Isocitrate dehydrogenase 1 and 2 mutations, 2-hydroxyglutarate levels, and response to standard chemotherapy for patients with newly diagnosed acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) cells harboring mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) produce the oncometabolite 2-hydroxyglutarate (2HG). This study prospectively evaluated the 2HG levels, IDH1/2 mutational status, and outcomes of patients receiving standard chemotherapy for newly diagnosed AML. METHODS: Serial samples of serum, urine, and bone marrow aspirates were collected from patients newly diagnosed with AML, and 2HG levels were measured with mass spectrometry. Patients with baseline serum 2HG levels greater than 1000 ng/mL or marrow pellet 2HG levels greater than 1000 ng/2 × 106 cells, which suggested the presence of an IDH1/2 mutation, underwent serial testing. IDH1/2 mutations and estimated variant allele frequencies were identified. AML characteristics were compared with the Wilcoxon test and Fisher's exact test. Disease-free survival and overall survival (OS) were evaluated with log-rank tests and Cox regression. RESULTS: Two hundred and two patients were treated for AML; 51 harbored IDH1/2 mutations. IDH1/2-mutated patients had significantly higher 2HG levels in serum, urine, bone marrow aspirates, and aspirate cell pellets than wild-type patients. A serum 2HG level greater than 534.5 ng/mL was 98.8% specific for the presence of an IDH1/2 mutation. Patients with IDH1/2-mutated AML treated with 7+3-based induction had a 2-year event-free survival (EFS) rate of 44% and a 2-year OS rate of 57%. There was no difference in complete remission rates, EFS, or OS between IDH1/2-mutated and wild-type patients. Decreased serum 2HG levels on day 14 as a proportion of the baseline were significantly associated with improvements in EFS (P = .047) and OS (P = .019) in a multivariate analysis. CONCLUSIONS: Among patients with IDH1/2-mutated AML, 2HG levels are highly specific for the mutational status at diagnosis, and they have prognostic relevance in patients receiving standard chemotherapy.

Cabozantinib is well tolerated in acute myeloid leukemia and effectively inhibits the resistance-conferring FLT3/tyrosine kinase domain/F691 mutation.

BACKGROUND: Cabozantinib, a tyrosine kinase inhibitor of FMS-like tyrosine kinase 3 (FLT3), MET, AXL, vascular endothelial growth factor receptor, and KIT, is approved for use in multiple malignancies. We assessed the safety and tolerability of cabozantinib in AML, given up-regulation of multiple relevant pathways. METHODS: Adults were eligible if they were 18 years old or older with relapsed/refractory AML or if they were 70 years old or older with newly diagnosed AML but were ineligible for conventional therapy. Cabozantinib was administered in 28-day cycles, and dose escalation occurred via cohorts. A pharmacodynamic evaluation of serial plasma samples via a plasma inhibitory assay (PIA) was used to assess FLT3-inhibitory activity in FLT3-mutant cell lines. RESULTS: Among 18 patients enrolled, 5 were found to harbor FLT3/ITD mutations. Sixteen patients (89%) had relapsed/refractory AML, and most were treated with 2 or more lines of prior treatment. No dose-limiting toxicities (DLTs) were detected at the first dose level (40 mg daily), but 2 patients experienced DLTs at the next level (60 mg daily). The remaining patients were then dosed at 40 mg daily, the maximum tolerated dose (MTD). Additional grade 2 or higher toxicities, possibly/probably related to cabozantinib, included fatigue, nausea, transaminitis, and electrolyte imbalance. No patients had a marrow response according to formal criteria, but 4 had peripheral blast reductions; 2 of these 4 patients transiently cleared circulating blasts. One patient experienced a reduction in marrow blasts, and 1 had stable disease. The FLT3-inhibitory activity of plasma samples, as assessed with the PIA, revealed potent and sustained inhibition in FLT3/ITD and, notably, F691 tyrosine kinase domain (TKD)-mutant cells. CONCLUSIONS: Cabozantinib is well tolerated in AML patients at an MTD of 40 mg daily and is a potent inhibitor of FLT3/ITD- and F691 TKD-altered tyrosine kinases. Cancer 2018;124:306-14. © 2017 American Cancer Society.

Association between insurance status at diagnosis and overall survival in chronic myeloid leukemia: A population-based study.

