES (p = 0.514) measures. CONCLUSIONS: All CRS endotype clusters responded favorably to surgery and showed improvements in patient-reported and objective outcome measures. Thus, ESS should be considered a more generalized CRS therapy, and benefits appear to not be limited to specific endotypes.

PREDICT validity for prognosis of breast cancer patients with pathogenic BRCA1/2 variants.

We assessed the PREDICT v 2.2 for prognosis of breast cancer patients with pathogenic germline BRCA1 and BRCA2 variants, using follow-up data from 5453 BRCA1/2 carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC). PREDICT for estrogen receptor (ER)-negative breast cancer had modest discrimination for BRCA1 carrier patients overall (Gönen & Heller unbiased concordance 0.65 in CIMBA, 0.64 in BCAC), but it distinguished clearly the high-mortality group from lower risk categories. In an analysis of low to high risk categories by PREDICT score percentiles, the observed mortality was consistently lower than the expected mortality, but the confidence intervals always included the calibration slope. Altogether, our results encourage the use of the PREDICT ER-negative model in management of breast cancer patients with germline BRCA1 variants. For the PREDICT ER-positive model, the discrimination was slightly lower in BRCA2 variant carriers (concordance 0.60 in CIMBA, 0.65 in BCAC). Especially, inclusion of the tumor grade distorted the prognostic estimates. The breast cancer mortality of BRCA2 carriers was underestimated at the low end of the PREDICT score distribution, whereas at the high end, the mortality was overestimated. These data suggest that BRCA2 status should also be taken into consideration with tumor characteristics, when estimating the prognosis of ER-positive breast cancer patients.

The impact of race on olfaction: A systematic review and meta-analysis.

BACKGROUND: Many studies have identified a higher degree of Olfactory Dysfunction (OD) in Black patients compared to White patients. This study aims to analyze olfactory outcomes in different races. METHODS: The PubMed, Scopus, and CINAHL databases were searched from inception to September 5, 2022, for English-language articles documenting self-reported and psychophysical OD stratified by race. A meta-analysis of proportions, comparison of weighted proportions, and comparison of means were performed in MedCalc 20.218. In the quantitative analysis, 79,297 patients were included, comprising 79.3% Whites, 16.1% Blacks, and 4.6% Hispanics. RESULTS: A total of 14 studies were meta-analyzed. The prevalence of self-reported OD in Hispanic, White, and Black patients was 19.5% (95% CI, 16.6% to 22.6%), 17.2% (95% CI, 10.5% to 25.0%), and 13.9% (95% CI, 9.3% to 19.2%), respectively (p < 0.0007). The prevalence of psychophysical OD in Black, White, and Hispanic patients was 30.3% (95% CI, 24.2% to 36.9%), 24.2% (95% CI, 20.1% to 28.5%), and 18.4% (95% CI, 16.3% to 20.7%), respectively (p < 0.0001). Blacks reported a greater extent of unrecognized OD compared to Whites, with a difference of 16.5% (95% CI, 15.0% to 17.9%) versus 5.8% (95% CI, 3.4% to 8.0%), respectively (p < 0.0001). Hispanic rates of self-reported OD and psychophysical OD were not statistically different. CONCLUSIONS: Our findings suggest that Blacks have the highest rate of psychophysical OD and are more likely to underreport their awareness compared to Whites.

Biodiversity and Functional Attributes of Rhizospheric Microbiomes: Potential Tools for Sustainable Agriculture.

The quest for increasing agricultural yield due to increasing population pressure and demands for healthy food has inevitably led to the indiscriminate use of chemical fertilizers. On the contrary, the exposure of the crops to abiotic stress and biotic stress interferes with crop growth further hindering the productivity. Sustainable agricultural practices are of major importance to enhance production and feed the rising population. The use of plant growth promoting (PGP) rhizospheric microbes is emerging as an efficient approach to ameliorate global dependence on chemicals, improve stress tolerance of plants, boost up growth and ensure food security. Rhizosphere associated microbiomes promote the growth by enhancing the uptake of the nutrients, producing plant growth regulators, iron chelating complexes, shaping the root system under stress conditions and decreasing the levels of inhibitory ethylene concentrations and protecting plants from oxidative stress. Plant growth-promoting rhizospheric microbes belong to diverse range of genera including Acinetobacter, Achromobacter, Aspergillus, Bacillus, Burkholderia, Flavobacterium, Klebsiella, Micrococcus, Penicillium, Pseudomonas, Serratia and Trichoderma. Plant growth promoting microbes are an interesting aspect of research for scientific community and a number of formulations of beneficial microbes are also commercially available. Thus, recent progress in our understanding on rhizospheric microbiomes along with their major roles and mechanisms of action under natural and stressful conditions should facilitate their application as a reliable component in the management of sustainable agricultural system. This review highlights the diversity of plant growth promoting rhizospheric microbes, their mechanisms of plant growth promotion, their role under biotic and abiotic stress and status of biofertilizers. The article further focuses on the role of omics approaches in plant growth promoting rhizospheric microbes and draft genome of PGP microbes.

