DNA-binding protein-A promotes kidney ischemia/reperfusion injury and participates in mitochondrial function.

DNA-binding protein-A (DbpA; gene: Ybx3) belongs to the cold shock protein family with known functions in cell cycling, transcription, translation, and tight junction communication. In chronic nephritis, DbpA is upregulated. However, its activities in acute injury models, such as kidney ischemia/reperfusion injury (IRI), are unclear. To study this, mice harboring Ybx3+/+, Ybx3+/- or the Ybx3-/- genotype were characterized over 24 months and following experimental kidney IRI. Mitochondrial function, number and integrity were analyzed by mitochondrial stress tests, MitoTracker staining and electron microscopy. Western Blot, immunohistochemistry and flow cytometry were performed to quantify tubular cell damage and immune cell infiltration. DbpA was found to be dispensable for kidney development and tissue homeostasis under healthy conditions. Furthermore, endogenous DbpA protein localizes within mitochondria in primary tubular epithelial cells. Genetic deletion of Ybx3 elevates the mitochondrial membrane potential, lipid uptake and metabolism, oxygen consumption rates and glycolytic activities of tubular epithelial cells. Ybx3-/- mice demonstrated protection from IRI with less immune cell infiltration, endoplasmic reticulum stress and tubular cell damage. A presumed protective mechanism was identified via upregulated antioxidant activities and reduced ferroptosis, when Ybx3 was deleted. Thus, our studies reveal DbpA acts as a mitochondrial protein with profound adverse effects on cell metabolism and highlights a protective effect against IRI when Ybx3 is genetically deleted. Hence, preemptive DbpA targeting in situations with expected IRI, such as kidney transplantation or cardiac surgery, may preserve post-procedure kidney function.

Reduced mortality associated with pulmonary embolism response team consultation for intermediate and high-risk pulmonary embolism: a retrospective cohort study.

BACKGROUND: The management of acute pulmonary embolism (PE) has become increasingly complex with the expansion of advanced therapeutic options, resulting in the development and widespread adoption of multidisciplinary Pulmonary Embolism Response Teams (PERTs). Much of the literature evaluating the impact of PERTs has been limited by pre- postimplementation study design, leading to confounding by changes in global practice patterns over time, and has yielded mixed results. To address this ambiguity, we conducted a retrospective cohort study to evaluate the impact of the distinct exposures of PERT availability and direct PERT consultation. METHODS: At a single tertiary center, we conducted propensity-matched analyses of hospitalized patients with intermediate or high-risk PE. To assess the impact of PERT availability, we evaluated the changes in 30-day mortality, hospital length of stay (HLOS), time to therapeutic anticoagulation (TAC), in-hospital bleeding complications, and use of advanced therapies between the two years preceding and following PERT implementation. To evaluate the impact of direct PERT consultation, we conducted the same analyses in the post-PERT era, comparing patients who did and did not receive PERT consultation. RESULTS: Six hundred eighty four patients were included, of which 315 were pre-PERT patients. Of the 367 postPERT patients, 201 received PERT consultation. For patients who received PERT consultation, we observed a significant reduction in 30-day mortality (5% vs 20%, OR 0.38, p = 0.0024), HLOS. (-5.4 days, p < 0.001), TAC (-0.25 h, p = 0.041), and in-hospital bleeding (OR 0.28, p = 0.011). These differences were not observed evaluating the impact of PERT presence in pre-vs postimplementation eras. CONCLUSIONS: We observed a significant reduction in 30-day mortality, hospital LOS, TAC, and in-hospital bleeding complications for patients who received PERT consultation without an observed difference in these metrics when comparing the pre- vs post-implementation eras. This suggests the benefits stem from direct PERT involvement rather than the mere existence of PERT. Our data supports that PERT consultation may provide benefit to patients with acute intermediate or high-risk PE and can be achieved without a concomitant increase in advanced therapies.

Comparative Analysis of Acute Kidney Injury Models and Related Fibrogenic Responses: Convergence on Methylation Patterns Regulated by Cold Shock Protein.