BACKGROUND: Chronic myeloid leukemia (CML) can be treated effectively with tyrosine kinase inhibitor therapy directed at BCR-ABL, but access to care, medication cost, and adherence may be barriers to treatment. This study was designed to determine whether the insurance status at diagnosis influences CML patient outcomes. METHODS: The Surveillance, Epidemiology, and End Results database was used to identify 5784 patients, aged 15 years or older, who were diagnosed with CML between 2007 and 2012 and whose insurance status was documented at diagnosis. The primary outcome was 5-year overall survival (OS). Covariates of interest included the age at diagnosis, race, ethnicity, sex, county-level socioeconomic status, and marital status. OS was evaluated with a log-rank test and Kaplan-Meier estimates. RESULTS: Among patients aged 15 to 64 years, insurance status was associated with OS (P < .001): being uninsured or having Medicaid was associated with worse 5-year OS in comparison with being insured (uninsured patients, 72.7%; Medicaid patients, 73.1%; insured patients, 86.6%). For patients who were 65 years old or older, insurance had less of an impact on OS (P = .07), with similar 5-year OS rates for patients with Medicaid and those with other insurance (40.2% vs 43.4%). In a multivariate analysis of patients aged 15 to 64 years, both uninsured patients (hazard ratio [HR], 1.93; P < .001) and Medicaid patients (HR, 1.83; P < .001) had an increased hazard of death in comparison with insured patients; patients younger than 40 years, female patients, and married patients also had a lower hazard of death. CONCLUSION: These findings suggest that CML patients under the age of 65 years who are uninsured or have Medicaid have significantly worse survival than patients with other insurance coverage. Cancer 2017;123:2561-69. © 2017 American Cancer Society.

Phase I study of the aurora A kinase inhibitor alisertib with induction chemotherapy in patients with acute myeloid leukemia.

Aberrant expression of aurora kinase A is implicated in the genesis of various neoplasms, including acute myeloid leukemia. Alisertib, an aurora A kinase inhibitor, has demonstrated efficacy as monotherapy in trials of myeloid malignancy, and this efficacy appears enhanced in combination with conventional chemotherapies. In this phase I, dose-escalation study, newly diagnosed patients received conventional induction with cytarabine and idarubicin, after which alisertib was administered for 7 days. Dose escalation occurred via cohorts. Patients could then receive up to four cycles of consolidation, incorporating alisertib, and thereafter alisertib maintenance for up to 12 months. Twenty-two patients were enrolled. One dose limiting toxicity occurred at dose level 2 (prolonged thrombocytopenia), and the recommended phase 2 dose was established at 30mg twice daily. Common therapy-related toxicities included cytopenias and mucositis. Only three (14%) patients had persistent disease at mid-cycle, requiring "5+2" reinduction. The composite remission rate (complete remission and complete remission with incomplete neutrophil recovery) was 86% (nineteen of twenty-two patients; 90% CI 68-96%). Among those over age 65 and those with high-risk disease (secondary acute leukemia or cytogenetically high-risk disease), the composite remission rate was 88% and 100%, respectively. The median follow up was 13.5 months. Of those treated at the recommended phase 2 dose, the 12-month overall survival and progression-free survival were 62% (90% CI 33-81%) and 42% (90% CI 17-65%), respectively. Alisertib is well tolerated when combined with induction chemotherapy in acute myeloid leukemia, with a promising suggestion of efficacy. (clinicaltrials.gov Identifier:01779843).

Elevation of Urinary 2-Hydroxyglutarate in IDH-Mutant Glioma.

