The Spatial Extracellular Proteomic Tumor Microenvironment Distinguishes Molecular Subtypes of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) mortality rates continue to increase faster than those of other cancer types due to high heterogeneity, which limits diagnosis and treatment. Pathological and molecular subtyping have identified that HCC tumors with poor outcomes are characterized by intratumoral collagenous accumulation. However, the translational and post-translational regulation of tumor collagen, which is critical to the outcome, remains largely unknown. Here, we investigate the spatial extracellular proteome to understand the differences associated with HCC tumors defined by Hoshida transcriptomic subtypes of poor outcome (Subtype 1; S1; n = 12) and better outcome (Subtype 3; S3; n = 24) that show differential stroma-regulated pathways. Collagen-targeted mass spectrometry imaging (MSI) with the same-tissue reference libraries, built from untargeted and targeted LC-MS/MS was used to spatially define the extracellular microenvironment from clinically-characterized, formalin-fixed, paraffin-embedded tissue sections. Collagen α-1(I) chain domains for discoidin-domain receptor and integrin binding showed distinctive spatial distribution within the tumor microenvironment. Hydroxylated proline (HYP)-containing peptides from the triple helical regions of fibrillar collagens distinguished S1 from S3 tumors. Exploratory machine learning on multiple peptides extracted from the tumor regions could distinguish S1 and S3 tumors (with an area under the receiver operating curve of ≥0.98; 95% confidence intervals between 0.976 and 1.00; and accuracies above 94%). An overall finding was that the extracellular microenvironment has a high potential to predict clinically relevant outcomes in HCC.

The retrotransposon - derived capsid genes PNMA1 and PNMA4 maintain reproductive capacity.

The human genome contains 24 gag -like capsid genes derived from deactivated retrotransposons conserved among eutherians. Although some of their encoded proteins retain the ability to form capsids and even transfer cargo, their fitness benefit has remained elusive. Here we show that the gag -like genes PNMA1 and PNMA4 support reproductive capacity. Six-week-old mice lacking either Pnma1 or Pnma4 are indistinguishable from wild-type littermates, but by six months the mutant mice become prematurely subfertile, with precipitous drops in sex hormone levels, gonadal atrophy, and abdominal obesity; overall they produce markedly fewer offspring than controls. Analysis of donated human ovaries shows that expression of both genes declines normally with aging, while several PNMA1 and PNMA4 variants identified in genome-wide association studies are causally associated with low testosterone, altered puberty onset, or obesity. These findings expand our understanding of factors that maintain human reproductive health and lend insight into the domestication of retrotransposon-derived genes.

Pavement ant extract is a chemotaxis repellent for C. elegans.

Ant behavior relies on a collection of natural products, from following trail pheromones during foraging to warding off potential predators. How nervous systems sense these compounds to initiate a behavioral response remains unclear. Here, we used Caenorhabditis elegans chemotaxis assays to investigate how ant compounds are detected by heterospecific nervous systems. We found that C. elegans avoid extracts of the pavement ant ( Tetramorium immigrans ) and either osm-9 or tax-4 ion channels are required for this response. These experiments were conducted in an undergraduate laboratory course, demonstrating that new insights into interspecies interactions can be generated through genuine research experiences in a classroom setting.

DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.

Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors for a wide range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed "DrugMap," an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NF-κB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NF-κB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription-factor activity.

Primitive purine biosynthesis connects ancient geochemistry to modern metabolism.

An unresolved question in the origin and evolution of life is whether a continuous path from geochemical precursors to the majority of molecules in the biosphere can be reconstructed from modern-day biochemistry. Here we identified a feasible path by simulating the evolution of biosphere-scale metabolism, using only known biochemical reactions and models of primitive coenzymes. We find that purine synthesis constitutes a bottleneck for metabolic expansion, which can be alleviated by non-autocatalytic phosphoryl coupling agents. Early phases of the expansion are enriched with enzymes that are metal dependent and structurally symmetric, supporting models of early biochemical evolution. This expansion trajectory suggests distinct hypotheses regarding the tempo, mode and timing of metabolic pathway evolution, including a late appearance of methane metabolisms and oxygenic photosynthesis consistent with the geochemical record. The concordance between biological and geological analyses suggests that this trajectory provides a plausible evolutionary history for the vast majority of core biochemistry.

DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.

Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors of a wide-range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed DrugMap , an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NFκB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NFκB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription factor activity.

Life detection in a universe of false positives: Can the Fatal Flaws of Exoplanet Biosignatures be Overcome Absent a Theory of Life?

Astrobiology aims to determine the distribution and diversity of life in the universe. But as the word "biosignature" suggests, what will be detected is not life itself, but an observation implicating living systems. Our limited access to other worlds suggests this observation is more likely to reflect out-of-equilibrium gasses than a writhing octopus. Yet, anything short of a writhing octopus will raise skepticism about what has been detected. Resolving that skepticism requires a theory to delineate processes due to life and those due to abiotic mechanisms. This poses an existential question for life detection: How do astrobiologists plan to detect life on exoplanets via features shared between non-living and living systems? We argue that you cannot without an underlying theory of life. We illustrate this by analyzing the hypothetical detection of an "Earth 2.0" exoplanet. Without a theory of life, we argue the community should focus on identifying unambiguous features of life via four areas: examining life on Earth, building life in the lab, probing the solar system, and searching for technosignatures. Ultimately, we ask, what exactly do astrobiologists hope to learn by searching for life?

Identifying robust adaptive irrigation operating policies to balance deeply uncertain economic food production and groundwater sustainability trade-offs.

Increasing irrigation demand has heavily relied on groundwater use, especially in places with highly variable water supplies that are vulnerable to drought. Groundwater management in agriculture is becoming increasingly challenging given the growing effects from overdraft and groundwater depletion worldwide. However, multiple challenges emerge when seeking to develop sustainable groundwater management in irrigated systems, such as trade-offs between the economic revenues from food production and groundwater resources, as well as the broad array of uncertainties in food-water systems. In this study we explore the applicability of Evolutionary Multi-Objective Direct Policy Search (EMODPS) to identify adaptive irrigation policies that water agencies and farmers can implement including operational decisions related to land use and groundwater use controls as well as groundwater pumping fees. The EMODPS framework yields state-aware, adaptive policies that respond dynamically as system state conditions change, for example with variable surface water (e.g., shifting management strategies across wet versus dry years). For this study, we focus on the Semitropic Water Storage district located in the San Joaquin Valley, California to provide broader insights relevant to ongoing efforts to improve groundwater sustainability in the state. Our findings demonstrate that adaptive irrigation policies can achieve sufficiently flexible groundwater management to acceptably balance revenue and sustainability goals across a wide range of uncertain future scenarios. Among the evaluated policy decisions, pumping restrictions and reductions in inflexible irrigation demands from tree crops are actions that can support dry-year pumping while maximizing groundwater storage recovery during wet years. Policies suggest that an adaptive pumping fee is the most flexible decision to control groundwater pumping and land use.

Systemic Financial Risk Arising from Residential Flood Losses.

Direct damage from flooding at residential properties has typically been categorized as insured, with liabilities accruing to insurers, or uninsured, with costs accruing to property owners. However, residential flooding can also expose lenders and local governments to financial risk, though the distribution of this risk is not well understood. Flood losses are not limited to direct damages, but also include indirect effects such as decreases in property values, which can be substantial, though are rarely well quantified. The combination of direct damage and property value decrease influences rates of mortgage default and property abandonment in the wake of a flood, creating financial risk. In this research, property-level data on sales, mortgages, and insurance claims are used in combination with machine learning techniques and geostatistical methods to provide estimates of flood losses that are then utilized to evaluate the risk of default and abandonment in eastern North Carolina following Hurricane Florence (2018). Within the study area, Hurricane Florence generated $366M in observed insured damages and an estimated $1.77B in combined uninsured damages and property value decreases. Property owners, lenders, and local governments were exposed to an additional $562M in potential losses due to increased rates of default and abandonment. Areas with lower pre-flood property values were exposed to greater risk than areas with higher valued properties. Results suggest more highly resolved estimates of a flooding event's systemic financial risk may be useful in developing improved flood resilience strategies.