BACKGROUND: Fibrosis is characterized by excessive extracellular matrix formation in solid organs, disrupting tissue architecture and function. The Y-box binding protein-1 (YB-1) regulates fibrosis-related genes (e.g., Col1a1, Mmp2, and Tgfß1) and contributes significantly to disease progression. This study aims to identify fibrogenic signatures and the underlying signaling pathways modulated by YB-1. METHODS: Transcriptomic changes associated with matrix gene patterns in human chronic kidney diseases and murine acute injury models were analyzed with a focus on known YB-1 targets. Ybx1-knockout mouse strains (Ybx1ΔRosaERT+TX and Ybx1ΔLysM) were subjected to various kidney injury models. Fibrosis patterns were characterized by histopathological staining, transcriptome analysis, qRT-PCR, methylation analysis, zymography, and Western blotting. RESULTS: Integrative transcriptomic analyses revealed that YB-1 is involved in several fibrogenic signatures related to the matrisome, the WNT, YAP/TAZ, and TGFß pathways, and regulates Klotho expression. Changes in the methylation status of the Klotho promoter by specific methyltransferases (DNMT) are linked to YB-1 expression, extending to other fibrogenic genes. Notably, kidney-resident cells play a significant role in YB-1-modulated fibrogenic signaling, whereas infiltrating myeloid immune cells have a minimal impact. CONCLUSIONS: YB-1 emerges as a master regulator of fibrogenesis, guiding DNMT1 to fibrosis-related genes. This highlights YB-1 as a potential target for epigenetic therapies interfering in this process.

Comparison of anticoagulation vs mechanical thrombectomy for the treatment of iliofemoral deep vein thrombosis.

OBJECTIVE: To compare the comparative effects of treatment with contemporary mechanical thrombectomy (MT) or anticoagulation (AC) on Villalta scores and post-thrombotic syndrome (PTS) incidence through 12 months in iliofemoral deep vein thrombosis (DVT). METHODS: Patients with DVT in the Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) randomized trial and the ClotTriever Outcomes (CLOUT) registry were included in this analysis. Both studies evaluated the effects of thrombus removal on the incidence of PTS. Patients with bilateral DVT, isolated femoral-popliteal DVT, symptom duration of >4 weeks, or incomplete case data for matching covariates were excluded. Propensity scores were used to match patients 1:1 who received AC (from ATTRACT) with those treated with mechanical thrombectomy (from CLOUT) using nearest neighbor matching on nine baseline covariates, including age, body mass index, leg treated, provoked DVT, prior venous thromboembolism, race, sex, Villalta score, and symptom duration. Clinical outcomes, including Villalta score and PTS, were assessed. Logistic regression was used to estimate the likelihood of developing PTS at 12 months. RESULTS: A total of 164 pairs were matched, with no significant differences in baseline characteristics after matching. There were fewer patients with any PTS at 6 months (19% vs 46%; P < .001) and 12 months (17% vs 38%; P < .001) in the MT treatment group. Modeling revealed that, after adjusting for baseline Villalta scores, patients treated with AC had significantly higher odds of developing any PTS (odds ratio, 3.1; 95% confidence interval, 1.5-6.2; P = .002) or moderate to severe PTS (odds ratio, 3.1; 95% confidence interval, 1.1-8.4; P = .027) at 12 months compared with those treated with MT. Mean Villalta scores were lower through 12 months among those receiving MT vs AC (3.3 vs 6.3 at 30 days, 2.5 vs 5.5 at 6 months, and 2.6 vs 4.9 at 12 months; P < .001 for all). CONCLUSIONS: MT treatment of iliofemoral DVT was associated with significantly lower Villalta scores and a lower incidence of PTS through 12 months compared with treatment using AC. Results from currently enrolling clinical trials will further clarify the role of these therapies in the prevention of PTS after an acute DVT event.

Glomerular-tubular crosstalk via cold shock Y-box binding protein-1 in the kidney.