BACKGROUND: Recurrent mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes, which are frequent in gliomas, result in marked accumulation of the metabolic by-product 2-hydroxyglutarate (2-HG) within tumors. In other malignancies, such as acute myeloid leukemia, presence of IDH mutation is associated with elevated 2-HG levels in serum or urine compartments. Circulating 2-HG in patients with glial malignancies has not been thoroughly investigated. METHODS: In this study, we analyzed 2-HG levels in the serum and urine of a large set of patients with IDH-mutant and IDH-wild-type glioma, and the cerebrospinal fluid (CSF) from a subset of this cohort. RESULTS: We found that 2-HG was elevated in the urine of patients with IDH-mutant versus IDH-wild-type glioma, although no significant differences in 2-HG levels were observed in the serum or the small set of CSF samples obtained. Among patients with IDH-mutant glioma, 2-HG levels did not differ based on the histopathologic grade, genetic subtype (TP53 mutant or 1p/19q codeleted), presence of a canonical (IDH1 R132H) or noncanonical (any other IDH variant) mutation, or treatment type. CONCLUSION: Our finding suggests that urinary 2-HG is increased among patients with IDH-mutant gliomas, and may represent a future surrogate, noninvasive biomarker to aid in diagnosis, prognosis, and management. IMPLICATIONS FOR PRACTICE: Patients with glioma who harbor mutations in isocitrate dehydrogenase genes showed selective elevation of the oncometabolite 2-hydroxyglutarate in the urine. Similar elevations were not identified in the serum or cerebrospinal fluid. 2-Hydroxyglutarate may serve as a useful, noninvasive biomarker to stratify patients newly diagnosed with glioma with regard to prognosis and management.

Isocitrate dehydrogenase 1 (IDH1) mutation in breast adenocarcinoma is associated with elevated levels of serum and urine 2-hydroxyglutarate.

Mutations in the IDH1 and IDH2 (isocitrate dehydrogenase) genes have been discovered across a range of solid-organ and hematologic malignancies, including acute myeloid leukemia, glioma, chondrosarcoma, and cholangiocarcinoma. An intriguing aspect of IDH-mutant tumors is the aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in these malignancies. We describe the first reported case of an IDH1 p.R132L mutation in a patient with hormone receptor-positive (HR+) breast adenocarcinoma. This patient was initially treated for locally advanced disease, but then suffered a relapse and metastasis, at which point an IDH1-R132 mutation was discovered in an affected lymph node. The mutation was subsequently found in the primary tumor tissue and all metastatic sites, but not in an uninvolved lymph node. In addition, the patient's serum and urine displayed marked elevations in the concentration of 2-HG, significantly higher than that measured in six other patients with metastatic HR+ breast carcinoma whose tumors were found to harbor wild-type IDH1. In summary, IDH1 mutations may impact a rare subgroup of patients with breast adenocarcinoma. This may suggest future avenues for disease monitoring through noninvasive measurement of 2-HG, as well as for the development and study of targeted therapies against the aberrant IDH1 enzyme.

Incidence of Thrombosis in COVID-19 Patients Compared to Non-COVID-19 Sepsis Patients in the Intensive Care Unit.

Background/Objectives: The hypercoagulable state associated with COVID-19 infection is associated with adverse outcomes and mortality. Studies have also demonstrated high rates of venous thromboembolism (VTE) events among patients with sepsis. We aimed to evaluate how the increase in thrombotic events in critically ill patients with COVID-19 infection compares to that of critically ill patients with non-COVID-19 sepsis. Methods: A chart review was performed of patients 18 years or older admitted to the intensive care unit (ICU) at Tampa General Hospital between 1 January 2020 and 31 December 2020 diagnosed with COVID-19 or sepsis secondary to other pathogens. Non-COVID-19 sepsis patients and COVID-19 patients were propensity-matched 3:1 on the Charlson Comorbidity Index. Multivariate analyses adjusting for confounding were conducted to report odds ratio (OR) and 95% confidence intervals (95% CIs) of predictors for thrombotic events and overall mortality. Results: After propensity score matching, 492 sepsis patients and 164 COVID-19 patients were included in the analysis. COVID-19 patients were significantly older (p = 0.021) and showed higher BMI (p < 0.001) than sepsis patients. COVID-19 patients did not show significantly higher odds of thrombosis after adjustment for confounders (OR 0.85, 95% CI 0.42-1.72), but had significantly lower odds of mortality than sepsis patients (OR 0.33, 95% CI 0.16-0.66). Conclusions: Our results suggest that further study is required to lower the rate of VTE in COVID-19 and non-COVID-19 sepsis patients admitted to the ICU; it is also reasonable to consider similar thromboembolism practices between these two patient groups.

Thrombomodulin is a determinant of metastasis through a mechanism linked to the thrombin binding domain but not the lectin-like domain.

