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We prove the Extended Delta Conjecture of Haglund, Remmel, and Wilson, a combinatorial formula for $\Delta _{h_l}\Delta' _{e_k} e_{n}$, where $\Delta' _{e_k}$ and $\Delta_{h_l}$ are Macdonald eigenoperators and $e_n$ is an elementary symmetric function. We actually prove a stronger identity of infinite series of $GL_m$ characters expressed in terms of LLT series. This is achieved through new results in the theory of the Schiffmann algebra and its action on the algebra of symmetric functions., Comment: 31 pages, 3 figures

The Peterson comparison formula proved by Woodward relates the three-pointed Gromov-Witten invariants for the quantum cohomology of partial flag varieties to those for the complete flag. Another such comparison can be obtained by composing a combinatorial version of the Peterson isomorphism with a result of Lapointe and Morse relating quantum Littlewood-Richardson coefficients for the Grassmannian to k-Schur analogs in the homology of the affine Grassmannian obtained by adding rim hooks. We show that these comparisons on quantum cohomology are equivalent, up to Postnikov's strange duality isomorphism., 28 pages; added several references, final version to appear in Algebr. Represent. Theory

Delirium occurs frequently after lung transplantation and is associated with poor clinical outcomes. Significantly prolonged jugular venous congestion (JVC) occurs during off-pump lung transplantation and is thought to impair cerebral perfusion. Our study aimed to test the hypothesis that increased intraoperative JVC is associated with an increased risk of postoperative delirium among lung transplantation recipients.This is a retrospective observational cohort study. Adult patients who received off-pump lung transplantation at the Vanderbilt University Medical Center between 2006 and 2016 are included. The magnitude of JVC was calculated by the area under the curve (AUC) of the central venous pressure (CVP) above the threshold of 12 mmHg. Postoperative delirium was assessed by Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) criteria during their ICU stay. Multivariate regression analysis was used to determine the association of intraoperative JVC with postoperative delirium, adjusting for baseline demographics, surgical, and intraoperative characteristics.Thirty-two (23.5%) out of 136 patients developed delirium in the ICU. There was no statistical difference in terms of intraoperative JVC between patients with delirium and those without (4058 ± 6650 vs. 3495 ± 10 151 mmHg min; p = .772). Furthermore, during multivariate regression analysis, JVC was not associated with an increased risk of delirium (odds ratio: 1.03 per 100 mmHg min increase in venous congestion; 95% confidence interval: .31, 3.39; p = .96).Delirium occurred frequently after off-pump lung transplantation. Although physiologically plausible, the present study did not find an association between increased JVC during off-pump lung transplantation and an increased risk of postoperative delirium.

Assessing the risk of common, complex diseases requires consideration of clinical risk factors as well as monogenic and polygenic risks, which in turn may be reflected in family history. Returning risks to individuals and providers may influence preventive care or use of prophylactic therapies for those individuals at high genetic risk.To enable integrated genetic risk assessment, the eMERGE (electronic MEdical Records and GEnomics) network is enrolling 25,000 diverse individuals in a prospective cohort study across 10 sites. The network developed methods to return cross-ancestry polygenic risk scores (PRS), monogenic risks, family history, and clinical risk assessments via a Genome Informed Risk Assessment (GIRA) report and will assess uptake of care recommendations after return of results.GIRAs include summary care recommendations for 11 conditions, education pages, and clinical laboratory reports. The return of high-risk GIRA to individuals and providers includes guidelines for care and lifestyle recommendations. Assembling the GIRA required infrastructure and workflows for ingesting and presenting content from multiple sources. Recruitment began in February 2022.Return of a novel report for communicating monogenic, polygenic, and family history based risk factors will inform the benefits of integrated genetic risk assessment for routine health care.

The 2016 World Health Organization entity 'Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB or FGFR1, or with PCM1-JAK2' encompasses a group of rare neoplasms that result from the formation of a fusion gene that leads to expression of an aberrant tyrosine kinase. This entity also contains variant JAK2 fusion partners, and detection of this defining event can be facilitated by various cytogenetic and molecular methods. Cryptic rearrangements of 9p24/JAK2 can be particularly challenging to identify. We describe the use of chromosomal microarray analysis (CMA), fluorescence in situ hybridization (FISH) with a probe for JAK2, and genomic mate pair analysis to describe a complex karyotype with a t(9;22) that produced a functional BCR-JAK2 fusion, leading to the appropriate diagnosis for the patient. This case highlights the importance of using an integrated genomic approach to fully define complex aberrations to assign proper diagnoses.