Glomerular-tubular crosstalk within the kidney has been proposed, but the paracrine signals enabling this remain largely unknown. The cold-shock protein Y-box binding protein 1 (YBX1) is known to regulate inflammation and kidney diseases but its role in podocytes remains undetermined. Therefore, we analyzed mice with podocyte specific Ybx1 deletion (Ybx1ΔPod). Albuminuria was increased in unchallenged Ybx1ΔPod mice, which surprisingly was associated with reduced glomerular, but enhanced tubular damage. Tubular toll-like receptor 4 (TLR4) expression, node-like receptor protein 3 (NLRP3) inflammasome activation and kidney inflammatory cell infiltrates were all increased in Ybx1ΔPod mice. In vitro, extracellular YBX1 inhibited NLRP3 inflammasome activation in tubular cells. Co-immunoprecipitation, immunohistochemical analyses, microscale cell-free thermophoresis assays, and blunting of the YBX1-mediated TLR4-inhibition by a unique YBX1-derived decapeptide suggests a direct interaction of YBX1 and TLR4. Since YBX1 can be secreted upon post-translational acetylation, we hypothesized that YBX1 secreted from podocytes can inhibit TLR4 signaling in tubular cells. Indeed, mice expressing a non-secreted YBX1 variant specifically in podocytes (Ybx1PodK2A mice) phenocopied Ybx1ΔPod mice, demonstrating a tubular-protective effect of YBX1 secreted from podocytes. Lipopolysaccharide-induced tubular injury was aggravated in Ybx1ΔPod and Ybx1PodK2A mice, indicating a pathophysiological relevance of this glomerular-tubular crosstalk. Thus, our data show that YBX1 is physiologically secreted from podocytes, thereby negatively modulating sterile inflammation in the tubular compartment, apparently by binding to and inhibiting tubular TLR4 signaling. Hence, we have uncovered an YBX1-dependent molecular mechanism of glomerular-tubular crosstalk.

Six-Month Outcomes of Mechanical Thrombectomy for Treating Deep Vein Thrombosis: Analysis from the 500-Patient CLOUT Registry.

PURPOSE: Mechanical thrombectomy for the treatment of deep vein thrombosis (DVT) is being increasingly utilized to reduce symptoms and prevent postthrombotic syndrome (PTS), but more data on clinical outcomes are needed. Mechanical thrombectomy was studied in the ClotTriever Outcomes (CLOUT) registry with 6-month full analysis outcomes reported herein. MATERIALS AND METHODS: The CLOUT registry is a prospective, all-comer study that enrolled 500 lower extremity DVT patients across 43 US sites treated with mechanical thrombectomy using the ClotTriever System. Core-lab assessed Marder scores and physician-assessed venous patency by duplex ultrasound, PTS assessment using Villalta score, venous symptom severity, pain, and quality of life scores through 6 months were analyzed. Adverse events were identified and independently adjudicated. RESULTS: All-cause mortality at 30 days was 0.9%, and 8.6% of subjects experienced a serious adverse event (SAE) within the first 30 days, 1 of which (0.2%) was device related. SAE rethrombosis/residual thrombus incidence was 4.8% at 30 days and 8.0% at 6 months. Between baseline and 6 months, venous flow increased from 27.2% to 92.5% of limbs (P < 0.0001), and venous compressibility improved from 28.0% to 91.8% (P < 0.0001), while median Villalta scores improved from 9.0 at baseline to 1.0 at 6 months (P < 0.0001). Significant improvements in venous symptom severity, pain, and quality of life were also demonstrated. Outcomes from iliofemoral and isolated femoral-popliteal segments showed similar improvements. CONCLUSION: Outcomes from the CLOUT study, a large prospective registry for DVT, indicate that mechanical thrombectomy is safe and demonstrates significant improvement in symptoms and health status through 6 months. Level of Evidence 3: Non-randomized controlled cohort/follow-up study.

Excessive sodium chloride ingestion promotes inflammation and kidney fibrosis in aging mice.

In aging kidneys, a decline of function resulting from extracellular matrix (ECM) deposition and organ fibrosis is regarded as "physiological." Whether a direct link between high salt intake and fibrosis in aging kidney exists autonomously from arterial hypertension is unclear. This study explores kidney intrinsic changes (inflammation, ECM derangement) induced by a high-salt diet (HSD) in a murine model lacking arterial hypertension. The contribution of cold shock Y-box binding protein (YB-1) as a key orchestrator of organ fibrosis to the observed differences is determined by comparison with a knockout strain (Ybx1ΔRosaERT+TX). Comparisons of tissue from mice fed with normal-salt diet (NSD, standard chow) or high-salt diet (HSD, 4% NaCl in chow; 1% NaCl in water) for up to 16 mo revealed that with HSD tubular cell numbers decrease and tubulointerstitial scarring [periodic acid-Schiff (PAS), Masson's trichrome, Sirius red staining] prevails. In Ybx1ΔRosaERT+TX animals tubular cell damage, a loss of cell contacts with profound tubulointerstitial alterations, and tubular cell senescence was seen. A distinct tubulointerstitial distribution of fibrinogen, collagen type VI, and tenascin-C was detected under HSD, transcriptome analyses determined patterns of matrisome regulation. Temporal increase of immune cell infiltration was seen under HSD of wild type, but not Ybx1ΔRosaERT+TX animals. In vitro Ybx1ΔRosaERT+TX bone marrow-derived macrophages exhibited a defect in polarization (IL-4/IL-13) and abrogated response to sodium chloride. Taken together, HSD promotes progressive kidney fibrosis with premature cell aging, ECM deposition, and immune cell recruitment that is exacerbated in Ybx1ΔRosaERT+TX animals.NEW & NOTEWORTHY Short-term experimental studies link excessive sodium ingestion with extracellular matrix accumulation and inflammatory cell recruitment, yet long-term data are scarce. Our findings with a high-salt diet over 16 mo in aging mice pinpoints to a decisive tipping point after 12 mo with tubular stress response, skewed matrisome transcriptome, and immune cell infiltration. Cell senescence was aggravated in knockout animals for cold shock Y-box binding protein (YB-1), suggesting a novel protective protein function.