Thrombomodulin (TM) is a predominantly endothelial transmembrane glycoprotein that modulates hemostatic function through a domain that controls thrombin-mediated proteolysis and an N-terminal lectin-like domain that controls inflammatory processes. To test the hypothesis that TM is a determinant of malignancy and dissect the importance of these functional domains in cancer biology, metastatic potential was evaluated in TM(Pro) mice expressing a mutant form of TM with reduced thrombin affinity and TM(LeD) mice lacking the N-terminal lectin-like domain. Studies of TM(Pro) mice revealed that TM is a powerful determinant of hematogenous metastasis. TM(Pro) mice exhibited a strongly prometastatic phenotype relative to control mice that was found to result from increased survival of tumor cells newly localized to the lung rather than any alteration in tumor growth. The impact of the TM(Pro) mutation on metastasis was dependent on both tumor cell-associated tissue factor and thrombin procoagulant function. In contrast, expression of a mutant form of TM lacking the lectin-like domain had no significant impact on metastasis. These studies directly demonstrate for the first time that TM-mediated regulation of tumor cell-driven procoagulant function strongly influences metastatic potential and suggest that endothelial cell-associated modulators of hemostasis may represent novel therapeutic targets in limiting tumor dissemination.

Exploring the desires and sexual culture of men who have sex with male-to-female transgender women.

Men who have sex with transgender women (MSTW) currently constitute a gap in the research community's understanding of male sexuality and sexual desire. In an effort to address this lack of knowledge, an ethnographic study of MSTW in New York City was conducted between December 2005 and May 2007, including in-depth interviews with MSTW (n = 15), key informant interviews (n = 13), and ethnographic observation of semi-private "tranny" parties held at various venues throughout New York City. The specific objectives were to: (1) describe the sex marketplaces and the sexual experiences of an ethnographic sample of MSTW in New York City and (2) describe the ways MSTW construct their sexual partnering practices and the meanings attributed to those practices in relation to varying social contexts (in and outside the sex marketplace). In this analysis, we described the MSTW sex market landscape in New York and identified three major recurrent themes in the ways that MSTW organized their sexual desire for TW transitioning from sex marketplaces to social spaces in their lives: (1) phallus-centric trade sex market focus; (2) relational-companionship market focus; and (3) specialized market focus. Although the findings from the study are not representative of the broader MSTW population, they represent an important step in amassing a body of knowledge about an understudied and underserved sex market upon which future research is needed.

Generational changes in the meanings of sex, sexual identity and stigma among Latino young and adult men.

In this paper we examine the sexual identities of Latino men who have sex with men and women, in which an analysis was made of 150 sexual histories of Latino men aged 18-60. This study asks how the bisexual identity and experience of stigma is different for Latino men along the generational spectrum and how do these differences relate to kinship support and gender ideology? In the process of analysis, two main clusters of characteristics were identified to reflect this population: young men aged 18-25, whose open bisexual identity correlated positively with kinship/peer support and flexible gender and sexual roles, and men aged 26-60, who refused or were reluctant to identify as bisexual despite the fact that they were sexually active with both men and women. This group as a whole had less kinship and peer support, were more likely to identify with traditional gender roles and were less sexually versatile. Finally, a third group reflected Latino men across the generational divide who were less concerned with same-sex stigma, but who nevertheless felt the bisexual label to be confining, illegitimate or otherwise negative.

Implementation of a Cancer Rehabilitation Navigation Program: a qualitative analysis of implementation determinants and strategies.

BACKGROUND: Cancer rehabilitation navigation (CRNav) is a care delivery model that expedites identification and management of symptom-related functional morbidity for individuals undergoing cancer treatment. A CRNav program is unique in that it embeds a cancer rehabilitation professional in the cancer center for patient screening and assessment. The implementation of CRNav programs has not been studied and doing so could facilitate greater uptake of these programs. METHODS: Using implementation science frameworks, we conducted a qualitative, post-implementation analysis of a CRNav program that was implemented in 2019. Semi-structured, 1:1 interviews were guided by the Consolidated Framework for Implementation Research (CFIR) and a combination of deductive and inductive analyses, using a priori established codes, was used to assess the implementation context, and identify emergent themes of barriers and facilitators to implementation. Participant described implementation strategies were characterized and defined using the Expert Consensus Recommendations for Implementing Change (ERIC) taxonomy. RESULTS: Eleven stakeholders including physicians, administrators, clinical staff, and patients, involved with program development and the implementation effort, participated in interviews. Predominant barriers to implementation included developing the program infrastructure, and lack of awareness of rehabilitation services among oncology professionals, predominant facilitators of implementation included; physical co-location of the navigator in the cancer center, individual characteristics of the navigator, and unique characteristics of the program. Strategies described that supported implementation included developing stakeholder interrelationships, evaluating and iteratively adapting the program, creating infrastructure, training and education, and supporting clinicians. CONCLUSION: This analysis uses implementation science to methodically analyze and characterize factors that may contribute to successful implementation of a CRNav program. These findings could be used alongside a prospective context-specific analysis to tailor future implementation efforts. IMPLICATIONS FOR CANCER SURVIVORS: Implementing a CRNav program expedites a patient's direct contact with a rehabilitation provider complementing the cancer care delivery team, and providing an additive and often missing service.

