A role for keratin 17 during DNA damage response and tumor initiation.

High levels of the intermediate filament protein keratin 17 (K17) are associated with poor prognoses for several human carcinomas. Studies in mouse models have shown that K17 expression is positively associated with growth, survival, and inflammation in skin and that lack of K17 delays onset of tumorigenesis. K17 occurs in the nucleus of human and mouse tumor keratinocytes where it impacts chromatin architecture, gene expression, and cell proliferation. We report here that K17 is induced following DNA damage and promotes keratinocyte survival. The presence of nuclear K17 is required at an early stage of the double-stranded break (DSB) arm of the DNA damage and repair (DDR) cascade, consistent with its ability to associate with key DDR effectors, including γ-H2A.X, 53BP1, and DNA-PKcs. Mice lacking K17 or with attenuated K17 nuclear import showed curtailed initiation in a two-step skin carcinogenesis paradigm. The impact of nuclear-localized K17 on DDR and cell survival provides a basis for the link between K17 induction and poor clinical outcomes for several human carcinomas.

Unique technique to relieve left ventricular assist device electromagnetic interference with an implantable cardioverter defibrillator.

We introduced a simple technique to eliminate electromagnetic interference between a left ventricular assist device (LVAD) and an implantable cardioverter defibrillator (ICD). A 43-year-old male with heart failure and a reduced ejection fraction who had an ICD presented with decompensated heart failure and received an LVAD as a bridge to transplant. Remote monitoring showed persistent atrial fibrillation causing an inappropriate ICD shock leading to a decision to disable shock therapies. However, an in-office interrogation was unsuccessful due to electromagnetic interference. Patient was instructed to extend his arm above his head on the ipsilateral side of the ICD, thus increasing the distance between LVAD and ICD, eliminating the interaction to allow reprogramming of the device.

TCR+CD4-CD8- (double negative) T cells protect from cisplatin-induced renal epithelial cell apoptosis and acute kidney injury.

Acute kidney injury (AKI) due to cisplatin is a significant problem that limits its use as an effective chemotherapeutic agent. T cell receptor+CD4-CD8- double negative (DN) T cells constitute the major T cell population in the human and mouse kidney, express programmed cell death protein (PD)-1, and protect from ischemic AKI. However, the pathophysiological roles of DN T cells in cisplatin-induced AKI is unknown. In this study, wild-type mice were treated with cisplatin (30 mg/kg) or vehicle, and the effects on kidney DN T cell numbers and function were measured. In vitro experiments evaluated effects of kidney DN T cells on cisplatin-induced apoptosis and PD ligand 1 (PD-L1) in renal epithelial cells. Adoptive transfer experiments assessed the therapeutic potential of DN T cells during cisplatin-induced AKI. Our results show that kidney DN T cell population increased at 24 h and declined by 72 h after cisplatin treatment. Cisplatin treatment increased kidney DN T cell proliferation, apoptosis, CD69, and IL-10 expression, whereas CD62L, CD44, IL-17A, interferon-γ, and TNF-α were downregulated. Cisplatin treatment decreased both PD-1 and natural killer 1.1 subsets of kidney DN T cells with a pronounced effect on the PD-1 subset. In vitro kidney DN T cell coculture decreased cisplatin-induced apoptosis in kidney proximal tubular epithelial cells, increased Bcl-2, and decreased cleaved caspase 3 expression. Cisplatin-induced expression of PD ligand 1 was reduced in proximal tubular epithelial cells cocultured with DN T cells. Adoptive transfer of DN T cells attenuated kidney dysfunction and structural damage from cisplatin-induced AKI. These results demonstrate that kidney DN T cells respond rapidly and play a protective role during cisplatin-induced AKI.

Delayed Surgical Management of Type A Intramural Hematoma Is Not Associated with Worse Outcomes Than Emergent Operation.

OBJECTIVES: Management of acute aortic intramural hematomas (IMHs) involving the ascending aorta and root remains controversial. Some series have suggested that delaying operative intervention beyond the first 24-hours may be beneficial. METHODS: A retrospective single-institution analysis was performed to identify patients presenting with type A IMH. These patients were classified by whether they underwent surgery within 24 hours or delayed operative intervention. Patients with additional indications for emergent operation, such as acute aortic regurgitation or malperfusion syndromes, were excluded. Outcomes were assessed with logistic regression, and the Kaplan-Meier method was used to analyze long-term survival. RESULTS: Of the 129 patients with acute type A aortic pathology, 36 (27.9%) presented with isolated IMH. IMH patients were less likely to present with acute aortic regurgitation (8.6% versus 27.9%, P = .020) or limb ischemia (0% versus 12.6%, P = .027). Of the IMH patients without other emergent operative indications, 23 (67.6%) underwent surgery within 24 hours. Delayed operative repair was not associated with increased risk of mortality, stroke, or renal failure (all P >.05). Survival analysis showed no difference in survival at 1 year. CONCLUSIONS: In well-selected patients, delayed operation for type An intramural hematoma is not associated with adverse outcomes.