Cold Shock Domain Protein DbpA Orchestrates Tubular Cell Damage and Interstitial Fibrosis in Inflammatory Kidney Disease.

DNA-binding protein A (DbpA) belongs to the Y-box family of cold shock domain proteins that exert transcriptional and translational activities in the cell via their ability to bind and regulate mRNA. To investigate the role of DbpA in kidney disease, we utilized the murine unilateral ureter obstruction (UUO) model, which recapitulates many features of obstructive nephropathy seen in humans. We observed that DbpA protein expression is induced within the renal interstitium following disease induction. Compared with wild-type animals, obstructed kidneys from Ybx3-deficient mice are protected from tissue injury, with a significant reduction in the number of infiltrating immune cells as well as in extracellular matrix deposition. RNAseq data from UUO kidneys show that Ybx3 is expressed by activated fibroblasts, which reside within the renal interstitium. Our data support a role for DbpA in orchestrating renal fibrosis and suggest that strategies targeting DbpA may be a therapeutic option to slow disease progression.

Inferior Vena Cava Filter Retrieval Rates Associated With Passive and Active Surveillance Strategies Adopted by Implanting Physicians.

Importance: Inferior vena cava filters are commonly implanted and infrequently retrieved. Nonretrieval contributes to significant morbidity, motivating US Food and Drug Administration and multisociety communications emphasizing the need for improved device surveillance. Current guidelines suggest that implanting physicians and referring physicians should be responsible for device follow-up, but it is not known whether shared responsibility contributes to lower retrieval. Objective: To determine if primary responsibility for follow-up care assumed by the implanting physician team is associated with increased device retrieval. Design, Setting, and Participants: This retrospective cohort study examined a prospectively collected registry of patients with inferior vena cava filters implanted from June 2011 to September 2019. Medical record review and data analysis was completed in 2021. The study included 699 patients who underwent implantation of retrievable inferior vena cava filters at an academic quaternary care center. Exposures: Prior to 2016, implanting physicians had a passive surveillance strategy whereby letters highlighting indications for and the need for timely retrieval were mailed to patients and ordering clinicians. Starting in 2016, implanting physicians assumed active responsibility for surveillance, whereby candidacy for device retrieval was assessed periodically via phone calls and retrieval scheduled when appropriate. Main Outcomes and Measures: The main outcome was the odds of inferior vena cava filter nonretrieval. Within regression modeling of the association between the surveillance method and nonretrieval, additional covariates of patient demographics, concomitant malignant neoplasm, and presence of thromboembolic disease were included. Results: Of the 699 patients who received retrievable filter implants, 386 (55.2%) were followed up with passive surveillance, 313 (44.8%) with active surveillance, 346 (49.5%) were female, 100 (14.3%) were Black individuals, and 502 (71.8%) were White individuals. The mean (SD) age at filter implantation was 57.1 (16.0) years. Mean (SD) yearly filter retrieval increased following the adoption of active surveillance, from 190 of 386 (48.7%) to 192 of 313 (61.3%) (P < .001). Fewer filters were deemed permanent in the active group vs passive group (5 of 313 [1.6%] vs 47 of 386 [12.2%]; P < .001). Age at the time of implantation (OR, 1.02; 95% CI, 1.01-1.03), concomitant malignant neoplasm (OR, 2.18; 95% CI, 1.47-3.24), and passive contact method (OR, 1.70; 95% CI, 1.18-2.47) were associated with increased odds of filter nonretrieval. Conclusions and Relevance: The findings of this cohort study suggest that active surveillance by implanting physicians is associated with improved inferior vena cava filter retrieval. These findings support encouraging physicians who implant the filter to take primary responsibility for tracking and retrieval.