Advances in Hemophilia A Management.

Hemophilia A is an inherited insufficiency of Factor VIII (FVIII), one of the critical clotting factors. The gold standard for the management of moderate-to-severe hemophilia A is prophylaxis using regular replacement therapy with clotting factor concentrates. Compared with conventional treatment, extended half-life products reduce the burden of frequent factor replacement injections. Of note, up to 30% of patients with hemophilia A receiving prophylactic factor infusions develop "inhibitors," neutralizing anti-FVIII autoantibodies. Therapeutic options for patients with hemophilia A and inhibitors include the immune tolerance induction (ie, eradication of inhibitors) and the management of acute bleeds with bypassing agents and/or emicizumab. Emicizumab is a biphasic monoclonal antibody mimicking activated FVIII, approved for patients with hemophilia A with/without inhibitors. Gene therapy is an emerging therapy for hemophilia A, essentially curing patients with hemophilia A or transforming them to a milder phenotype by establishing continuous endogenous expression of FVIII after one-time treatment.

Does Molecular Profiling of KRAS-Mutant Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Help in Treatment Strategy Planning?

Background: Several studies suggest that patients with KRAS-mutant NSCLC fail to benefit from standard systemic therapies and do not respond to EGFR inhibitors. Most recently, KRAS 12c data suggest specific treatment for improving ORR and OS. There is a clear need for therapies specifically developed for these patients. Moreover, data that might be suggestive of a response to specific therapies, such as BRCA1, are needed, and two mutations that were studied in other malignancies show more response to PARP inhibitors. Molecular profiling has the potential to identify other potential targets that may provide better treatment and novel targeted therapy for KRAS-mutated NSCLC. Methods: We purified RNA from archived tissues of patients with stage I and II NSCLC with wild-type (wt) and mutant (mt) KRAS tumors; paired normal tissue adjacent to the tumor from 20 and 17 patients, respectively, and assessed, using real-time reverse transcriptase−polymerase chain reaction (RT-PCR), the expression of four genes involved in DNA synthesis and repair, including thymidylate synthase (TS), BRCA1, ECCR1, RAP80, and the proto-oncogene SRC. Additionally, we assessed the expression of PD-L1 in mt KRAS tumors with immunohistochemistry using an antibody against PD-L1. Results: Our results show that in mtKRAS tumors, the level of expression of ERCC1, TS, and SRC was significantly increased in comparison to paired normal lung tissue (p ≤ 0.04). The expression of BRCA1 and RAP80 was similar in both mt KRAS tumors and paired normal tissue. Furthermore, the expression of BRCA1, TS, and SRC was significantly increased in wt KRAS tumors relative to their expression in the normal lung tissue (p < 0.044). The expression of ERCC1 and RAP80 was similar in wt KRAS tumors and paired normal tissue. Interestingly, SRC expression in mtKRAS tumors was decreased in comparison to wt KRAS tumors. Notably, there was an expression of PD-L1 in the tumor and stromal cells in a few (5 out of 20) mtKRAS tumors. Our results suggest that a greater ERCC1 expression in mt KRAS tumors might increase platinum resistance in this group of patients, whereas the greater expression of BRCA1 in wt KRAS tumor might be suggestive of the sensitivity of taxanes. Our data also suggest that the combination of an SRC inhibitor with a TS inhibitor, such as pemetrexed, might improve the outcome of patients with NSCLC and in particular, patients with wt KRAS tumors. PD-L1 expression in tumors, and especially stromal cells, suggests a better outcome. Conclusion: mt KRAS NSCLC patients might benefit from a treatment strategy that targets KRAS in combination with therapeutic agents based on pharmacogenomic markers, such as SRC and BRCA1. mtKRAS tumors are likely to be platinum-, taxane-, and pemetrexed-resistant, as well as having a low level of PD-L1 expression; thus, they are less likely to receive single-agent immunotherapy, such as pembrolizumab, as the first-line therapy. wt KRAS tumors with BRCA1 positivity tend to be sensitive to taxane therapy and, potentially, platinum. Our results suggest the need to develop targeted therapies for KRAS-mutant NSCLC or combine the targeting of oncogenic KRAS in addition to other therapeutic agents specific to the molecular profile of the tumor.