MitraClip for Severe Mitral Regurgitation from Chordal Rupture during Balloon Aortic Valvuloplasty.

Transcatheter aortic valve replacement (TAVR) has become an established alternative to surgical aortic valve replacement for high-, intermediate-, and low-risk patients. Paravalvular leak (PVL) is a complication of TAVR that can be effectively treated with balloon dilation and vascular plugs. We report a case of an 86-year-old male presenting with symptomatic severe aortic stenosis. After the index TAVR procedure, mild-to-moderate PVL was noted. Two years post-operation, the patient presented with symptomatic severe PVL, which was initially treated by balloon dilation with additional volume. During balloon dilation, the balloon slipped into the left ventricle and tore a chord, leading to new severe mitral regurgitation (MR) while the PVL remained unchanged. Subsequently, an Amplatzer vascular plug II (Abbott) was successfully used to reduce the PVL to mild, and a MitraClip NTR (Abbott) was used to successfully reduce the MR to trivial. Although balloon dilation can be an effective method for reducing PVL, mitral valve chordal rupture is a rare complication if the wire is entrapped in the chordae and the balloon slips into the ventricle.

Neighborhood Impact Factor to Study Cell-Fate Decision-Making in Cellular Communities.

Cell-fate determination is a function of cell-intrinsic and -extrinsic signaling cues. Understanding the design principles governing fate control in multicellular systems remains difficult to understand and analyze. To address the current challenges of spatial analysis of potential signaling events, we have developed a pipeline for assessment of the neighboring cells at defined areas in the vicinity of target cells using a newly defined concept of Neighborhood Impact Factor. We have used our pipeline to interrogate cellular decision-making in a genetically derived multi-lineage liver organoid from induced pluripotent stem cells. We examined endothelial versus hepatocyte fate determination for cells with similar expression level of an engineered driver gene circuit. Our analysis suggests that the relative level of gene expression to the neighbor population can control the final fate choice in our engineered liver multicellular system.

Elevated neutrophil to lymphocyte ratio is associated with poor long-term survival and graft failure after lung transplantation.

PURPOSE: We aimed to assess the prognostic value of Neutrophil to Lymphocyte Ratio (NLR) on long-term outcomes and graft dysfunction after lung transplantation. METHODS: We retrospectively reviewed all patients receiving a lung transplant at our institution from 2011 to 2014. The primary exposure was elevated NLR at the time of transplant, defined by NLR>4. The primary outcomes were graft failure and three-year all-cause mortality. Multivariate logistic regression and Kaplan-Meier survival analysis were used to analyze outcomes. RESULTS: 95 patients were included. 40 patients (42%) had an elevated NLR. Elevated NLR was associated with graft failure (OR: 4.7 [1.2-18.8], p = 0.02), and three-year mortality (OR: 5.4 [1.3-23.2], p = 0.03) on multivariate logistic regression. Patients with elevated NLR demonstrated significantly lower survival on Kaplan-Meier analysis (50% versus 74%, p = 0.02). The c-statistic for our multivariate model was 0.91. CONCLUSION: Elevated neutrophil to lymphocyte ratio is associated with poor long-term survival and graft failure after lung transplantation.

CD3+CD4-CD8- Double-negative αß T cells attenuate lung ischemia-reperfusion injury.

OBJECTIVE: Lung ischemia-reperfusion injury (IRI) is a common complication after lung transplantation, and immune cells have been implicated in modulating outcomes. We hypothesized that a newly described subset of αß T-cell receptor positive cells; that is, CD4-CD8- (double negative [DN]) T cells, are found in lungs and can protect against lung IRI. METHODS: Ischemia was induced in C57BL/6 mice by left pulmonary artery and vein occlusion for 30 minutes followed by 180 minutes of reperfusion. These mice were paired with sham hilar dissected surgical controls. In mice undergoing IRI, adoptive transfer of DN T cells or conventional T cells was performed 12 hours before occlusion. Flow cytometry was used to quantify T cells and inflammatory cytokines, and apoptotic signaling pathways were evaluated with immunoblotting. Lung injury was assessed with Evans blue dye extravasation. RESULTS: DN T cells were significantly higher (5.29% ± 1% vs 2.21% ± 3%; P < .01) in IRI lungs and secreted higher levels of interleukin-10 (30% ± 5% vs 6% ± 1%; P < .01) compared with surgical sham controls. Immunoblotting, hematoxylin and eosin staining and Evans blue dye demonstrated that adoptive transfer of DN T cells significantly decreased interstitial edema (P < .01) and attenuated apoptosis/cleaved caspase-3 expression in the lungs following lung IRI (P < .01). CONCLUSIONS: DN T cells traffic into lungs during IRI, and have tissue protective functions regulating inflammation and apoptosis. We propose a potential novel immunoregulatory function of DN T cells during lung IRI.