Safety and Success Rates of Excimer Laser Sheath-Assisted Retrieval of Embedded Inferior Vena Cava Filters.

Importance: Despite historically high rates of use, most inferior vena cava (IVC) filters are not retrieved. The US Food and Drug Administration safety communications recommended retrieval when the IVC filter is no longer indicated out of concern for filter-related complications. However, failure rates are high when using standard techniques for retrieval of long-dwelling filters, and until recently, there have been no devices approved for retrieval of embedded IVC filters. Objective: To evaluate the safety and success of excimer laser sheath-assisted retrieval of embedded IVC filters. Design, Setting, and Participants: A retrospective, multicenter, clinical cohort study of excimer laser sheath-assisted IVC filter retrievals from 7 US sites was conducted between March 1, 2012, and February 28, 2021, among 265 patients who underwent IVC filter retrieval using the laser. Patients were substratified between a high-volume single center and a multicenter data set. A blinded physician committee adjudicated reported complications and their association with use of the laser. Exposures: Retrieval of IVC filters using excimer laser sheath. Main Outcomes and Measures: The primary safety end point was device-related major complication rate (Society of Interventional Radiology categories C to F, which included any adverse event associated with morbidity or disability that increases the level of care, results in hospital admission, or substantially lengthens the hospital stay). The primary success end point was technical success of IVC filter retrieval. The primary end points were compared with literature-derived, meta-analysis-suggested target performance goals. Results: The single-center experience included 139 participants (mean [SD] age, 52 [16] years; 78 female participants [56.1%]), and the multicenter experience included 126 participants (mean [SD] age, 52 [16] years; 75 female participants [59.5%]). The device-related major complication rate was 2.9% (4 of 139; 95% CI, 0.8%-7.2%; P = .001) for the single-center experience and 4.0% (5 of 126; 95% CI, 1.3%-9.0%; P = .01) for the multicenter experience, both of which were significantly lower than the primary safety performance goal (10%). No major complications were considered to be definitively associated with use of the laser. The technical success rate was 95.7% (133 of 139; 95% CI, 90.8%-98.4%; P = .007) for the single-center experience and 95.2% (120 of 126; 95% CI, 89.9%-98.2%; P = .02) for the multicenter experience, both of which were significantly higher than the primary performance goal (89.4%). Conclusions and Relevance: This cohort study demonstrated high technical success and low complication rates of excimer laser sheath-assisted retrieval of embedded IVC filters in centers with variable case volume and experience, which suggests a wide applicability of the technique with proper training. The excimer laser sheath offers physicians a valuable tool for retrieval of challenging embedded IVC filters.

Changes in the National Endovascular Management of Femoropopliteal Arterial Disease: An Analysis of the 2011-2019 Medicare Data.

PURPOSE: To describe national trends in the utilization of endovascular approaches (including balloon angioplasty, atherectomy, and stent placement) for the management of femoropopliteal peripheral arterial disease (PAD). MATERIALS AND METHODS: The Medicare Physician/Supplier Procedure Summary dataset containing 100% of Part B claims was interrogated for years 2011-2019. The Current Procedural Terminology codes specific for femoropopliteal angioplasty, stent placement, and atherectomy were used to create summary statistics for utilization by year, place of service (hospital inpatient, hospital outpatient, and office-based laboratory), and provider specialty (cardiology, radiology, and surgery). RESULTS: The use of atherectomy increased from 34,732 (33%) procedures in 2011 to 75,435 (53%) procedures in 2019, and atherectomy became the dominant treatment strategy for femoropopliteal PAD. The relative utilization of stent placement (36,793 [35%] to 28,899 [20%]) and angioplasty only (34,398 [32%] to 38,228 [27%]) decreased concomitantly from 2011 to 2019. By 2019, the use of atherectomy was twofold higher in office-based laboratories than in the outpatient hospital setting (44,767 and 20,901, respectively). Treatment strategy varied by provider specialty in 2011 when cardiologists used atherectomy most frequently (17,925 [43%]), whereas radiologists used angioplasty alone (5,928 [6%]) and surgeons stented (18,009 [37%]) most frequently. By 2019, all specialties utilized atherectomy most frequently (29,564 [59%] for cardiology, 10,912 [58%] radiology, and 33,649 [47%] surgery). CONCLUSIONS: The national approach to endovascular management of femoropopliteal PAD has changed since 2011 toward an implant-free strategy, including a multifold increase in the use of atherectomy. Discordant rates of atherectomy use between the ambulatory hospital and office-based settings highlight the need for comparative effectiveness studies to guide management.

