Redox signaling by glutathione peroxidase 2 links vascular modulation to metabolic plasticity of breast cancer.

In search of redox mechanisms in breast cancer, we uncovered a striking role for glutathione peroxidase 2 (GPx2) in oncogenic signaling and patient survival. GPx2 loss stimulates malignant progression due to reactive oxygen species/hypoxia inducible factor-α (HIF1α)/VEGFA (vascular endothelial growth factor A) signaling, causing poor perfusion and hypoxia, which were reversed by GPx2 reexpression or HIF1α inhibition. Ingenuity Pathway Analysis revealed a link between GPx2 loss, tumor angiogenesis, metabolic modulation, and HIF1α signaling. Single-cell RNA analysis and bioenergetic profiling revealed that GPx2 loss stimulated the Warburg effect in most tumor cell subpopulations, except for one cluster, which was capable of oxidative phosphorylation and glycolysis, as confirmed by coexpression of phosphorylated-AMPK and GLUT1. These findings underscore a unique role for redox signaling by GPx2 dysregulation in breast cancer, underlying tumor heterogeneity, leading to metabolic plasticity and malignant progression.

Redox signalling regulates breast cancer metastasis via phenotypic and metabolic reprogramming due to p63 activation by HIF1α.

BACKGROUND: Redox signaling caused by knockdown (KD) of Glutathione Peroxidase 2 (GPx2) in the PyMT mammary tumour model promotes metastasis via phenotypic and metabolic reprogramming. However, the tumour cell subpopulations and transcriptional regulators governing these processes remained unknown. METHODS: We used single-cell transcriptomics to decipher the tumour cell subpopulations stimulated by GPx2 KD in the PyMT mammary tumour and paired pulmonary metastases. We analyzed the EMT spectrum across the various tumour cell clusters using pseudotime trajectory analysis and elucidated the transcriptional and metabolic regulation of the hybrid EMT state. RESULTS: Integration of single-cell transcriptomics between the PyMT/GPx2 KD primary tumour and paired lung metastases unraveled a basal/mesenchymal-like cluster and several luminal-like clusters spanning an EMT spectrum. Interestingly, the luminal clusters at the primary tumour gained mesenchymal gene expression, resulting in epithelial/mesenchymal subpopulations fueled by oxidative phosphorylation (OXPHOS) and glycolysis. By contrast, at distant metastasis, the basal/mesenchymal-like cluster gained luminal and mesenchymal gene expression, resulting in a hybrid subpopulation using OXPHOS, supporting adaptive plasticity. Furthermore, p63 was dramatically upregulated in all hybrid clusters, implying a role in regulating partial EMT and MET at primary and distant sites, respectively. Importantly, these effects were reversed by HIF1α loss or GPx2 gain of function, resulting in metastasis suppression. CONCLUSIONS: Collectively, these results underscored a dramatic effect of redox signaling on p63 activation by HIF1α, underlying phenotypic and metabolic plasticity leading to mammary tumour metastasis.

Pancreatic Cystic Lesions on MRI: What Is The Likelihood of a Present or Future Diagnosis of Pancreatic Carcinoma?

BACKGROUND: Pancreatic cystic lesions (PCLs) are followed for years due to older and likely biased works demonstrating a strong association with pancreatic carcinoma; more recent data are needed clarifying this relationship. PURPOSE: To determine the association between PCLs on MRI and a synchronous or future diagnosis of pancreatic carcinoma. STUDY TYPE: Single-center retrospective cohort. POPULATION: A total of 192 patients (111 female, 58%) with median age 66 years (range 26-87 years) with PCLs on abdominal MRI from 2011 to 2016. FIELD STRENGTH/SEQUENCES: 1.5 T and 3 T, including T2 WI, T1 WI, diffusion weighted imaging and contrast-enhanced T1 WI. ASSESSMENT: Each PCL was reviewed independently by 2 of 10 fellowship-trained abdominal radiologists. Fukuoka guideline worrisome features and high-risk stigmata were evaluated. Follow-up imaging and clinical notes were reviewed within a system that captures pancreatic carcinoma for the region, for a median follow-up of 67 months (interquartile range: 43-88 months). STATISTICAL TESTS: Pancreatic carcinoma prevalence and incidence rate for future carcinoma with 95% confidence intervals (95% CI). Fisher exact test, logistic regression with odds ratios (OR) and the Wilcoxon rank-sum test were used to assess PCL morphologic features with the Kolmogorov-Smirnov test used to assess for normality. P < 0.05 defined statistical significance. RESULTS: The prevalence of pancreatic carcinoma on initial MRI showing a PCL was 2.4% (95% CI: 0.9%, 5.2%). Thickened/enhancing cyst wall was associated with pancreatic carcinoma, OR 52 (95% CI: 4.5, 1203). Of 189 patients with a PCL but without pancreatic carcinoma at the time of initial MRI, one developed high-grade dysplasia and none developed invasive carcinoma for an incidence rate of 0.97 (95% CI: 0.02, 5.43) and 0 (95% CI: 0, 3.59) cases per 1000 person-years, respectively. DATA CONCLUSION: A low percentage of patients with a PCL on MRI had a pancreatic carcinoma at the time of initial evaluation and none developed carcinoma over a median 67 months of follow-up. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: 5.