Background Mechanisms of postoperative delirium remain poorly understood, limiting development of effective treatments. We tested the hypothesis that intraoperative oxidative damage is associated with delirium and neuronal injury and that disruption of the blood–brain barrier modifies these associations. Methods In a prespecified cohort study of 400 cardiac surgery patients enrolled in a clinical trial of atorvastatin to reduce kidney injury and delirium, we measured plasma concentrations of F2-isoprostanes and isofurans using gas chromatography-mass spectrometry to quantify oxidative damage, ubiquitin carboxyl-terminal hydrolase isozyme L1 to quantify neuronal injury, and S100 calcium-binding protein B using enzyme-linked immunosorbent assays to quantify blood–brain barrier disruption before, during, and after surgery. We performed the Confusion Assessment Method for the Intensive Care Unit twice daily to diagnose delirium. We measured the independent associations between intraoperative F2-isoprostanes and isofurans and delirium (primary outcome) and postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 (secondary outcome), and we assessed if S100 calcium-binding protein B modified these associations. Results Delirium occurred in 109 of 400 (27.3%) patients for a median (10th, 90th percentile) of 1.0 (0.5, 3.0) days. In the total cohort, plasma ubiquitin carboxyl-terminal hydrolase isozyme L1 concentration was 6.3 ng/ml (2.7, 14.9) at baseline and 12.4 ng/ml (7.9, 31.2) on postoperative day 1. F2-isoprostanes and isofurans increased throughout surgery, and the log-transformed sum of intraoperative F2-isoprostanes and isofurans was independently associated with increased odds of postoperative delirium (odds ratio, 3.70 [95% CI, 1.41 to 9.70]; P = 0.008) and with increased postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 (ratio of geometric means, 1.42 [1.11 to 1.81]; P = 0.005). The association between increased intraoperative F2-isoprostanes and isofurans and increased postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 was amplified in patients with elevated S100 calcium-binding protein B (P = 0.049). Conclusions Intraoperative oxidative damage was associated with increased postoperative delirium and neuronal injury, and the association between oxidative damage and neuronal injury was stronger among patients with increased blood–brain barrier disruption. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Thrice-weekly hemodialysis can result in adequate urea clearance; however, the morbidity and mortality rates of patients treated with maintenance dialysis remain unacceptably high, partly because of nonadherence. African Americans have a higher prevalence of kidney failure treated with dialysis, greater dialysis nonadherence, and higher odds of hospitalization. We hypothesized that more precise ways of assessing dialysis treatment adherence will reflect the severity of nonadherence, distinguish patterns of nonadherence, and inform the design of personalized behavioral interventions.Retrospective cohort study.African American patients receiving hemodialysis for90 days.Hemodialysis.Dialysis adherence.Dialysis attendance data were displayed using a dot plot, categorized based on missed and shortened treatments, and examined for patterns. Descriptive characteristics were reported. In an exploratory analysis, associations between dialysis treatment adherence and participant characteristics were evaluated using ordinary least squares regression. An analysis was performed using missed minutes of dialysis and current metrics for measuring dialysis treatment adherence (ie, missed and shortened treatments).Among 113 African American patients treated with dialysis, 47% were men; the median age was 57 years (interquartile range, 46-70 years), and the median dialysis vintage was 54 months (interquartile range, 22-90 months). With rows ordered based on the total missed minutes of dialysis, the dot plot displayed a decreasing gradient in the severity of nonadherence, with novel dialysis treatment adherence categories termed as follows: consistent underdialysis, inconsistent dialysis, and consistent dialysis. Distinct patterns of nonadherence and heterogeneity emerged within these categories. Older age was consistently associated with better adherence, as determined by the analyses performed using the total missed minutes of dialysis as well as missed and shortened treatments.The study findings, although replicable and paradigm-shifting, might be limited by the short timeline, focus on adherence data specific to African American patients treated with dialysis, and restriction to dialysis units affiliated with 1 academic center.This study presents more precise and novel ways of measuring and displaying dialysis treatment adherence. The findings introduce a more personalized approach for evaluating actual dialysis uptake. Identification of unique patterns of adherence behavior is important to inform the design of effective behavioral interventions and improve outcomes for vulnerable African American patients treated with dialysis.

To determine the incidence and predictive factors of acute kidney injury (AKI) after off-pump lung transplantation.A retrospective cohort study.The operating room and intensive care unit.Adult patients who underwent lung transplant without cardiopulmonary bypass or extracorporeal membrane oxygenator between 2006 and 2016 at the Vanderbilt University Medical Center.None.The presence of postoperative AKI was assessed by the Kidney Disease: Improving Global Outcomes criteria in the first seven postoperative days. Multivariate logistic regression analysis was used to determine the independent predictive factors of AKI. One hundred forty-eight patients were included in the final analysis, of whom 63 (42.6%) subsequently developed AKI: 43 (29.0%) stage 1, ten (6.8%) stage 2, and ten (6.8%) stage 3. Patients who had AKI had a longer hospital length of stay (12 days [interquartile range (IQR): 10-17] vs ten days [IQR: 8-12], p0.001). For every one-year increase in age, the odds of AKI decreased by 8% (odds ratio [OR] 0.92, 95% confidence interval [CI]: 0.87-0.98, p = 0.008). The odds of having AKI in patients with bilateral lung transplant was lower than patients with unilateral transplant (OR 0.09, 95% CI: 0.01-0.63, p = 0.015). Additionally, a diagnosis of chronic obstructive pulmonary disease increased the odds of AKI by four-fold compared with a diagnosis of idiopathic pulmonary fibrosis (OR 4.73, 95% CI: 1.44-15.56, p = 0.011).AKI is a common complication after off-pump lung transplantation and is associated with increased hospital length of stay. Younger age, unilateral lung transplant, and diagnosis of chronic obstructive pulmonary disease are independently associated with AKI.

Introduction High dietary acid load and metabolic acidosis are associated with an accelerated decline in kidney function and may contribute to the observed heterogeneity in end-stage renal disease (ESRD) risk according to APOL1 genotype. Our objective was to examine the associations of metabolic acidosis and dietary acid load with kidney disease progression, according to APOL1 genotype, among individuals with chronic kidney disease (CKD). Methods We studied 1048 African American participants in the Chronic Renal Insufficiency Cohort. Metabolic acidosis was defined as blood levels of serum bicarbonate less than 22 mEq/L, and dietary acid load was quantified by potential renal acid load (PRAL) using data from the Diet Health Questionnaire. APOL1 status was defined as having 2 risk variants, consisting of either possible combination of the G1 and G2 risk alleles. We tested associations of APOL1 and dietary and metabolic acidosis with CKD progression, defined as time to ESRD or 50% decline in eGFR. Results During a median follow-up period of 7 years, 379 participants had an incident CKD progression event (6.4 events per 100 person-years). After full adjustment, among participants with 2 APOL1 variants, the analysis failed to detect an association between metabolic acidosis or dietary acid load and CKD progression (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.96–1.11 per 1 mEq/L higher serum bicarbonate and an HR, 1.03; 95% CI, 0.92–1.15 per 10 mEq/L higher PRAL). Similar associations were noted among participants without the APOL1 high-risk genotype. Conclusion In a population at high risk of developing ESRD, metabolic acidosis and dietary acid load were not associated with CKD progression., Graphical abstract