Midkine release during hemodialysis is predictive of hypervolemia and associates with excess (cardiovascular) mortality in patients with end-stage renal disease: a prospective study.

BACKGROUND: In end-stage renal disease, a high cardiovascular risk profile and endothelial damage prevails. The heparin-binding growth factor midkine stimulates neo-angiogenesis in ischemic diseases, coordinates neutrophil influx, and raises blood pressure through stimulated angiotensin synthesis. METHODS: We determined changes of midkine serum levels during hemodialysis sessions under the assumption that endothelial cell-derived midkine is released. Periprocedural differences (∆midkine) were calculated and correlated with cardiovacular biomarkers and fluid status (clinical assessment, V. cava collapse, comet tail phenomenon), cardiovascular morbidities, mortality rates. Blood was collected before and after dialysis from hemodialysis patients (n = 171; diabetes: n = 70; hypervolemia: n = 83; both: n = 32). RESULTS: Baseline midkine levels were ~ fourfold elevated compared to healthy controls (n = 100). Further, on average a tenfold rise was detected during dialysis, the extent of which was partially related to non-fractionated heparin application (r2 = 0.17). Inter-individual differences were highly reproducible. Hypervolemic patients responded with a less than average rise in midkine levels during dialysis (p < 0.02), this difference became more obvious with co-existing diabetes (p < 0.001 for long dialysis-free interval) and was confirmed in an independently enrolled dialysis cohort (n = 88). In Kaplan Meier survival curves, low delta midkine levels correlated with cardiovascular/overall mortality rates, similar to elevated uPAR levels, whereas other markers (NTproANP, galectin, tenascin-C) were less predictive. Following intervention with successful fluid removal in hypervolemic dialysis patients to optimize fluid homeostasis, midkine values increased (p < 0.002), which was not observed in patients that failed to decrease weight. CONCLUSION: Thus, for dialysis patients inadequate periprocedural midkine upregulation is linked with hypervolemia and associates with cardiovascular events.

High salt diet-induced proximal tubular phenotypic changes and sodium-glucose cotransporter-2 expression are coordinated by cold shock Y-box binding protein-1.

High salt diet (HSD) is a hallmark of blood pressure elevations, weight gain and diabetes onset in the metabolic syndrome. In kidney, compensatory mechanisms are activated to balance salt turnover and maintain homeostasis. Data on the long-term effects of HSD with respect to tubular cell functions and kidney architecture that exclude confounding indirect blood pressure effects are scarce. Additionally we focus on cold shock Y-box binding protein-1 as a tubular cell protective factor. A HSD model (4% NaCl in chow; 1% NaCl in water) was compared to normal salt diet (NSD, standard chow) over 16 months using wild type mice and an inducible conditional whole body knockout for cold shock Y-box binding protein-1 (BL6J/N, Ybx1). HSD induced no difference in blood pressure over 16 months, comparing NSD/HSD and Ybx1 wild type/knockout. Nevertheless, marked phenotypic changes were detected. Glucosuria and subnephrotic albuminuria ensued in wild type animals under HSD, which subsided in Ybx1-deficient animals. At the same time megalin receptors were upregulated. The sodium-glucose cotransporter-2 (SGLT2) was completely downregulated in wild type HSD animals that developed glucosuria. In Ybx1 knockouts, expression of AQP1 and SGLT2 was maintained under HSD; proximal tubular widening and glomerular tubularization developed. Concurrently, amino aciduria of neutral and hydrophobic amino acids was seen. In vitro translation confirmed that YB-1 translationally represses Sglt2 transcripts. Our data reveal profound effects of HSD primarily within glomeruli and proximal tubular segments. YB-1 is regulated by HSD and orchestrates HSD-dependent changes; notably, sets reabsorption thresholds for amino acids, proteins and glucose.

Novel Insights into YB-1 Signaling and Cell Death Decisions.