MRI vs. CT for pancreatic adenocarcinoma vascular invasion: comparative diagnostic test accuracy systematic review and meta-analysis.

OBJECTIVES: To perform a systematic review comparing the diagnostic accuracy of MRI vs. CT for assessing pancreatic ductal adenocarcinoma (PDAC) vascular invasion. METHODS: MEDLINE, EMBASE, Cochrane Central, and Scopus were searched until December 2021 for diagnostic accuracy studies comparing MRI vs. CT to evaluate vascular invasion of pathologically confirmed PDAC in the same patients. Findings on resection or exploratory laparotomy were the preferred reference standard. Data extraction, risk of bias, and applicability assessment were performed by two authors using the Quality Assessment of Diagnostic Accuracy Studies-Comparative Tool. Bivariate random-effects meta-analysis and meta-regression were performed with 95% confidence intervals (95% CI). RESULTS: Three studies were included assessing 474 vessels without vascular invasion and 65 with vascular invasion in 107 patients. All patients were imaged using MRI at ≥ 1.5 T and a pancreatic protocol CT. No difference was shown between MRI and CT for diagnosing PDAC vascular invasion: MRI/CT sensitivity (95% CI) were 71% (47-87%)/74% (56-86%), and specificity were 97% (94-99%)/97% (94-98%). Sources of bias included selection bias from only a subset of CT patients undergoing MRI and verification bias from patients with unresectable disease not confirmed on surgery. No patients received neoadjuvant therapy prior to staging. CONCLUSIONS: Based on limited data, no difference was observed between MRI and pancreatic protocol CT for PDAC vascular invasion assessment. MRI may be an adequate substitute for pancreatic protocol CT in some patients, particularly those who have already had a single-phase CT. Larger and more recent cohort studies at low risk of bias, including patients who have received neoadjuvant therapy, are needed. CLINICAL RELEVANCE STATEMENT: Abdominal MRI performed similarly to pancreatic protocol CT at assessing pancreatic ductal adenocarcinoma vascular invasion, suggesting local staging is adequate in some patients using MRI. More data are needed using larger, more recent cohorts including patients with neoadjuvant treatment. KEY POINTS: • Based on limited data, no difference was found between MRI and pancreatic protocol CT sensitivity and specificity for diagnosing PDAC vascular invasion (p = 0.81, 0.73 respectively). • Risk of bias could be reduced in future PDAC MRI vs CT comparative diagnostic test accuracy research by ensuring all enrolled patients undergo both imaging modalities being compared in random order and regardless of the findings on either modality. • More studies are needed that directly compare the diagnostic performance of MRI and CT for PDAC staging after neoadjuvant therapy.

Hypovascular pancreas head adenocarcinoma: CT texture analysis for assessment of resection margin status and high-risk features.

OBJECTIVES: To determine if CT texture analysis features are associated with hypovascular pancreas head adenocarcinoma (PHA) postoperative margin status, nodal status, grade, lymphovascular invasion (LVI), and perineural invasion (PNI). METHODS: This Research Ethics Board-approved retrospective cohort study included 131 consecutive patients with resected PHA. Tumors were segmented on preoperative contrast-enhanced CT. Tumor diameter and texture analysis features including mean, minimum and maximum Hounsfield units, standard deviation, skewness, kurtosis, and entropy and gray-level co-occurrence matrix (GLCM) features correlation and dissimilarity were extracted. Two-sample t test and logistic regression were used to compare parameters for prediction of margin status, nodal status, grade, LVI, and PNI. Diagnostic accuracy was assessed using receiver operating characteristic curves and Youden method was used to establish cutpoints. RESULTS: Margin status was associated with GLCM correlation (p = 0.012) and dissimilarity (p = 0.003); nodal status was associated with standard deviation (p = 0.026) and entropy (p = 0.031); grade was associated with kurtosis (p = 0.031); LVI was associated with standard deviation (p = 0.047), entropy (p = 0.026), and GLCM correlation (p = 0.033) and dissimilarity (p = 0.011). No associations were found for PNI (p > 0.05). Logistic regression yielded an area under the curve of 0.70 for nodal disease, 0.70 for LVI, 0.68 for grade, and 0.65 for margin status. Optimal sensitivity/specificity was as follows: nodal disease 73%/72%, LVI 72%/65%, grade 55%/83%, and margin status 63%/66%. CONCLUSIONS: CT texture analysis features demonstrate fair diagnostic accuracy for assessment of hypovascular PHA nodal disease, LVI, grade, and postoperative margin status. Additional research is rapidly needed to identify these high-risk features with better accuracy. KEY POINTS: • CT texture analysis features are associated with pancreas head adenocarcinoma postoperative margin status which may help inform treatment decisions as a negative resection margin is required for cure. • CT texture analysis features are associated with pancreas head adenocarcinoma nodal disease, a poor prognostic feature. • Indicators of more aggressive pancreas head adenocarcinoma biology including tumor grade and LVI can be diagnosed using CT texture analysis with fair accuracy.