Background Chemotherapy regimens that include the utilization of gemcitabine are the standard of care in pancreatic cancer patients. However, most patients with advanced pancreatic cancer die within the first 2 years after diagnosis, even when treated with standard of care chemotherapy. This study aims to explore combination therapies that could boost the efficacy of standard of care regimens in pancreatic cancer patients. Methods In this study, we used PV-10, a 10% solution of rose bengal, to induce the death of human pancreatic tumor cells in vitro. Murine in vivo studies were carried out to examine the effectiveness of the direct injection of PV-10 into syngeneic pancreatic tumors in causing lesion-specific ablation. Intralesional PV-10 treatment was combined with systemic gemcitabine treatment in tumor-bearing mice to investigate the control of growth among treated tumors and distal uninjected tumors. The involvement of the immune-mediated clearance of tumors was examined in immunogenic tumor models that express ovalbumin (OVA). Results In this study, we demonstrate that the injection of PV-10 into mouse pancreatic tumors caused lesion-specific ablation. We show that the combination of intralesional PV-10 with the systemic administration of gemcitabine caused lesion-specific ablation and delayed the growth of distal uninjected tumors. We observed that this treatment strategy was markedly more successful in immunogenic tumors that express the neoantigen OVA, suggesting that the combination therapy enhanced the immune clearance of tumors. Moreover, the regression of tumors in mice that received PV-10 in combination with gemcitabine was associated with the depletion of splenic CD11b+Gr-1+ cells and increases in damage associated molecular patterns HMGB1, S100A8, and IL-1α. Conclusions These results demonstrate that intralesional therapy with PV-10 in combination with gemcitabine can enhance anti-tumor activity against pancreatic tumors and raises the potential for this strategy to be used for the treatment of patients with pancreatic cancer.

There is a lack of literature regarding the most effective timing to initiate physical therapy (PT) among traumatically injured patients. We aim to evaluate the association between early PT/mobilization versus delayed or late PT/mobilization and clinical outcomes of trauma patients.A retrospective cohort analysis of an urban level-I trauma center from 2014 to 2019 was performed. Univariate analyses and multivariable logistic regression were performed with significance defined as P0.05.A total of 11,937 patients were analyzed. Among patients without a traumatic brain injury (TBI), late PT initiation times were associated with 60% lower odds of being discharged home without services (P0.05), significantly increased hospital and ICU length of stay (H-LOS, ICU-LOS) (P0.05), and significantly higher odds of complications (VTE, pneumonia, pressure ulcers, ARDS) (P0.001). Among patients with a TBI, late PT initiation time had 76% lower odds of being discharged home without services (P0.05) and significantly longer H-LOS and ICU-LOS (P0.05) however did not experience significantly higher odds of complications (P0.05).Among traumatically injured patients, early PT is associated with decreased odds of complications, shorter H-LOS and ICU-LOS, and a favorable discharge disposition to home without services. Adoption of early PT initiation/mobilization protocols and establishment of prophylactic measures against complications associated with delayed PT is critical to maximize quality of care and trauma patient outcomes. Multi-center prospective studies are needed to ascertain the impact of PT initiation times in greater detail and to minimize trauma patient morbidity.

Background Chemotherapy regimens that include gemcitabine are considered standard of care in patients with advanced pancreatic ductal adenocarcinoma (PDAC). However, most patients with PDAC die within 2 years of diagnosis, even with these standard of care regimens. In this study, we explored the ability of intratumoral injections of PV-10, a 10% solution of rose bengal, to induce lesion-specific ablation and control of metastatic pancreatic tumors in a murine model. Methods PV-10 was cultured with human pancreatic cancer cell lines overnight and cell death was measured via Annexin-V and DAPI staining. Murine pancreatic tumor cells (Panc02) were injected subcutaneously in one flank to establish a single tumor model; to establish a bilateral tumor model, Panc02 tumor cells were implanted in the opposite flanks. On day 7, a single tumor was treated with intralesional PV-10. Gemcitabine (60 mg/kg) was injected intraperitoneally twice per week for 2 weeks. These experiments were repeated using Panc02 cells modified to overexpress the neoantigen ovalbumin (OVA). Control mouse tumor were directly injected with PBS. Tumor growth of PV-10 injected tumors and non-injected bystander tumors on the opposite flank were measured. Damage associated molecular patterns (DAMPs) in serum and immune cell frequencies within the spleens of tumor-bearing mice were measured to identify an associated systemic response with tumor lytic treatment regimen. Results We established that less than 50% of human and murine pancreatic cells were alive after a 24 hour incubation with 200µM PV-10 in vitro. The combination of intralesional PV-10 with the systemic administration of gemcitabine delayed the growth treated tumors and non-injected distal tumors. In contrast, gemcitabine monotherapy failed to delay tumor growth in bilateral Panc02 tumor models. We observed that this treatment strategy was markedly more successful in immunogenic Panc02OVA tumors resulting in lesion-specific ablation in 5/8 mice compared to 0/8 mice that were treated with gemcitabine monotherapy. This suggests that the combination therapy enhanced the immune-mediated clearance of tumors. Moreover, regression of tumors in mice that received PV-10 in combination with gemcitabine was associated with the depletion of splenic CD11b+Gr-1+ cells and increases in damage associated molecular patterns HMGB1, S100A8, and IL-1α. Conclusions Together, these results demonstrate that intralesional therapy with PV-10 can enhance the efficacy gemcitabine against pancreatic tumors. Ethics Approval Studies were performed under approved Institutional Review Board (IRB) laboratory protocols at the H. Lee Moffitt Cancer Center (Tampa, FL).

Myxoid lesions of the breast can be diagnostically challenging entities. We report 4 cases of CD34+ fibromyxoid lesion that have been previously diagnosed as “benign myxoid lesion,” “nodular mucinosis,” or “mammary myofibroblastoma, myxoid type” on the basis of CD34-positivity. The lesions were microscopically well circumscribed and composed of a paucicellular spindle cell proliferation in a background of myxoid stroma. No epithelial component was identified. The spindle cells showed immunohistochemical reactivity for CD34 and smooth muscle actin. Based on morphologic and immunohistochemical similarities between these cases and myxoid myofibroblastoma, we compared 4 myxoid lesions with cases of typical myofibroblastoma, utilizing retinoblastoma (Rb) antibody and fluorescent in situ hybridization for 13q14 gene rearrangement (encoding the Rb gene). The myxoid lesions showed retention of Rb protein by immunohistochemistry, whereas Rb expression was lost in cases of myofibroblastoma. We identified loss of 13q14 in 3 of 4 cases of myofibroblastoma. Notably, 13q14 gene rearrangement was not observed in any of the myxoid lesions. Our data show that there is at least a subset of CD34+ fibromyxoid lesions that, despite overlapping morphologic and immunohistochemical phenotype and proposed common histogenesis with myofibroblastomas, is genetically distinct from the latter based on Rb analysis.