Inhibiting N-glycan processing increases the antibody binding affinity and effector function of human natural killer cells.

Novel approaches are required to improve the efficacy of immunotherapies and increase the proportion of patients who experience a benefit. Antibody-dependent cell-mediated cytotoxicity (ADCC) contributes to the efficacy of many monoclonal antibodies therapies. Natural killer (NK) cells mediate ADCC, though responses are highly variable and depend on prior treatment as well as other factors. Thus, strategies to increase NK cell activity are expected to improve multiple therapies. Both cytokine treatment and NK cell receptor engineering are being explored to increase ADCC. Post-translational modifications, including glycosylation, are widely recognized as mediators of cellular processes but minimally explored as an alternative strategy to increase ADCC. We evaluated the impact of treatment with kifunensine, an inhibitor of asparagine-linked (N-)glycan processing, on ADCC using primary and cultured human NK cells. We also probed affinity using binding assays and CD16a structure with nuclear magnetic resonance spectroscopy. Treating primary human NK cells and cultured YTS-CD16a cells with kifunensine doubled ADCC in a CD16a-dependent manner. Kifunensine treatment also increased the antibody-binding affinity of CD16a on the NK cell surface. Structural interrogation identified a single CD16a region, proximal to the N162 glycan and the antibody-binding interface, perturbed by the N-glycan composition. The observed increase in NK cell activity following kifunensine treatment synergized with afucosylated antibodies, further increasing ADCC by an additional 33%. These results demonstrate native N-glycan processing is an important factor that limits NK cell ADCC. Furthermore, optimal antibody and CD16a glycoforms are defined that provide the greatest ADCC activity.

Systematic identification of anticancer drug targets reveals a nucleus-to-mitochondria ROS-sensing pathway.

Multiple anticancer drugs have been proposed to cause cell death, in part, by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs, exactly how the resultant ROS function and are sensed is poorly understood. It remains unclear which proteins the ROS modify and their roles in drug sensitivity/resistance. To answer these questions, we examined 11 anticancer drugs with an integrated proteogenomic approach identifying not only many unique targets but also shared ones-including ribosomal components, suggesting common mechanisms by which drugs regulate translation. We focus on CHK1 that we find is a nuclear H2O2 sensor that launches a cellular program to dampen ROS. CHK1 phosphorylates the mitochondrial DNA-binding protein SSBP1 to prevent its mitochondrial localization, which in turn decreases nuclear H2O2. Our results reveal a druggable nucleus-to-mitochondria ROS-sensing pathway-required to resolve nuclear H2O2 accumulation and mediate resistance to platinum-based agents in ovarian cancers.

Identification of chemotherapy targets reveals a nucleus-to-mitochondria ROS sensing pathway.

Multiple chemotherapies are proposed to cause cell death in part by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs exactly how the resultant ROS function and are sensed is poorly understood. In particular, it's unclear which proteins the ROS modify and their roles in chemotherapy sensitivity/resistance. To answer these questions, we examined 11 chemotherapies with an integrated proteogenomic approach identifying many unique targets for these drugs but also shared ones including ribosomal components, suggesting one mechanism by which chemotherapies regulate translation. We focus on CHK1 which we find is a nuclear H 2 O 2 sensor that promotes an anti-ROS cellular program. CHK1 acts by phosphorylating the mitochondrial-DNA binding protein SSBP1, preventing its mitochondrial localization, which in turn decreases nuclear H 2 O 2 . Our results reveal a druggable nucleus-to-mitochondria ROS sensing pathway required to resolve nuclear H 2 O 2 accumulation, which mediates resistance to platinum-based chemotherapies in ovarian cancers.