Diagnostic Accuracy of Single-Phase Computed Tomography Texture Analysis for Prediction of LI-RADS v2018 Category.

OBJECTIVE: The aim of this study was to determine if texture analysis can classify liver observations likely to be hepatocellular carcinoma based on the Liver Imaging Reporting and Data System (LI-RADS) using single portal venous phase computed tomography. METHODS: This research ethics board-approved retrospective cohort study included 64 consecutive LI-RADS observations. Individual observation texture analysis features were compared using Kruskal-Wallis and 2 sample t tests. Logistic regression was used for prediction of LI-RADS group. Diagnostic accuracy was assessed using receiver operating characteristic curves and Youden method. RESULTS: Multiple texture features were associated with LI-RADS including the mean HU (P = 0.003), median (P = 0.002), minimum (P = 0.010), maximum (P = 0.013), standard deviation (P = 0.009), skewness (P = 0.007), and entropy (P < 0.001). On logistic regression, LI-RADS group could be predicted with area under the curve, sensitivity, and specificity of 0.98, 96%, and 100%, respectively. CONCLUSIONS: Texture analysis features on portal venous phase computed tomography can identify liver observations likely to be hepatocellular carcinoma, which may preclude the need to recall some patients for additional multiphase imaging.

Structural diversity of xylans in the cell walls of monocots.

MAIN CONCLUSION: Xylans in the cell walls of monocots are structurally diverse. Arabinofuranose-containing glucuronoxylans are characteristic of commelinids. However, other structural features are not correlated with the major transitions in monocot evolution. Most studies of xylan structure in monocot cell walls have emphasized members of the Poaceae (grasses). Thus, there is a paucity of information regarding xylan structure in other commelinid and in non-commelinid monocot walls. Here, we describe the major structural features of the xylans produced by plants selected from ten of the twelve monocot orders. Glucuronoxylans comparable to eudicot secondary wall glucuronoxylans are abundant in non-commelinid walls. However, the α-D-glucuronic acid/4-O-methyl-α-D-glucuronic acid is often substituted at O-2 by an α-L-arabinopyranose residue in Alismatales and Asparagales glucuronoxylans. Glucuronoarabinoxylans were the only xylans detected in the cell walls of five different members of the Poaceae family (grasses). By contrast, both glucuronoxylan and glucuronoarabinoxylan are formed by the Zingiberales and Commelinales (commelinids). At least one species of each monocot order, including the Poales, forms xylan with the reducing end sequence -4)-ß-D-Xylp-(1,3)-α-L-Rhap-(1,2)-α-D-GalpA-(1,4)-D-Xyl first identified in eudicot and gymnosperm glucuronoxylans. This sequence was not discernible in the arabinopyranose-containing glucuronoxylans of the Alismatales and Asparagales or the glucuronoarabinoxylans of the Poaceae. Rather, our data provide additional evidence that in Poaceae glucuronoarabinoxylan, the reducing end xylose residue is often substituted at O-2 with 4-O-methyl glucuronic acid or at O-3 with arabinofuranose. The variations in xylan structure and their implications for the evolution and biosynthesis of monocot cell walls are discussed.

Open-Flask Synthesis of Amine-Boranes via Tandem Amine-Ammonium Salt Equilibration-Metathesis.

An amine-ammonium salt equilibration-metathesis sequence provides high-purity amine-boranes in excellent yields from sodium borohydride in refluxing reagent-grade tetrahydrofuran in an open flask.

Posterior talus osteochondroma a rare location, treated by posterior ankle arthroscopy.