BACKGROUND:Burnout affects all medical specialists, and concern about it has become common in today’s health care environment. The gold standard of burnout measurement in health care professionals is the Maslach Burnout Inventory-Human Services Survey (MBI-HSS), which measures emotional exhaustion

We definitively establish that the theory of symmetric Macdonald polynomials aligns with quantum and affine Schubert calculus using a discovery that distinguished weak chains can be identified by chains in the strong (Bruhat) order poset on the type-$A$ affine Weyl group. We construct two one-parameter families of functions that respectively transition positively with Hall-Littlewood and Macdonald's $P$-functions, and specialize to the representatives for Schubert classes of homology and cohomology of the affine Grassmannian. Our approach leads us to conjecture that all elements in a defining set of 3-point genus 0 Gromov-Witten invariants for flag manifolds can be formulated as strong covers., Comment: 29 pages

Background Recent data suggest that sodium (Na+) is stored in the muscle and skin without commensurate water retention in maintenance hemodialysis (MHD) patients. In this study, we hypothesized that excessive Na+ accumulation would be associated with abnormalities in peripheral insulin action. Methods Eleven MHD patients and eight controls underwent hyperinsulinemic–euglycemic–euaminoacidemic clamp studies to measure glucose (GDR) and leucine disposal rates (LDR), as well as lower left leg 23Na magnetic resonance imaging to measure Na+ concentration in the muscle and skin tissue. Results The median GDR and LDR levels were lower, and the median muscle Na+ concentration was higher in MHD patients compared with controls. No significant difference was found regarding skin Na+ concentration between group comparisons. Linear regression revealed inverse relationships between muscle Na+ concentration and GDR and LDR in MHD patients, whereas no relationship was observed in controls. There was no association between skin Na+ content and GDR or LDR in either MHD patients or controls. Conclusions These data suggest that excessive muscle Na+ content might be a determinant of IR in MHD patients, although the causality and mechanisms remain to be proven.

Emm55 is a bacterial gene derived from Streptococcus pyogenes (S. pyogenes) that was cloned into a plasmid DNA vaccine (pAc/emm55). In this study, we investigated the anti-tumor efficacy of pAc/emm55 in a B16 murine melanoma model. Intralesional (IL) injections of pAc/emm55 significantly delayed tumor growth compared to the pAc/Empty group. There was a significant increase in the CD8(+) T cells infiltrating into the tumors after pAc/emm55 treatment compared to the control group. In addition, we observed that IL injection of pAc/emm55 increased antigen-specific T cell infiltration into tumors. Depletion of CD4(+) or CD8(+) T cells abrogated the anti-tumor effect of pAc/emm55. Combination treatment of IL injection of pAc/emm55 with anti-PD-1 antibody significantly delayed tumor growth compared to either monotherapy. pAc/emm55 treatment combined with PD-1 blockade enhanced anti-tumor immune response and improved systemic anti-tumor immunity. Together, these strategies may lead to improvements in the treatment of patients with melanoma.

ObjectiveTo examine whether lifestyle factors, including sedentary time and physical activity, could independently contribute to risk of end-stage renal disease (ESRD).Study designCase-cohort study.SettingSouth-eastern USA.ParticipantsThe Southern Community Cohort Study recruited ~86 000 black and white participants from 2002 to 2009. We assembled a case cohort of 692 incident ESRD cases and a probability sample of 4113 participants.PredictorsSedentary time was calculated as hours/day from daily sitting activities. Physical activity was calculated as metabolic equivalent (MET)-hours/day from engagement in light, moderate and vigorous activities.OutcomesIncident ESRD.ResultsAt baseline, among the subcohort, mean (SD) age was 52 (8.6) years, and median (25th, 75th centile) estimated glomerular filtration rate (eGFR) was 102.8 (85.9–117.9) mL/min/1.73 m2. Medians (25th–75th centile) for sedentary time and physical activity were 8.0 (5.5–12.0) hours/day and 17.2 (8.7–31.9) MET-hours/day, respectively. Median follow-up was 9.4 years. We observed significant interactions between eGFR and both physical activity and sedentary behaviour (p2. The inverse association is most pronounced at physical activity levels >27 MET-hours/day. High levels of sitting time were associated with increased ESRD risk only among those with reduced kidney function (eGFR ≤30 mL/min/1.73 m2); this association was attenuated after excluding the first 2 years of follow-up.ConclusionsIn a population with a high prevalence of chronic kidney disease risk factors such as hypertension and diabetes, physical activity appears to be associated with reduced risk of ESRD among those with preserved kidney function. A positive association between sitting time and ESRD observed among those with advanced kidney disease is likely due to reverse causation.

We introduce a type $A$ crystal structure on decreasing factorizations of fully-commutative elements in the 0-Hecke monoid which we call $\star$-crystal. This crystal is a $K$-theoretic generalization of the crystal on decreasing factorizations in the symmetric group of the first and last author. We prove that under the residue map the $\star$-crystal intertwines with the crystal on set-valued tableaux recently introduced by Monical, Pechenik and Scrimshaw. We also define a new insertion from decreasing factorization to pairs of semistandard Young tableaux and prove several properties, such as its relation to the Hecke insertion and the uncrowding algorithm. The new insertion also intertwines with the crystal operators., Comment: 37 pages; in revision 1 Sections 3.1, 4.3 and 4.4 were updated; in revision 2 the phrase 321-avoiding is replaced by fully-commutative, typos are fixed, reference added

BackgroundThe therapeutic armamentarium of bladder cancer has been recently enriched with the introduction of new therapies including immune checkpoint inhibitors, receptor tyrosine kinase inhibitors and antibody drug conjugates, however treatment responses and duration of responses are still less than expected. Adoptive cellular therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has potential to treat bladder cancer, as previously demonstrated by successful expansion of tumor reactive T cells from human bladder tumors.MethodsA model system using OT-I T cells and an ovalbumin expressing MB49 tumor cell line (MB49OVA) was developed to study ACT in bladder cancer. Systemic ACT-treated mice were given T cells intravenously after lymphodepleting chemotherapy and followed by interleukin (IL)-2 administration. Intravesical ACT treated mice were given T cells directly into the bladder, without chemotherapy or IL-2. TILs were isolated from MB49 orthotopic tumors and expanded ex vivo in IL-2. Immune cell infiltrates were analyzed by flow cytometry. T cell infiltration was studied using a CXCR3 blocking antibody.ResultsSystemic ACT-treated mice had a decrease in tumor growth, increase in T cell infiltration and long-term immune protection compared with control-treated mice. OT-I T cells delivered intravesically were able to control tumor growth without lymphodepleting chemotherapy or IL-2 in MB49OVA orthotopic tumors. Intravesical delivery of TIL expanded from MB49 tumors was also able to decrease tumor growth in mice with MB49 orthotopic tumors. Blocking CXCR3 on OT-I T cells prior to intravesical delivery decreased T cell infiltration into the tumor and prevented the control of tumor growth.ConclusionsThis study demonstrates how TIL therapy can be used in treating different stages of bladder cancer.