Positron emission tomography/computed tomography differentiates resectable thymoma from anterior mediastinal lymphoma.

OBJECTIVE: Discrete anterior mediastinal masses most often represent thymoma or lymphoma. Lymphoma treatment is nonsurgical and requires biopsy. Noninvasive thymoma is ideally resected without biopsy, which may potentiate pleural metastases. This study sought to determine if clinical criteria or positron emission tomography/computed tomography could accurately differentiate the 2, guiding a direct surgery versus biopsy decision. METHODS: A total of 48 subjects with resectable thymoma and 29 subjects with anterior mediastinal lymphoma treated from 2006 to 2019 were retrospectively examined. All had pretreatment positron emission tomography/computed tomography and appeared resectable (solitary, without clear invasion or metastasis). Reliability of clinical criteria (age and B symptoms) and positron emission tomography/computed tomography maximum standardized uptake value were assessed in differentiating thymoma and lymphoma using Wilcoxon rank-sum test, chi-square test, and logistic regression. Receiver operating characteristic analysis identified the maximum standardized uptake value threshold most associated with thymoma. RESULTS: There was no association between tumor type and age group (P = .183) between those with thymoma versus anterior mediastinal lymphoma. Patients with thymoma were less likely to report B symptoms (P < .001). The median maximum standardized uptake value of thymoma and lymphoma differed dramatically: 4.35 versus 18.00 (P < .001). Maximum standardized uptake value was independently associated with tumor type on multivariable regression. On receiver operating characteristic analysis, lower maximum standardized uptake value was associated with thymoma. Maximum standardized uptake value less than 12.85 was associated with thymoma with 100.00% sensitivity and 88.89% positive predictive value. Maximum standardized uptake value less than 7.50 demonstrated 100.00% positive predictive value for thymoma. CONCLUSIONS: Positron emission tomography/computed tomography maximum standardized uptake value of resectable anterior mediastinal masses may help guide a direct surgery versus biopsy decision. Tumors with maximum standardized uptake value less than 7.50 are likely thymoma and thus perhaps appropriately resected without biopsy. Tumors with maximum standardized uptake value greater than 7.50 should be biopsied to rule out lymphoma. Lymphoma is likely with maximum standardized uptake value greater than 12.85.

Disrupted network switching in euthymic bipolar disorder: Working memory and self-referential paradigms.

BACKGROUND: Patients with bipolar disorder (BD) frequently suffer from neurocognitive deficits that can persist during periods of clinical stability. Specifically, impairments in executive functioning such as working memory and in self-processing have been identified as the main components of the neurocognitive profile observed in euthymic BD patients. The study of the neurobiological correlates of these state-independent alterations may be a prerequisite to develop reliable biomarkers in BD. METHODS: A sample of 27 euthymic BD patients and 25 healthy participants (HC) completed working memory and self-referential functional Magnetic Resonance Imaging (fMRI) tasks. Activation maps obtained for each group and contrast images (i.e., 2-back > 1-back/self > control) were used for comparisons between patients and HC. RESULTS: Euthymic BD patients, in comparison to HC, showed a higher ventromedial prefrontal cortex activation during working memory, a result driven by the lack of deactivation in BD patients. In addition, euthymic BD patients displayed a greater dorsomedial and dorsolateral prefrontal cortex activation during self-reference processing. LIMITATIONS: Pharmacotherapy was described but not included as a confounder in our models. Sample size was modest. CONCLUSION: Our findings revealed a lack of deactivation in the anterior default mode network (aDMN) during a working memory task, a finding consistent with prior research in BD patients, but also a higher activation in frontal regions within the central executive network (CEN) during self-processing. These results suggest that an imbalance of neural network dynamics underlying external/internal oriented cognition (the CEN and the aDMN, respectively) may be one of the first reliable biomarkers in euthymic bipolar patients.

Evolution and antiviral activity of a human protein of retroviral origin.