YB-1 belongs to the evolutionarily conserved cold-shock domain protein family of RNA binding proteins. YB-1 is a well-known transcriptional and translational regulator, involved in cell cycle progression, DNA damage repair, RNA splicing, and stress responses. Cell stress occurs in many forms, e.g., radiation, hyperthermia, lipopolysaccharide (LPS) produced by bacteria, and interferons released in response to viral infection. Binding of the latter factors to their receptors induces kinase activation, which results in the phosphorylation of YB-1. These pathways also activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a well-known transcription factor. NF-κB is upregulated following cellular stress and orchestrates inflammatory responses, cell proliferation, and differentiation. Inflammation and cancer are known to share common mechanisms, such as the recruitment of infiltrating macrophages and development of an inflammatory microenvironment. Several recent papers elaborate the role of YB-1 in activating NF-κB and signaling cell survival. Depleting YB-1 may tip the balance from survival to enhanced apoptosis. Therefore, strategies that target YB-1 might be a viable therapeutic option to treat inflammatory diseases and improve tumor therapy.

YB-1 Is Altered in Pregnancy-Associated Disorders and Affects Trophoblast in Vitro Properties via Alternation of Multiple Molecular Traits.

Cold shock Y-box binding protein-1 (YB-1) coordinates several molecular processes between the nucleus and the cytoplasm and plays a crucial role in cell function. Moreover, it is involved in cancer progression, invasion, and metastasis. As trophoblast cells share similar characteristics with cancer cells, we hypothesized that YB-1 might also be necessary for trophoblast functionality. In samples of patients with intrauterine growth restriction, YB-1 mRNA levels were decreased, while they were increased in preeclampsia and unchanged in spontaneous abortions when compared to normal pregnant controls. Studies with overexpression and downregulation of YB-1 were performed to assess the key trophoblast processes in two trophoblast cell lines HTR8/SVneo and JEG3. Overexpression of YB-1 or exposure of trophoblast cells to recombinant YB-1 caused enhanced proliferation, while knockdown of YB-1 lead to proliferative disadvantage in JEG3 or HTR8/SVneo cells. The invasion and migration properties were affected at different degrees among the trophoblast cell lines. Trophoblast expression of genes mediating migration, invasion, apoptosis, and inflammation was altered upon YB-1 downregulation. Moreover, IL-6 secretion was excessively increased in HTR8/SVneo. Ultimately, YB-1 directly binds to NF-κB enhancer mark in HTR8/SVneo cells. Our data show that YB-1 protein is important for trophoblast cell functioning and, when downregulated, leads to trophoblast disadvantage that at least in part is mediated by NF-κB.

Uterine Artery Embolization for Primary Postpartum Hemorrhage.

Postpartum hemorrhage (PPH) is a common source of morbidity and mortality for delivering mothers worldwide, resulting in greater than 100,000 deaths per annum. Pathologic postpartum hemorrhage is defined as blood loss greater than 500 mL for vaginal deliveries and 1,000 mL for caesarean births, which occurs in up to 10% of deliveries. Severe postpartum hemorrhage can progress to shock, disseminated intravascular coagulation (DIC) and death. PPH is further characterized by time of onset; primary PPH occurs within 24 hours of parturition, and secondary PPH beyond that. Secondary hemorrhage is discussed in a separate article in this issue, this article will exclusively explore primary postpartum hemorrhage. PPH arises from a number of etiologies, including uterine atony, birth canal/perineal lacerations and intrapelvic arterial injuries. PPH is primarily managed by standard medical obstetric maneuvers including uterotonics, fundal massage, intrauterine (Bakri) balloon tamponade and direct control of hemorrhage where applicable. Definitive control with hysterectomy is preserved for hemorrhage refractory to conservative and minimally-invasive management. First described in 1979, angiography and trans-catheter embolization represent valuable tools in the control of postpartum hemorrhage of most etiologies. Embolization is an acceptable, effective alternative to hysterectomy, particularly in patients who desire future fertility. It has high clinical success rates and a body of literature supporting preserved post-embolization fertility.

Comparative efficacy and safety of the Captus device for inferior vena cava filter retrieval.