We make a broad conjecture about the $k$-Schur positivity of Catalan functions, symmetric functions which generalize the (parabolic) Hall-Littlewood polynomials. We resolve the conjecture with positive combinatorial formulas in cases which address the $k$-Schur expansion of (1) Hall-Littlewood polynomials, proving the $q=0$ case of the strengthened Macdonald positivity conjecture of Lapointe, Lascoux, and Morse; (2) the product of a Schur function and a $k$-Schur function when the indexing partitions concatenate to a partition, describing a class of Gromov-Witten invariants for the quantum cohomology of complete flag varieties; (3) $k$-split polynomials, proving a substantial case of a problem of Broer and Shimozono-Weyman on parabolic Hall-Littlewood polynomials. In addition, we prove the conjecture that $k$-Schur functions defined in terms of $k$-split polynomials agree with strong tableau $k$-Schur functions., Comment: 33 pages

Bladder cancer remains a leading cause of death and one of the most expensive cancers to treat in the United States. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) is a personalized therapeutic approach that has the potential to treat bladder cancer at every stage of disease. We have previously demonstrated the ability to expand tumor reactive T cells from transurethral resection, radical cystectomy, and metastatic lymph node tumor specimens collected from bladder cancer patients. In this study, our goal is to investigate different delivery approaches of ACT in vivo to determine the best strategy to decrease tumor burden and advise clinical trial design. Experiments were performed using MB49 murine bladder cancer cells transfected to express ovalbumin (MB49OVA). MB49OVA cells are recognized by OVA-specific OT-I T cells as determined by IFN-gamma production in vitro. Our methods include both subcutaneous and orthotopic bladder tumor models. In vivo, we first tested systemic delivery of OT-I T cells (5.0 × 10e6) by tail vein injection after lymphodepletion with a regimen of cyclophosphamide followed by fludarabine in mice bearing subcutaneous MB49OVA tumors. ACT-treated mice experienced significant tumor regression (p=0.02), improved survival (median survival PBS=47 days, ACT=undefined, p=0.01), and increased tumor infiltration of CD3+, CD4+, and CD8+ T cells. OT-I T cells as well as endogenous OVA-specific CD8+ T cells were detectable in the spleens and tumors of treated mice. Next we tested the efficacy of intravesical delivery of OT-I T cells in mice bearing orthotopic MB49OVA tumors, without prior lymphodepletion. OT-I T cells (4.0 × 10e6) were delivered directly to the bladder via catherization and tumor growth was monitored weekly via ultrasound imaging. Infiltration of CellTrace Violet-labeled OT-I T cells into orthotopic tumors was detected after 3 hours of incubation by flow cytometry analysis of resected tumor. Orthotopic bladder tumor growth was significantly abrogated in ACT-treated mice compared with PBS control-treated mice (p=0.001) and improved survival was observed (median survival PBS=35 days, ACT=undefined). An increase in CD8+ T-cell infiltration was measured in tumors of mice at day 60 post treatment. In order to evaluate the efficacy of TIL transfer in these bladder tumor models, T cells infiltrating subcutaneous MB49OVA tumors were isolated and cultured in vitro in media containing IL-2. After 1 week, bladder TIL demonstrated reactivity against MB49OVA and MB49 parental cells as determined by IFN-gamma production. Future work will implement the adoptive transfer of MB49 TIL for the treatment of orthotopic bladder tumors alone or in combination with anti-PD-L1 therapy. Taken together, these data suggest that ACT using bladder tumor-specific T cells has the potential to reduce bladder tumor burden when given either systemically or intravesically directly into the bladder. Citation Format: Brittany L. Bunch, Jennifer Morse, Sarah Asby, Michael Poch, Shari Pilon-Thomas. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) for the treatment of bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A01.

Immunotherapy, including adoptive cell transfer (ACT) with tumor-infiltrating lymphocytes (TIL) predominantly targets improvement in MHC Class I-mediated anti-tumor immune responses. The primary objective of this study is to better understand the role of CD4+ TIL in ACT as a complementary avenue for therapeutic efficacy. Briefly, CD4+ TIL were isolated by negative selection from metastatic melanoma patients who received TIL therapy at Moffitt Cancer Center on IRB approved protocols. Individual T cell clones were tracked by TCRbeta sequencing to quantify clonal persistence in patients. CD4+ TIL clones were found to be decidedly persistent in a candidate patient who achieved a complete response (CR) after infusion of 88% CD4+ T cells. CD4+ TIL from additional patients were stimulated with anti-CD3/CD28 in vitro and those who were clinical responders demonstrated a pleiotropic cytokine profile marked by an elevated ratio of Th1:Th2 cytokines (p=0.07, n=13). When cultured with APCs loaded with autologous tumor (AT), CD4+ TIL produced high levels of IFN-gamma in an MHC Class II-dependent manner. Induction of MHC Class II on melanoma cell lines and AT determined that CD4+ TIL secreted IFNg and TNFa directly in response to AT. ACT of tumor-reactive CD4+ TIL in immunodeficient (NSG) mice provided significant control of AT growth when compared to non-reactive CD4+ TIL. Preliminary data in syngeneic mouse models also suggests that antigen-specific CD4+ T cells aid in initial tumor rejection, memory formation and epitope spreading, resulting in an overall increased therapeutic efficacy during ACT. This data supports the conclusion that CD4+ TIL are tumor-reactive and instrumental to an effective anti-tumor immune response in cancer patients.