Endogenous retroviruses are abundant components of mammalian genomes descended from ancient germline infections. In several mammals, the envelope proteins encoded by these elements protect against exogenous viruses, but this activity has not been documented with endogenously expressed envelopes in humans. We report that the human genome harbors a large pool of envelope-derived sequences with the potential to restrict retroviral infection. To test this, we characterized an envelope-derived protein, Suppressyn. We found that Suppressyn is expressed in human preimplantation embryos and developing placenta using its ancestral retroviral promoter. Cell culture assays showed that Suppressyn, and its hominoid orthologs, could restrict infection by extant mammalian type D retroviruses. Our data support a generalizable model of retroviral envelope co-option for host immunity and genome defense.

An open source computational workflow for the discovery of autocatalytic networks in abiotic reactions.

A central question in origins of life research is how non-entailed chemical processes, which simply dissipate chemical energy because they can do so due to immediate reaction kinetics and thermodynamics, enabled the origin of highly-entailed ones, in which concatenated kinetically and thermodynamically favorable processes enhanced some processes over others. Some degree of molecular complexity likely had to be supplied by environmental processes to produce entailed self-replicating processes. The origin of entailment, therefore, must connect to fundamental chemistry that builds molecular complexity. We present here an open-source chemoinformatic workflow to model abiological chemistry to discover such entailment. This pipeline automates generation of chemical reaction networks and their analysis to discover novel compounds and autocatalytic processes. We demonstrate this pipeline's capabilities against a well-studied model system by vetting it against experimental data. This workflow can enable rapid identification of products of complex chemistries and their underlying synthetic relationships to help identify autocatalysis, and potentially self-organization, in such systems. The algorithms used in this study are open-source and reconfigurable by other user-developed workflows.

An Evaluation of Annual Adherence to Lung Cancer Screening in a Large National Cohort.

INTRODUCTION: Lung cancer screening reduces mortality in large RCTs where adherence is high. Unfortunately, recently published adherence rates do not replicate those seen in trials. Previous publications support a centralized approach to ensure patient eligibility and improve adherence. METHODS: Investigators reviewed a large, geographically diverse cohort of patients from 14 health systems, with 73 centers across the U.S. Lung cancer screening patients were screened from 2015 to 2019 and tracked utilizing a commercial system. Data were analyzed in 2019-2021. Demographics, eligibility, imaging results, and cancer diagnosis were collected. Overall return was calculated for 2 years (Time 0-Time 1 and Time 1-Time 2) on the basis of follow-up through March 31, 2020. Only U.S. Preventive Services Task Force-eligible patients with a normal or benign result (Lung-Reporting and Data System 1 or 2) at baseline (Time 0) were included in annual adherence calculations. RESULTS: A total of 30,166 patients were screened; 50% were male, with a mean age of 65 years. Most individuals currently smoked (58.3%), with an average of 48.3 pack years. A total of 58% were White, 6% were Black, and 34% had race information unavailable. U.S. Preventive Services Task Force eligibility criteria were not met by 10.6%. Of the 26,958 patients eligible at baseline, 76% were Lung-Reporting and Data System 1 or 2. Annual adherence at Year 1 (Time 0-Time 1) was 48.4%. Adherence at Year 2 (Time 1-Time 2) was 44.4%. A total of 93 U.S. Preventive Services Task Force‒eligible patients were diagnosed with lung cancers, mostly during the first annual follow-up. CONCLUSIONS: In this large cohort screened and managed primarily using a commercial tracking platform, most patients were U.S. Preventive Services Task Force eligible. However, annual adherence was poor despite this resource, suggesting that additional interventions are needed to recognize the full mortality benefit from screening programs.

Guideline-Recommended Lung Cancer Screening Adherence Is Superior With a Centralized Approach.