The common cause of posterior ankle impingement syndrome is impingement of the Os trigonum or the posterior talar process. We report a case of a 46-year-old lady having osteochondroma of the posterior talar process, a rare occurrence at this site. This patient was treated with posterior ankle arthroscopic excision through the 2-portal posterior ankle arthroscopy technique in the prone position. 6 months post-operatively, her ankle pain disappeared and ankle range of movement improved significantly and there is no recurrence of the tumour.

Amine-boranes: green hypergolic fuels with consistently low ignition delays.

Complexation of amines with borane converts them to hypergols or decreases their ignition delays (IDs) multifold (with white fuming nitric acid as the oxidant). With consistently low IDs, amine-boranes represent a class of compounds that can be promising alternatives to toxic hydrazine and its derivatives as propellants. A structure-hypergolicity relationship study reveals the necessary features for the low ID.

A scoping review of natural language processing of radiology reports in breast cancer.

Various natural language processing (NLP) algorithms have been applied in the literature to analyze radiology reports pertaining to the diagnosis and subsequent care of cancer patients. Applications of this technology include cohort selection for clinical trials, population of large-scale data registries, and quality improvement in radiology workflows including mammography screening. This scoping review is the first to examine such applications in the specific context of breast cancer. Out of 210 identified articles initially, 44 met our inclusion criteria for this review. Extracted data elements included both clinical and technical details of studies that developed or evaluated NLP algorithms applied to free-text radiology reports of breast cancer. Our review illustrates an emphasis on applications in diagnostic and screening processes over treatment or therapeutic applications and describes growth in deep learning and transfer learning approaches in recent years, although rule-based approaches continue to be useful. Furthermore, we observe increased efforts in code and software sharing but not with data sharing.

Sequential transcatheter aortic and pulmonic valve replacement in bioprosthetic valve dysfunction: a case report.

Background: Transcatheter valve replacement is a less invasive alternative to surgical valve replacement and has become increasingly popular. It is often the preferred approach for patients with high surgical risk. In patients with multiple prior sternotomies and multi-valvular failure, sequential transcatheter valve replacements may be a viable option. Case summary: We present the case of a 61-year-old-man with two prior sternotomies who underwent sequential transcatheter replacements of the aortic and pulmonic valves for symptomatic aortic and pulmonary stenosis. He was deemed high risk for a repeat sternotomy. The decision to perform sequential transcatheter aortic valve replacement (TAVR) and transcatheter pulmonic valve replacement (TPVR) a month apart was made. Patient underwent valve-in-valve TAVR in a stentless bioprosthetic valve with 29-mm Edwards Sapien 3 followed by TPVR with 26-mm Edwards Sapien 3. He tolerated both procedures well and was asymptomatic at 1-month follow up. Discussion: To our knowledge, this is the first reported successful case of sequential TAVR and TPVR with right ventricular outflow tract stenting in a patient with both aortic and pulmonic bioprosthetic valve dysfunction. Our case demonstrates that transcatheter approach to multi-valvular replacements may be a viable option for high-risk surgical patients.

Functional characterization of a single nucleotide polymorphism associated with Alzheimer's disease in a hiPSC-based neuron model.

Neurodegenerative diseases encompass a group of debilitating conditions resulting from progressive nerve cell death. Of these, Alzheimer's disease (AD) occurs most frequently, but is currently incurable and has limited treatment success. Late onset AD, the most common form, is highly heritable but is caused by a combination of non-genetic risk factors and many low-effect genetic variants whose disease-causing mechanisms remain unclear. By mining the FinnGen study database of phenome-wide association studies, we identified a rare variant, rs148726219, enriched in the Finnish population that is associated with AD risk and dementia, and appears to have arisen on a common haplotype with older AD-associated variants such as rs429358. The rs148726219 variant lies in an overlapping intron of the FosB proto-oncogene (FOSB) and ERCC excision repair 1 (ERCC1) genes. To understand the impact of this SNP on disease phenotypes, we performed CRISPR/Cas9 editing in a human induced pluripotent stem cell (hiPSC) line to generate isogenic clones harboring heterozygous and homozygous alleles of rs148726219. hiPSC clones differentiated into induced excitatory neurons (iNs) did not exhibit detectable molecular or morphological variation in differentiation potential compared to isogenic controls. However, global transcriptome analysis showed differential regulation of nearby genes and upregulation of several biological pathways related to neuronal function, particularly synaptogenesis and calcium signaling, specifically in mature iNs harboring rs148726219 homozygous and heterozygous alleles. Functional differences in iN circuit maturation as measured by calcium imaging were observed across genotypes. Edited mature iNs also displayed downregulation of unfolded protein response and cell death pathways. This study implicates a phenotypic impact of rs148726219 in the context of mature neurons, consistent with its identification in late onset AD, and underscores a hiPSC-based experimental model to functionalize GWAS-identified variants.