Intralesional (IL) injection of Rose Bengal (PV-10) induces regression of injected and uninjected lesions in several murine tumor models. In this study, we investigated the anti-tumor response of combining IL PV-10 with blockade of the PD-1 / PD-L1 pathway and the role of immune cell populations in eliciting this response. To investigate the role of T cell subsets in mediating an immune response, B16 or M05 melanoma-bearing mice received combination therapy as well as CD8+, CD4+, or CD25+ depleting antibodies. Tumor growth was measured. T cells were collected from spleens or tumors, and phenotype, activation markers, and reactivity were measured. Splenocytes from mice treated with combination therapy had increased OVA antigen-specific CD8+ T cells in M05-tumor-bearing mice. Depletion of CD4+ T cells or regulatory T cells (Tregs) in combination with IL PV-10 and anti-PD-1 antibody treatment resulted in an enhanced anti-tumor effect. Treatment with CD8+ depleting antibody abrogated anti-tumor immunity. These results support a clinical study for the safety and anti-tumor immune responses with combination therapy of IL PV-10 and PD-1/PD-L1 blockade.

The non-negative integer cocharge statistic on words was introduced in the 1970's by Lascoux and Sch\"utzenberger to combinatorially characterize the Hall-Littlewood polynomials. Cocharge has since been used to explain phenomena ranging from the graded decomposition of Garsia-Procesi modules to the cohomology structure of the Grassman variety. Although its application to contemporary variations of these problems had been deemed intractable, we prove that the two-parameter, symmetric Macdonald polynomials are generating functions of a distinguished family of colored words. Cocharge adorns one parameter and the second measures its deviation from cocharge on words without color. We use the same framework to expand the plactic monoid, apply Kashiwara's crystal theory to various Garsia-Haiman modules, and to address problems in K-theoretic Schubert calculus., Comment: 25 pages

4-1BB (CD137) is a co-stimulatory receptor expressed on activated T cells and other immune cells and is associated with enhanced T cell proliferation, survival, and increased cytokine production upon engagement with its ligand (4-1BBL). We have previously shown that addition of agonistic 4-1BB antibody to tumor fragments increased tumor infiltrating lymphocyte (TIL) expansion in human melanoma and pancreatic tumors. Furthermore, agonistic 4-1BB antibody led to increased expression of maturation markers in resident dendritic cells (DCs) present within tumor fragments. While the role of 4-1BB in T cell biology is well described, little is known about 4-1BB signaling in tumor-resident DCs. We hypothesized that 4-1BB agonism in tumor-resident DCs would promote anti-tumor T cell immune responses. To evaluate the role of 4-1BB signaling on dendritic cells, murine bone marrow derived-DCs were cultured with agonistic 4-1BB antibody and loaded with OVA protein. Treatment with agonistic 4-1BB in vitro led to increased OVA-FITC uptake by DCs (32.6% compared to 15.9% in DCs treated with control antibody). DCs treated with agonistic 4-1BB antibody demonstrated increased T cell stimulatory capacity upon co-culture with OVA-specific OT-I and OT-II T cells. We next compared systemic and intralesional (IL) treatment with agonistic 4-1BB antibody. For the systemic model, mice were injected subcutaneously (SC) with B16 melanoma or Panc02 pancreatic tumor cells and treated by intraperitoneal injection of control or anti-4-1BB antibodies. Mice treated systemically with agonistic 4-1BB antibody exhibited a minimal reduction in tumor growth. In contrast, IL injection of agonistic 4-1BB antibody led to dramatic decreases in tumor growth. Next, we wanted to determine whether IL treatment with agonistic 4-1BB antibody would improve DC stimulatory capacity. Mice bearing B16 or Panc02 tumors were treated IL with normal control or anti-4-1BB antibody. After 7 days, tumor-resident CD11b+ DCs exhibited enhanced in vivo antigen uptake. In addition, an increased number of CD8+ T cells was measured within tumors treated with agonistic 4-1BB antibody (28.1% compared to 20% in NrIgG-treated Panc02OVA tumors and 19.45% compared to 7.3% in NrIgG treated B16-OVA tumors; p=0.0059). Together, these studies demonstrate that agonistic 4-1BB can enhance the ability of DCs to stimulate T cells and IL administration of agonistic 4-1BB antibody can significantly reduce tumor growth. This suggests that IL treatment of agonistic 4-1BB may yield greater efficacy than systemic therapy in patients with melanoma or pancreatic cancer. Citation Format: Amy Mackay Weber, Patrick Innamarato, Jennifer Morse, Scott Kidd, Sarah Asby, Amod Sarnaik, Shari Pilon-Thomas. Targeting 4-1BB in tumors enhances anti-tumor immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2403.

Establishing a program to monitor waste anesthetic gas (WAG) in order to limit personnel exposure requires measuring the levels of WAG emitted and determining the effectiveness of scavenging methods to reduce such levels. In this study, the authors used infrared spectroscopy to measure levels of WAG emitted while anesthetizing mice with isoflurane for 15 min. They evaluated four different WAG scavenging conditions during induction and maintenance anesthesia: two conditions that used passive techniques and two that used active techniques. Isoflurane concentrations were measured at three different locations: in the operator's vicinity, at the mouse-facemask interface and in the room environment. Passive scavenging of WAG improved when chambers were purged with oxygen after induction and when a diaphragm-sealed facemask delivered a reduced anesthetic flow rate during maintenance anesthesia. Active scavenging of WAG improved when a relief intake opening was provided in the induction chamber's vacuum line, vacuum draw after induction was regulated and the anesthetic flow rate and vacuum scavenging draw were balanced during maintenance anesthesia using a facemask that separated the breathing space from the scavenging zone. Additionally, time-weighted average isoflurane WAG levels detected by personal dosimeters correlated with real-time measurements made using infrared spectroscopy. These observations contribute to the development of a substantiated program for monitoring WAG air quality.