BACKGROUND: To recognize fully the benefit of lung cancer screening (LCS), annual adherence must approach the high levels seen in the National Lung Screening Trial. Emerging data suggest that annual adherence is poor and that a centralized approach to screening improves adherence. RESEARCH QUESTIONS: Do differences in adherence exist between a centralized and decentralized approach to LCS within a hybrid program and what are predictors of adherence? STUDY DESIGN AND METHODS: A retrospective evaluation of a single-center hybrid LCS program was conducted to compare outcomes including patient eligibility and adherence between the centralized and decentralized approaches. Patient demographics and outcomes were compared between those screened with a centralized and decentralized approach and between adherent and nonadherent patients using two-sample t tests, χ 2 tests, or analyses of variance, as appropriate. Annual adherence analysis was conducted using data from patients who remained eligible for screening with a baseline Lung CT Screening Reporting and Data System (Lung-RADS) score of 1 or 2. Logistic regression was used to estimate the association between adherence and the primary exposure, adjusting for potential confounders. RESULTS: A cohort of 1,117 patients underwent baseline low-dose CT imaging. Two hundred eleven patients (19%) were ineligible by United States Preventative Services Task Force criteria and most (90%) were screened with the decentralized approach. After exclusions, 765 patients with Lung-RADS score of 1 or 2 remained eligible for annual screening. Overall adherence was 56%; however, adherence in the centralized program was 70%, compared with 41% with the decentralized approach (P < .001). Individuals screened in a decentralized approach were 73% less likely to be adherent (OR, 0.27; 95% CI, 0.19-0.37). A greater proportion of patients with three or more comorbidities were screened outside the centralized program. INTERPRETATION: Those screened using a centralized approach were more likely to meet eligibility criteria for LCS and more likely to return for annual screening than those screened using a decentralized approach.

Impact of Prebiotic ß-glucan Treatment at Juvenile Age on the Gut Microbiota Composition and the Eventual Type 1 Diabetes Onset in Non-obese Diabetic Mice.

Complex dietary polysaccharides such as ß-glucans are widely used for their anti-inflammatory properties. We reported before that oral administration of Yeast ß-glucan (YBG) in adult mice can help delay type 1 diabetes (T1D) onset and suppress gut inflammation through modulation of the structure and function of gut microbiota. Since juvenile age is characterized by profoundly changing immature gut microbiota, we examined the impact of oral treatment with YBG in non-obese diabetic (NOD) mice at this age. Juvenile mice that received daily oral administration of YBG starting at 15 days of age for 7 or 30 days were examined for changes in gut microbiota, immune characteristics, and T1D incidence. Mice that received YBG for 30 days but not 7 days, showed considerable changes in the composition and diversity of fecal microbiota as compared to controls. Predictive functional analysis, based on 16S rDNA sequences, revealed overrepresentation of glycan biosynthesis and metabolism, energy metabolism, and fatty acid biosynthesis pathways in mice that received YBG for 30 days. Immune phenotype of the colon showed skewing toward immune regulatory and Th17 cytokines with increases in IL-10, IL-17, and IL-21 and a decrease in TNF-α, although increases in some pro-inflammatory cytokines (IL-1b, IFN-γ) were observed. Most importantly, mice that received YBG treatment for 30 days showed significantly suppressed insulitis and delayed onset of hyperglycemia compared to controls. Overall, this study suggests that oral consumption of YBG beginning at pre-diabetic juvenile ages could have positive maturational changes to gut microbiota and immune functions and could result in a delay in the disease onset in those who are pre-disposed to T1D.

Endovascular Release of a 50-Year-Old Adams-Deweese IVC Clip to Facilitate Percutaneous Repair of Mitral Valve Regurgitation.

Percutaneous mitral valve (MV) repair using MitraClip requires large-caliber venous access. We describe a patient with a ligated inferior vena cava due to an Adams-DeWeese clip placed 50 years prior, who had progressive shortness of breath and lower extremity symptoms secondary to severe mitral regurgitation and chronic iliocaval deep venous thrombosis. Due to comorbidities, MitraClip was recommended over surgery for MV repair. Caval luminal gain was required to facilitate endovascular access for the MitraClip system. Stent-mediated release of the inferior vena cava clip allowed successful passage of the delivery sheath from the common femoral vein to MV and subsequent valve repair.