Polymorphism in interferon alpha/beta receptor contributes to glucocorticoid response and outcome of ARDS and COVID-19.

BACKGROUND: The use of glucocorticoids has given contradictory results for treating acute respiratory distress syndrome (ARDS). The use of intravenous Interferon beta (IFN ß) for the treatment of ARDS was recently tested in a phase III ARDS trial (INTEREST), in which more than half of the patients simultaneously received glucocorticoids. Trial results showed deleterious effects of glucocorticoids when administered together with IFN ß, and therefore, we aimed at finding the reason behind this. METHODS: We first sequenced the genes encoding the IFN α/ß receptor of the patients, who participated in the INTEREST study (ClinicalTrials.gov Identifier:  NCT02622724 , November 24, 2015) in which the patients were randomized to receive an intravenous injection of IFN ß-1a (144 patients) or placebo (152 patients). Genetic background was analyzed against clinical outcome, concomitant medication, and pro-inflammatory cytokine levels. Thereafter, we tested the influence of the genetic background on IFN α/ß receptor expression in lung organ cultures and whether, it has any effect on transcription factors STAT1 and STAT2 involved in IFN signaling. RESULTS: We found a novel disease association of a SNP rs9984273, which is situated in the interferon α/ß receptor subunit 2 (IFNAR2) gene in an area corresponding to a binding motif of the glucocorticoid receptor (GR). The minor allele of SNP rs9984273 associates with higher IFNAR expression, more rapid decrease of IFN γ and interleukin-6 (IL-6) levels and better outcome in IFN ß treated patients with ARDS, while the major allele associates with a poor outcome especially under concomitant IFN ß and glucocorticoid treatment. Moreover, the minor allele of rs9984273 associates with a less severe form of coronavirus diseases (COVID-19) according to the COVID-19 Host Genetics Initiative database. CONCLUSIONS: The distribution of this SNP within clinical study arms may explain the contradictory results of multiple ARDS studies and outcomes in COVID-19 concerning type I IFN signaling and glucocorticoids.

Economics of Medical and Surgical Management of Chronic Rhinosinusitis with Nasal Polyps: A Contemporary Review.

BACKGROUND: Chronic rhinosinusitis (CRS) with nasal polyposis (CRSwNP) is a chronic inflammatory condition with significant patient morbidity and associated healthcare costs. While the economic burden of CRS overall has been previously described, the economic impact of CRSwNP has received less attention. Patients with CRSwNP have higher disease burden and healthcare resource utilization than those with CRS without nasal polyposis. Rapid evolution of medical management in recent years with the use of targeted biologics warrants further investigation into the economic burden of CRSwNP. OBJECTIVE: Provide an updated review of the literature on the economic impact of CRSwNP. METHODS: A literature review. RESULTS: Research shows that patients with CRSwNP have higher direct costs and usage of ambulatory services compared to matched non-CRS controls. Patients undergoing functional endoscopic sinus surgery (FESS) incur roughly $13,000 in costs which is particularly relevant given the rate of disease recidivism and need for revision surgery associated with CRSwNP. Disease burden additionally leads to indirect costs through loss of wages and productivity due to work absenteeism and presenteeism, with estimates of up to roughly $10,000 lost in mean annual productivity cost in refractory CRSwNP. Several studies have shown FESS to be more cost-effective in intermediate and long-term management than medical therapy with biologics, despite similar long-term outcomes with respect to quality-of-life metrics. CONCLUSION: CRSwNP is a chronic condition with high recurrence rates making it a challenge to manage over time. Current research suggests that FESS is more cost-effective than medical management, including use of newer biologics. Further investigation into both direct and indirect costs associated with medical management is warranted to perform accurate cost-effectiveness analyses and allow for the best allocation of limited healthcare resources.