The ability of land plants to synthesize glucuronoxylans predates the evolution of tracheophytes.

Glucuronoxylans with a backbone of 1,4-linked ß-D-xylosyl residues are ubiquitous in the secondary walls of gymnosperms and angiosperms. Xylans have been reported to be present in hornwort cell walls, but their structures have not been determined. In contrast, the presence of xylans in the cell walls of mosses and liverworts remains a subject of debate. Here we present data that unequivocally establishes that the cell walls of leafy tissue and axillary hair cells of the moss Physcomitrella patens contain a glucuronoxylan that is structurally similar to glucuronoxylans in the secondary cell walls of vascular plants. Some of the 1,4-linked ß-D-xylopyranosyl residues in the backbone of this glucuronoxylan bear an α-D-glucosyluronic acid (GlcpA) sidechain at O-2. In contrast, the lycopodiophyte Selaginella kraussiana synthesizes a glucuronoxylan substituted with 4-O-Me-α-D-GlcpA sidechains, as do many hardwood species. The monilophyte Equisetum hyemale produces a glucuronoxylan with both 4-O-Me-α-D-GlcpA and α-D-GlcpA sidechains, as does Arabidopsis. The seedless plant glucuronoxylans contain no discernible amounts of the reducing-end sequence that is characteristic of gymnosperm and eudicot xylans. Phylogenetic studies showed that the P. patens genome contains genes with high sequence similarity to Arabidopsis CAZy family GT8, GT43 and GT47 glycosyltransferases that are likely involved in xylan synthesis. We conclude that mosses synthesize glucuronoxylan that is structurally similar to the glucuronoxylans present in the secondary cell walls of lycopodiophytes, monilophytes, and many seed-bearing plants, and that several of the glycosyltransferases required for glucuronoxylan synthesis evolved before the evolution of tracheophytes.

scShapes: a statistical framework for identifying distribution shapes in single-cell RNA-sequencing data.

BACKGROUND: Single-cell RNA sequencing (scRNA-seq) methods have been advantageous for quantifying cell-to-cell variation by profiling the transcriptomes of individual cells. For scRNA-seq data, variability in gene expression reflects the degree of variation in gene expression from one cell to another. Analyses that focus on cell-cell variability therefore are useful for going beyond changes based on average expression and, instead, identifying genes with homogeneous expression versus those that vary widely from cell to cell. RESULTS: We present a novel statistical framework, scShapes, for identifying differential distributions in single-cell RNA-sequencing data using generalized linear models. Most approaches for differential gene expression detect shifts in the mean value. However, as single-cell data are driven by overdispersion and dropouts, moving beyond means and using distributions that can handle excess zeros is critical. scShapes quantifies gene-specific cell-to-cell variability by testing for differences in the expression distribution while flexibly adjusting for covariates if required. We demonstrate that scShapes identifies subtle variations that are independent of altered mean expression and detects biologically relevant genes that were not discovered through standard approaches. CONCLUSIONS: This analysis also draws attention to genes that switch distribution shapes from a unimodal distribution to a zero-inflated distribution and raises open questions about the plausible biological mechanisms that may give rise to this, such as transcriptional bursting. Overall, the results from scShapes help to expand our understanding of the role that gene expression plays in the transcriptional regulation of a specific perturbation or cellular phenotype. Our framework scShapes is incorporated into a Bioconductor R package (https://www.bioconductor.org/packages/release/bioc/html/scShapes.html).

Geroscience-guided repurposing of FDA-approved drugs to target aging: A proposed process and prioritization.

Common chronic diseases represent the greatest driver of rising healthcare costs, as well as declining function, independence, and quality of life. Geroscience-guided approaches seek to delay the onset and progression of multiple chronic conditions by targeting fundamental biological pathways of aging. This approach is more likely to improve overall health and function in old age than treating individual diseases, by addressing aging the largest and mostly ignored risk factor for the leading causes of morbidity in older adults. Nevertheless, challenges in repurposing existing and moving newly discovered interventions from the bench to clinical care have impeded the progress of this potentially transformational paradigm shift. In this article, we propose the creation of a standardized process for evaluating FDA-approved medications for their geroscience potential. Criteria for systematically evaluating the existing literature that spans from animal models to human studies will permit the prioritization of efforts and financial investments for translating geroscience and allow immediate progress on the design of the next Targeting Aging with MEtformin (TAME)-like study involving such candidate gerotherapeutics.