Sarcopenia of the Psoas Muscles Is Associated With Poor Outcomes Following Lung Transplantation.

BACKGROUND: Sarcopenia, a known component of frailty, defined by diminished cross-sectional area of the psoas muscles, is associated with poor outcomes after a range of surgical procedures. However, little is known of the relationship between sarcopenia of the psoas muscles (SPM) and long-term survival, decline in pulmonary function, and graft failure after lung transplantation. METHODS: We reviewed patients who underwent primary lung transplantation at our institution from 2011 to 2014. Cross-sectional areas of the psoas muscles at the L4 vertebral level were measured using preoperative computed tomography. Gender-based cutoff values for sarcopenia were generated and validated. The primary outcomes were 1-, 2-, and 3-year all-cause mortality, forced expiratory volume in 1 second values, and graft function. Adjusted logistic regression and survival analysis was used to analyze outcomes. RESULTS: Ninety-five patients were included in this study; 39 (41.1%) patients were considered sarcopenic. SPM was significantly associated with short-term and midterm mortality on multivariate analysis (1 year: odds ratio [OR], 8.7, p = 0.017; 2 years: OR, 12.7, p < 0.01; 3 years: OR, 13.4, p < 0.01). Survival analysis showed significantly decreased survival in sarcopenic patients at 3 years (35.9% versus 76.8%; p < 0.01). SPM is also associated with decreased forced expiratory volume in 1 second (coefficient, -17.3; p = 0.03). Adjusted Cox analysis showed an increased hazard for all-cause mortality (hazard ratio, 5.8, p < 0.01) and graft failure (hazard ratio, 14.7, p < 0.01) in sarcopenic patients. CONCLUSIONS: This study demonstrates a significant association between SPM and death, pulmonary function, and graft failure in patients receiving a lung transplant. Determining SPM preoperatively may be a useful component of frailty assessment and a predictor of survival in this patient population.

Comparing Frailty Markers in Predicting Poor Outcomes after Transcatheter Aortic Valve Replacement.

INTRODUCTION: Frailty is an important component of risk prognostication in transcatheter aortic valve replacement (TAVR). Objective markers of frailty, including sarcopenia, the modified Frailty Index (mFI), and albumin levels, have emerged, but little is known how such markers compare to each other in predicting outcomes after TAVR. We sought to define and compare these markers in predicting long-term outcomes after TAVR. METHODS: Patients who underwent TAVR at our institution from 2011 to 2016 were included. Indexed cross-sectional areas of the lumbosacral muscles on preoperative computed tomography scans were used to assess sarcopenia. Optimal cutoffs for sarcopenia were defined using a statistically validated method. mFI was calculated using an 11-point scale of clinical characteristics. The primary outcome was 2-year all-cause mortality. Adjusted survival analysis was used to analyze outcomes. RESULTS: A total of 381 patients were included in this study. Sarcopenia of the psoas muscles was associated with an increased risk of mortality on univariate (HR: 2.3, P = 0.01) and multivariate (HR: 2.5, P = 0.01) analysis. Sarcopenia of the paravertebral muscles was associated with increased risk of mortality only on univariate analysis (HR: 2.1, P = 0.03). Increased preoperative albumin levels were associated with decreased risk of mortality on univariate (HR: 0.3, P < 0.01) and multivariate analysis (HR: 0.3, P < 0.01). The (mFI) was not associated with mortality on univariate or multivariate analysis. DISCUSSION: Novel cutoffs for sarcopenia of the psoas muscles were determined and associated with decreased survival after TAVR. Sarcopenia and albumin levels may be better tools for risk prediction than mFI in TAVR.

Adenomatoid tumor of the tunica albuginea.

Adenomatoid tumors are benign mesothelial tumors most commonly found in the paratesticular structures, especially the epididymis. Herein, we report a case of adenomatoid tumor originating in the tunica albuginea and mimicking an intratesticular neoplasm. We review the ultrasonographic presentation and literature regarding adenomatoid tumors originating in the tunica albuginea and testicular parenchyma.

Renal epithelioid angiomyolipoma associated with hyperprolactinemia.

We report a unique case of a 42-year-old woman with a renal epithelioid angiomyolipoma associated with elevated serum prolactin levels and presenting with galactorrhea. Magnetic resonance imaging of the brain showed no pituitary abnormality, and abdominal imaging demonstrated a large right renal mass. Pathologic analysis of the radical nephrectomy specimen revealed an epithelioid angiomyolipoma. She had an uneventful postoperative recovery with complete normalization of her serum prolactin level and resolution of galactorrhea. To our knowledge, the association between epithelioid angiomyolipoma and hyperprolactinemia has never before been reported.