Long Intergenic Noncoding RNA MIAT as a Regulator of Human Th17 Cell Differentiation.

T helper 17 (Th17) cells protect against fungal and bacterial infections and are implicated in autoimmunity. Several long intergenic noncoding RNAs (lincRNA) are induced during Th17 differentiation, however, their contribution to Th17 differentiation is poorly understood. We aimed to characterize the function of the lincRNA Myocardial Infarction Associated Transcript (MIAT) during early human Th17 cell differentiation. We found MIAT to be upregulated early after induction of human Th17 cell differentiation along with an increase in the chromatin accessibility at the gene locus. STAT3, a key regulator of Th17 differentiation, directly bound to the MIAT promoter and induced its expression during the early stages of Th17 cell differentiation. MIAT resides in the nucleus and regulates the expression of several key Th17 genes, including IL17A, IL17F, CCR6 and CXCL13, possibly by altering the chromatin accessibility of key loci, including IL17A locus. Further, MIAT regulates the expression of protein kinase C alpha (PKCα), an upstream regulator of IL17A. A reanalysis of published single-cell RNA-seq data showed that MIAT was expressed in T cells from the synovium of RA patients. Our results demonstrate that MIAT contributes to human Th17 differentiation by upregulating several genes implicated in Th17 differentiation. High MIAT expression in T cells of RA patient synovia suggests a possible role of MIAT in Th17 mediated autoimmune pathologies.

Drought adaptive microbes as bioinoculants for the horticultural crops.

Drought stress is among the most destructive stresses for agricultural productivity. It interferes with normal metabolic activities of the plants resulting, a negative impact on physiology and morphology of the plants. The management of drought stress requires various adaptive and alleviation strategies in which stress adaptive microbiomes are exquisite bioresources for plant growth and alleviation of drought stress. Diverse drought adaptive microbes belonging to genera Achromobacter, Arthrobacter, Aspergillus, Bacillus, Pseudomonas, Penicillium and Streptomyces have been reported worldwide. These bioresources exhibit a wide range of mechanisms such as helping plant in nutrient acquisition, producing growth regulators, lowering the levels of stress ethylene, increasing the concentration of osmolytes, and preventing oxidative damage under water deficit environmental conditions. Horticulture is one of the potential agricultural sectors to speed up the economy, poverty and generation of employment for livelihood. The applications of drought adaptive plant growth promoting (PGP) microbes as biofertilizers and biopesticides for horticulture is a potential strategy to improve the productivity and protection of horticultural crops from abiotic and biotic stresses for agricultural sustainability.

Deep learning tools are top performers in long non-coding RNA prediction.

The increasing amount of transcriptomic data has brought to light vast numbers of potential novel RNA transcripts. Accurately distinguishing novel long non-coding RNAs (lncRNAs) from protein-coding messenger RNAs (mRNAs) has challenged bioinformatic tool developers. Most recently, tools implementing deep learning architectures have been developed for this task, with the potential of discovering sequence features and their interactions still not surfaced in current knowledge. We compared the performance of deep learning tools with other predictive tools that are currently used in lncRNA coding potential prediction. A total of 15 tools representing the variety of available methods were investigated. In addition to known annotated transcripts, we also evaluated the use of the tools in actual studies with real-life data. The robustness and scalability of the tools' performance was tested with varying sized test sets and test sets with different proportions of lncRNAs and mRNAs. In addition, the ease-of-use for each tested tool was scored. Deep learning tools were top performers in most metrics and labelled transcripts similarly with each other in the real-life dataset. However, the proportion of lncRNAs and mRNAs in the test sets affected the performance of all tools. Computational resources were utilized differently between the top-ranking tools, thus the nature of the study may affect the decision of choosing one well-performing tool over another. Nonetheless, the results suggest favouring the novel deep learning tools over other tools currently in broad use.

Tool evaluation for the detection of variably sized indels from next generation whole genome and targeted sequencing data.

Insertions and deletions (indels) in human genomes are associated with a wide range of phenotypes, including various clinical disorders. High-throughput, next generation sequencing (NGS) technologies enable the detection of short genetic variants, such as single nucleotide variants (SNVs) and indels. However, the variant calling accuracy for indels remains considerably lower than for SNVs. Here we present a comparative study of the performance of variant calling tools for indel calling, evaluated with a wide repertoire of NGS datasets. While there is no single optimal tool to suit all circumstances, our results demonstrate that the choice of variant calling tool greatly impacts the precision and recall of indel calling. Furthermore, to reliably detect indels, it is essential to choose NGS technologies that offer a long read length and high coverage coupled with specific variant calling tools.