PURPOSE: Retrievable inferior vena cava filters (IVCF) have been increasingly used for mechanical pulmonary embolism prophylaxis since their development. The Captus Vascular Retrieval System (Avantec Vascular, Sunnyvale, California) is a new device developed for retrieval of IVCF. This study compared the safety and efficacy of the new Captus device against the existing EnSnare Endovascular Snare System (Merit Medical, South Jordan, Utah) for IVCF retrieval. METHODS: Patients undergoing IVCF retrieval at a single institution between July 2015 and July 2020 were retrospectively identified. All adult patients (>18 years) undergoing filter retrieval with either Captus or Ensnare were included. Technical success and complications were compared by device. A complexity score was assigned to each case to adjust for selection bias. Logistic regression was used to model the association between device type and primary technical success. RESULTS: 99 IVCF retrievals met inclusion criteria, 59 with Captus and 40 with Ensnare. The majority of the cohort consisted of low complexity cases (n = 51, 86% Captus versus n = 31, 78% Ensnare; p = 0.28). Technical success for low and medium complexity retrievals was 88% and 62% with Captus and 96% and 33% with Ensnare. There was no significant association between device type and technical success, adjusting for case complexity (Captus OR 0.55, 95% CI 0.08-2.72, p = 0.49). There were no device-related complications. CONCLUSION: No statistically significant difference in device technical success or complications between the Ensnare and Captus devices for uncomplicated IVCF retrieval. PRECIS: The Captus Vascular Retrieval System is a new device for IVC filter retrieval which has similar technical success to the existing EnSnare.

YB-1 Interferes with TNFα-TNFR Binding and Modulates Progranulin-Mediated Inhibition of TNFα Signaling.

Inflammation and an influx of macrophages are common elements in many diseases. Among pro-inflammatory cytokines, tumor necrosis factor α (TNFα) plays a central role by amplifying the cytokine network. Progranulin (PGRN) is a growth factor that binds to TNF receptors and interferes with TNFα-mediated signaling. Extracellular PGRN is processed into granulins by proteases released from immune cells. PGRN exerts anti-inflammatory effects, whereas granulins are pro-inflammatory. The factors coordinating these ambivalent functions remain unclear. In our study, we identify Y-box binding protein-1 (YB-1) as a candidate for this immune-modulating activity. Using a yeast-2-hybrid assay with YB-1 protein as bait, clones encoding for progranulin were selected using stringent criteria for strong interaction. We demonstrate that at physiological concentrations, YB-1 interferes with the binding of TNFα to its receptors in a dose-dependent manner using a flow cytometry-based binding assay. We show that YB-1 in combination with progranulin interferes with TNFα-mediated signaling, supporting the functionality with an NF-κB luciferase reporter assay. Together, we show that YB-1 displays immunomodulating functions by affecting the binding of TNFα to its receptors and influencing TNFα-mediated signaling via its interaction with progranulin.

Fibrosis and Immune Cell Infiltration Are Separate Events Regulated by Cell-Specific Receptor Notch3 Expression.

BACKGROUND: Kidney injuries that result in chronic inflammation initiate crosstalk between stressed resident cells and infiltrating immune cells. In animal models, whole-body receptor Notch3 deficiency protects from leukocyte infiltration and organ fibrosis. However, the relative contribution of Notch3 expression in tissue versus infiltrating immune cells is unknown. METHODS: Chimeric mice deficient for Notch3 in hematopoietic cells and/or resident tissue cells were generated, and kidney fibrosis and inflammation after unilateral ureteral obstruction (UUO) were analyzed. Adoptive transfer of labeled bone marrow-derived cells validated the results in a murine Leishmania ear infection model. In vitro adhesion assays, integrin activation, and extracellular matrix production were analyzed. RESULTS: Fibrosis follows UUO, but inflammatory cell infiltration mostly depends upon Notch3 expression in hematopoietic cells, which coincides with an enhanced proinflammatory milieu (e.g., CCL2 and CCL5 upregulation). Notch3 expression on CD45+ leukocytes plays a prominent role in efficient cell transmigration. Functionally, leukocyte adhesion and integrin activation are abrogated in the absence of receptor Notch3. Chimeric animal models also reveal that tubulointerstitial fibrosis develops, even in the absence of prominent leukocyte infiltrates after ureteral obstruction. Deleting Notch3 receptors on resident cells blunts kidney fibrosis, ablates NF-κB signaling, and lessens matrix deposition. CONCLUSIONS: Cell-specific receptor Notch3 signaling independently orchestrates leukocyte infiltration and organ fibrosis. Interference with Notch3 signaling may present a novel therapeutic approach in inflammatory as well as fibrotic diseases.