Factors associated with opioid-involved overdose among previously incarcerated people in the U.S.: A community engaged narrative review.

BACKGROUND: People with a history of incarceration are at high risk for opioid overdose. A variety of factors contribute to this elevated risk though our understanding of these factors is deficient. Research to identify risk and protective factors for overdose is often conducted using administrative data or researcher-derived surveys and without explicit input from people with lived experience. We aimed to understand the scope of U.S. research on factors associated with opioid overdose among previously incarcerated people. We did this by conducting a narrative review of the literature and convening expert panels of people with lived experience. We then categorized these factors using a social determinants of health framework to help contextualize our findings. METHODS: We first conducted a narrative review of the published literature. A search was performed using PubMed and APA PsycInfo. We then convened two expert panels consisting of people with lived experience and people who work with people who were previously incarcerated. Experts were asked to evaluate the literature derived factors for completeness and add factors that were not identified. Finally, we categorized factors as either intermediary or structural according to the World Health Organization's Social Determinants of Health (SDOH) Framework. RESULTS: We identified 13 papers that met our inclusion criteria for the narrative review. Within these 13 papers, we identified 22 relevant factors for their role in the relationship between overdose and people with a history of incarceration, 16 were risk factors and six were protective factors. Five of these were structural factors (three risk and two protective) and 17 were intermediary factors (13 risk and four protective). The expert panels identified 21 additional factors, 10 of which were structural (six risk and four protective) and 11 of which were intermediary (eight risk and three protective). CONCLUSION: This narrative review along with expert panels demonstrates a gap in the published literature regarding factors associated with overdose among people who were previously incarcerated. Additionally, this review highlights a substantial gap with regard to the types of factors that are typically identified. Incorporating voices of people with lived experience is crucial to our understanding of overdose in this at-risk population.

Kupffer cell and interleukin-12-dependent loss of natural killer T cells in hepatosteatosis.

UNLABELLED: Hepatosteatosis is associated with increased expression of tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-12, major T helper (Th) 1 cytokines, and reduced hepatic natural killer T (NKT) cell numbers. The relationship between lipid accumulation, cytokine expression, and hepatic NKT cells is not known. This study was conducted to assess the role of IL-12 in the development of hepatic steatosis and its potential impact on liver NKT cells. Male C57Bl/6 wildtype (WT) and IL-12-deficient (IL-12(-/-)) mice were fed a choline-deficient diet (CDD) for 0, 10, or 20 weeks. CDD led to marked hepatosteatosis, reduced hepatic but not splenic NKT cell numbers and function, and increased hepatic expression of the T(h)1-type cytokines IL-12, interferon gamma (IFN-gamma), and TNF-alpha in WT mice. The absence of IL-12 resulted in similar CDD-induced hepatosteatosis, but preserved hepatic NKT cells and significantly reduced hepatic IFN-gamma and TNF-alpha expression. Treatment of CDD-fed mice with lipopolysaccharide led to a significant increase in hepatic IL-12 expression, and Kupffer cell (KC) depletion reduced liver IL-12 expression and restored NKT cells in CDD-induced fatty liver. Interestingly, KCs from CDD-fed mice failed to produce increased quantities of IL-12 upon activation in vitro when compared to similarly treated KCs from control fed mice, suggesting that secondary factors in vivo promote heightened IL-12 production. Finally, human livers with severe steatosis showed a substantial decrease in NKT cells. CONCLUSION: Hepatosteatosis reduces the numbers of hepatic NKT cells in a KC-and IL-12-dependent manner. Our results suggest a pivotal and multifunctional role of KC-derived IL-12 in the altered immune response in steatotic liver, a process that is likely active within human nonalcoholic fatty liver disease.