Background Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used and have been linked to acute kidney injury (AKI), chronic kidney disease (CKD) and cardiovascular disease (CVD). Patients who survive an AKI episode are at risk for future adverse kidney and cardiovascular outcomes. The objective of our study was to examine the prevalence and predictors of NSAID use among AKI survivors. Methods The Southern Community Cohort Study is a prospective study of low-income adults aged 40–79 in the southeastern US. Through linkage with Centers for Medicare and Medicaid Services, 826 participants with an AKI diagnosis (ICD-9 584.5-584.9) at any age prior to cohort enrollment were identified. At baseline, data were collected on regular use of prescription and over-the-counter NSAIDs, as well as demographic, medical and other characteristics. Additional comorbidities were ascertained via linkage with CMS or the US Renal Data System. Results One hundred fifty-four AKI survivors (19%) reported regular NSAID use at cohort enrollment (52 prescription, 81 OTC, 21 both) and the percentage of NSAID users did not vary by time since AKI event. Over 58% of users were taking NSAIDS regularly both before and after their AKI event. Hypertension (83%), arthritis (71%), heart failure (44%), CKD (36%) and diabetes (35%) were prevalent among NSAID users. In a multivariable model, history of arthritis (OR: 3.00; 95% CI: 1.92, 4.68) and acetaminophen use (OR: 2.43; 95% CI: 1.50, 3.93) were significantly associated with NSAID use, while prevalent CKD (OR: 0.63; 95% CI: 0.41, 0.98) and diabetes (OR: 0.44; 95% CI: 0.29, 0.69) were significantly inversely associated. Conclusions NSAID use among AKI survivors is common and highlights the need to understand physician and patient decision-making around NSAIDs and to develop effective strategies to reduce NSAID use in this vulnerable population. Electronic supplementary material The online version of this article (doi:10.1186/s12882-016-0411-7) contains supplementary material, which is available to authorized users.

O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1

Background Delirium affects 20–30% of patients after cardiac surgery and is associated with increased mortality and persistent cognitive decline. Hyperoxic reperfusion of ischemic tissues increases oxidative injury, but oxygen administration remains high during cardiac surgery. We tested the hypothesis that intraoperative hyperoxic cerebral reperfusion is associated with increased postoperative delirium and that oxidative injury mediates this association. Methods We prospectively measured cerebral oxygenation with bilateral oximetry monitors in 310 cardiac surgery patients, quantified intraoperative hyperoxic cerebral reperfusion by measuring the magnitude of cerebral oxygenation above baseline after any ischemic event, and assessed patients for delirium twice daily in the ICU following surgery using the confusion assessment method for ICU (CAM-ICU). We examined the association between hyperoxic cerebral reperfusion and postoperative delirium, adjusted for the extent of cerebral hypoxia, the extent of cerebral hyperoxia prior to any ischemia, and additional potential confounders and risk factors for delirium. To assess oxidative injury mediation, we examined the association between hyperoxic cerebral reperfusion and delirium after further adjusting for plasma levels of F 2 -isoprostanes and isofurans at baseline and ICU admission, the association between hyperoxic cerebral reperfusion and these markers of oxidative injury, and the association between these markers and delirium. Results Ninety of the 310 patients developed delirium following surgery. Every 10%·hour of intraoperative hyperoxic cerebral reperfusion was independently associated with a 65% increase in the odds of delirium (OR, 1.65 [95% CI, 1.12–2.44]; P=0.01). Hyperoxia prior to ischemia was also independently associated with delirium (1.10 [1.01–1.19]; P=0.02), but hypoxia was not (1.12 [0.97–1.29]; P=0.11). Increased hyperoxic cerebral reperfusion was associated with increased concentrations of F 2 -isoprostanes and isofurans at ICU admission, increased concentrations of these markers were associated with increased delirium, and the association between hyperoxic cerebral reperfusion and delirium was weaker after adjusting for these markers of oxidative injury. Conclusions Intraoperative hyperoxic cerebral reperfusion was associated with increased postoperative delirium, and increased oxidative injury following hyperoxic cerebral reperfusion may partially mediate this association. Further research is needed to assess the potential deleterious role of cerebral hyper-oxygenation during surgery.

We give a new description of the Pieri rule for $k$-Schur functions using the Bruhat order on the affine type-$A$ Weyl group. In doing so, we prove a new combinatorial formula for representatives of the Schubert classes for the cohomology of affine Grassmannians. We show how new combinatorics involved in our formulas gives the Kostka-Foulkes polynomials and discuss how this can be applied to study the transition matrices between Hall-Littlewood and $k$-Schur functions., Nous présentons une nouvelle description, issue de l'ordre de Bruhat du groupe de Weyl affine de type $A$, de la règle de Pieri pour les fonctions $k$-Schur. Ce faisant, nous obtenons une nouvelle formule combinatoire pour les représentants des classes de Schubert de la cohomologie des Grassmannienne affines. Nous décrivons aussi comment notre approche permet d'obtenir les polynômes de Kostka-Foulkes et comment elle peut être appliquée à l’étude des matrices de transition entre les polynômes de Hall-Littlewood et les fonctions $k$-Schur.

We introduce a family of tableaux that simultaneously generalizes the tableaux used to characterize Grothendieck polynomials and k -Schur functions. We prove that the polynomials drawn from these tableaux are the affine Grothendieck polynomials and k - K -Schur functions – Schubert representatives for the K -theory of affine Grassmannians and their dual in the nil Hecke ring. We prove a number of combinatorial properties including Pieri rules.

We prove that structure constants related to Hecke algebras at roots of unity are special cases of k k -Littlewood-Richardson coefficients associated to a product of k k -Schur functions. As a consequence, both the 3-point Gromov-Witten invariants appearing in the quantum cohomology of the Grassmannian, and the fusion coefficients for the WZW conformal field theories associated to s u ^ ( ℓ ) \widehat {su}(\ell ) are shown to be k k -Littlewood-Richardson coefficients. From this, Mark Shimozono conjectured that the k k -Schur functions form the Schubert basis for the homology of the loop Grassmannian, whereas k k -Schur coproducts correspond to the integral cohomology of the loop Grassmannian. We introduce dual k k -Schur functions defined on weights of k k -tableaux that, given Shimozono’s conjecture, form the Schubert basis for the cohomology of the loop Grassmannian. We derive several properties of these functions that extend those of skew Schur functions.