High miR-30 Expression Associates with Improved Breast Cancer Patient Survival and Treatment Outcome.

Deregulated miRNA expression has been suggested in several stages of breast cancer pathogenesis. We have studied the miR-30 family, in particular miR-30d, in relation to breast cancer patient survival and treatment outcomes. With tumor specimens from 1238 breast cancer patients, we analyzed the association of miR-30d expression with tumor characteristics with the 5-year occurrence of breast cancer-specific death or distant metastasis (BDDM), and with 10-year breast cancer survival (BCS). We conducted a two-stage drug-screen to investigate the impact of miR-30 family members (miR-30a-30e) on sensitivity to doxorubicin and lapatinib in six breast cancer cell lines HCC1937, HCC1954, MDA-MB-361, MCF7, MDA-MB-436 and CAL-120, using drug sensitivity scores (DSS) to compare the miR-30 family mimics to their specific inhibitors. The study was complemented with Ingenuity Pathway Analysis (IPA) with the METABRIC data. We found that while high miR-30d expression is typical for aggressive tumors, it predicts better metastasis-free (pBDDM = 0.035, HR = 0.63, 95% CI = 0.4-0.9) and breast cancer-specific survival (pBCS = 0.018, HR = 0.61, 95% CI = 0.4-0.9), especially in HER2-positive (pBDDM = 0.0009), ER-negative (pBDDM = 0.003), p53-positive (pBDDM = 0.011), and highly proliferating (pBDDM = 0.0004) subgroups, and after adjuvant chemotherapy (pBDDM = 0.035). MiR-30d predicted survival independently of standard prognostic markers (pBDDM = 0.0004). In the drug-screening test, the miR-30 family sensitized the HER2-positive HCC1954 cell line to lapatinib (p < 10-2) and HCC1937, MDA-MB-361, MDA-MB-436 and CAL120 to doxorubicin (p < 10-4) with an opposite impact on MCF7. According to the pathway analysis, the miR-30 family has a suppressive effect on cell motility and metastasis in breast cancer. Our results suggest prognostic and predictive potential for the miR-30 family, which warrants further investigation.

CIP2A Interacts with TopBP1 and Drives Basal-Like Breast Cancer Tumorigenesis.

Basal-like breast cancers (BLBC) are characterized by defects in homologous recombination (HR), deficient mitotic checkpoint, and high-proliferation activity. Here, we discover CIP2A as a candidate driver of BLBC. CIP2A was essential for DNA damage-induced initiation of mouse BLBC-like mammary tumors and for survival of HR-defective BLBC cells. CIP2A was dispensable for normal mammary gland development and for unperturbed mitosis, but selectively essential for mitotic progression of DNA damaged cells. A direct interaction between CIP2A and a DNA repair scaffold protein TopBP1 was identified, and CIP2A inhibition resulted in enhanced DNA damage-induced TopBP1 and RAD51 recruitment to chromatin in mammary epithelial cells. In addition to its role in tumor initiation, and survival of BRCA-deficient cells, CIP2A also drove proliferative MYC and E2F1 signaling in basal-like triple-negative breast cancer (BL-TNBC) cells. Clinically, high CIP2A expression was associated with poor patient prognosis in BL-TNBCs but not in other breast cancer subtypes. Small-molecule reactivators of PP2A (SMAP) inhibited CIP2A transcription, phenocopied the CIP2A-deficient DNA damage response (DDR), and inhibited growth of patient-derived BLBC xenograft. In summary, these results demonstrate that CIP2A directly interacts with TopBP1 and coordinates DNA damage-induced mitotic checkpoint and proliferation, thereby driving BLBC initiation and progression. SMAPs could serve as a surrogate therapeutic strategy to inhibit the oncogenic activity of CIP2A in BLBCs. SIGNIFICANCE: These results identify CIP2A as a nongenetic driver and therapeutic target in basal-like breast cancer that regulates DNA damage-induced G2-M checkpoint and proliferative signaling.

Corrigendum: Adult-Onset Anti-Citrullinated Peptide Antibody-Negative Destructive Rheumatoid Arthritis Is Characterized by a Disease-Specific CD8+ T Lymphocyte Signature.

[This corrects the article DOI: 10.3389/fimmu.2020.578848.].