We provide a new description of the Pieri rule of the homology of the affine Grassmannian and an affineanalogue of the charge statistics in terms of bounded partitions. This makes it possible to extend the formulation ofthe Kostka–Foulkes polynomials in terms of solvable lattice models by Nakayashiki and Yamada to the affine setting., Nous proposons une nouvelle description de la règle de Pieri de l’homologie de la variété Grassmannienneaffine et un analogue affine de la statistique de charge en termes de partitions bornées . Il est ainsi possible d’étendreau cas affine la formulation due à Nakayashiki et Yamada des polynômes de Kostka–Foulkes en termes de modèlesde réseaux résolubles.

The transcription factor NF-kappaB is believed to play a key pathophysiological role in chronic intestinal inflammation. Further characterization of its mechanism of regulation, predominantly through cell signaling pathways, may provide clues as to the means of its intervention. One such potential signaling candidate is the protein kinase CK2. Despite its known ability to influence NF-kappaB activation, it has received no attention in this particular setting.To characterize the aspects of its activation in response to IL-1beta in the colonic cell lines Caco2 and HCT116.A biochemical analysis of kinase activation was performed using phospho-specific antibodies as well as immune complex kinase assays; transcription factor activity was measured by transient transfection and luciferase-based NF-kappaB reporter assays; pro-inflammatory molecule expression was determined using RT-PCR.In this report, we show an enhanced activation of CK2 bound to IKKgamma or the p65 subunit of the NF-kappaB in response to IL-1beta stimulation of intestinal epithelial cells. Using two established NF-kappaB reporters, we demonstrate that CK2 is involved in NF-kappaB regulation through the p65 serine 529 site. Using co-immunoprecipitation studies, we also show that p65 is bound to CK2 predominantly in the nucleus. From a functional perspective, two CK2 specific inhibitors were then shown to attenuate IL-8 reporter activation. Finally, the expression of a series of pro-inflammatory molecules including IL-8, GRO-alpha, MCP-1, TNFalpha and iNOS were variably affected in response to CK2 inhibition.CK2 plays an active role in NF-kappaB signaling in intestinal epithelial cell lines and may represent a possible target for intervention.

The k-Young lattice Y k is a weak subposet of the Young lattice containing partitions whose first part is bounded by an integer k > 0. The Y k poset was introduced in connection with generalized Schur functions and later shown to be isomorphic to the weak order on the quotient of the affine symmetric group Sk + 1 by a maximal parabolic subgroup. We prove a number of properties for Y k including that the covering relation is preserved when elements are translated by rectangular partitions with hook-length k. We highlight the order ideal generated by an m x n rectangular shape. This order ideal, L k (m, n), reduces to L(m, n) for large k, and we prove it is isomorphic to the induced subposet of L(m, n) whose vertex set is restricted to elements with no more than k - m + 1 parts smaller than m. We provide explicit formulas for the number of elements and the rank-generating function of L k (m, n). We conclude with unimodality conjectures involving q-binomial coefficients and discuss how implications connect to recent work on sieved q-binomial coefficients.

We obtain general identities for the product of two Schur functions in the case where one of the functions is indexed by a rectangular partition, and give their t-analogs using vertex operators. We study subspaces forming a filtration for the symmetric function space that lends itself to generalizing the theory of Schur functions and also provides a convenient environment for studying the Macdonald polynomials. We use our identities to prove that the vertex operators leave such subspaces invariant. We finish by showing that these operators act simply on the k-Schur functions, thus leading to a concept of irreducibility for these functions., Comment: 18 pages

This purpose of this chapter is to introduce Stanley symmetric functions and affine Stanley symmetric functions from the combinatorial and algebraic point of view. The presentation roughly follows three lectures I gave at a conference titled “Affine Schubert Calculus” held in July of 2010 at the Fields Institute in Toronto.

The purpose of this chapter is to outline some of the results and open problems related to k-Schur functions, mostly in the setting of symmetric function theory. This chapter roughly follows the outline of several talks given by Luc Lapointe and Jennifer Morse at a conference titled “Affine Schubert Calculus” held in July of 2010 at the Fields Institute in Toronto.

This book is an exposition of the current state of research of affine Schubert calculus and $k$-Schur functions. This text is based on a series of lectures given at a workshop titled "Affine Schubert Calculus" that took place in July 2010 at the Fields Institute in Toronto, Ontario. The story of this research is told in three parts: 1. Primer on $k$-Schur Functions 2. Stanley symmetric functions and Peterson algebras 3. Affine Schubert calculus

This chapter discusses how k-Schur and dual k-Schur functions can be defined for all types. This is done via some combinatorial problems that come from the geometry of a very large family of generalized flag varieties. They apply to the expansion of products of Schur functions, k-Schur functions and their dual basis, and Schubert polynomials. Despite the geometric origin of these problems, concrete algebraic models will be given for the relevant cohomology rings and their Schubert bases.

Continuously monitoring vital signs on general care units may provide earlier detection and intervention of instabilities in patients. These earlier interventions could prevent deaths and admission to critical care units, thereby increasing patient safety and improving patient outcomes.

We study the class $\mathcal C$ of symmetric functions whose coefficients in the Schur basis can be described by generating functions for sets of tableaux with fixed shape. Included in this class are the Hall-Littlewood polynomials, $k$-atoms, and Stanley symmetric functions; functions whose Schur coefficients encode combinatorial, representation theoretic and geometric information. While Schur functions represent the cohomology of the Grassmannian variety of $GL_n$, Grothendieck functions $\{G_\lambda\}$ represent the $K$-theory of the same space. In this paper, we give a combinatorial description of the coefficients when any element of $\mathcal C$ is expanded in the $G$-basis or the basis dual to $\{G_\lambda\}$., Comment: 23 pages

Although, stratifin (SFN) is externalized by keratinocytes and stimulates the expression of matrix metalloproteinase-1 (MMP-1) in fibroblasts, its mechanism of externalization is not known. Here, we hypothesize that keratinocytes have a capacity to release stratifin through externalization of exosomes. To test this hypothesis, exosomes were purified from human keratinocyte conditioned medium (KCM) and analyzed for the presence of SFN by Western blot analysis using lysosomal-associated membrane protein 2 (LAMP-2) and heat shock cognate 70 (hsc70) as exosomal markers. The results showed the presence of SFN in keratinocyte lysate, concentrated KCM and exosomes, but not in concentrated unconditioned medium. Transmission electron microscopic examination revealed the presence of unique "saucer-like" structures characteristic of exosomes whose diameters were