Pivotal role of Smad3 in a mouse model of T cell-mediated hepatitis.

UNLABELLED: Transforming growth factor beta (TGFbeta) promotes hepatocellular apoptosis and suppresses hepatic lymphocyte responses in part through activation of Smad3. The purpose of the current study was to determine the importance of Smad3 signaling in an experimental model of autoimmune hepatitis induced by concanavalin A (ConA), a process involving T cell activation and hepatocellular apoptosis. C57Bl/6 wild-type (Wt) or Smad3-deficient (Smad3(-/-)) mice were injected intravenously with 15 mg/kg ConA or vehicle. Nine hours post ConA injection, Wt mice presented with severe hepatitis as assessed by increased liver transferases. This injury was associated with eosinophil accumulation and preceded at 3 hours post-injection by significant increases in hepatic T helper 1 (interferon gamma) and T helper 2 (interleukin-4) cytokine production. Absence of Smad3 significantly blunted hepatocellular injury 9 hours post ConA injection, which was associated with reduced early T helper 1 and T helper 2 cytokine production and eosinophil accumulation. Smad3(-/-) livers also showed significant reductions in hepatocellular apoptosis as assessed by terminal UTP nick-end labeling when compared to ConA-treated Wt mice in conjunction with reduced caspase 3 cleavage, which was likely mediated by a Smad3-dependent inhibition of the survival factor extracellular signal-regulated kinase 1/2. In vitro, Smad3(-/-) hepatocytes were resistant to TGFbeta-induced apoptosis, and this protection was dependent on extracellular signal-regulated kinase activation. CONCLUSION: Together, these results show, for the first time, the significance of Smad3 signaling in autoimmune hepatitis, underlining the control of Smad3-dependent TGFbeta signaling on proinflammatory cytokine production, eosinophil recruitment, and hepatocellular apoptosis. Interruption of this pathway could be beneficial clinically to limit acute fulminant liver pathologies.

Lessons learned from the development and implementation of a citywide stair prompt initiative.

Stair climbing is a readily available form of vigorous-intensity physical activity. Evidence indicates that placing stair prompt signs at points-of-decision (e.g. near elevators and stairways) is an inexpensive, effective strategy for increasing physical activity through stair use. This article aims to share the experience of the New York City Department of Health and Mental Hygiene (NYC DOHMH) in the outreach and implementation of a population-scale stair prompt initiative, including lessons learned from process evaluations, with other public health authorities conducting a similar program. Between May 2008 and August 2012, NYC DOHMH implemented a stair prompt initiative as one strategy in a comprehensive program to increase physical activity and healthy eating through physical improvements to NYC's buildings, streets and neighborhoods, particularly targeting facilities in underserved and low-income neighborhoods. Program evaluation was conducted using program planning documents to examine the process, and data from NYC information line call center, outreach tracking database, and site and phone audits to examine process outcomes. The initiative successfully distributed more than 30,000 stair prompts to building owners/managers of over 1000 buildings. Keys to success included multi-sector partnerships between NYC's Health Department and non-health government agencies and organizations (such as architecture and real estate organizations), a designated outreach coordinator, and outreach strategies targeting building owners/managers owning/managing multiple buildings and buildings serving underserved and at risk populations. A NYC citywide initiative successfully distributed stair prompts to the wider community to promote population-level health impacts; lessons learned may assist other jurisdictions considering similar initiatives to increase physical activity.

Extrahepatic cells contribute to the progenitor/stem cell response following reduced-size liver transplantation in mice.

The extent to which extrahepatic cells participate in liver regeneration following transplantation is not known. Either full-size or reduced-size livers from wild-type mice were implanted into green fluorescent protein-positive (GFP(+)) transgenic recipient mice to determine whether regenerated liver contained host-derived GFP(+) hepatic cells. After reduced-size liver transplantation, GFP(+) cells were localized to the portal zone of the liver lobule. Interestingly, GFP(+) cells stained for CD117, a marker for progenitor cells, beginning 2 days after transplantation. A significant number of GFP(+) CD117(+) cells were identified in donor livers after 28 days. GFP(+) cells comprised nearly 9% of the donor liver 28 days after reduced-size liver transplant. Moreover, GFP(+) cells also expressed the hepatic progenitor cell marker A6 and novel marker hepatic-specific antigen (HSA), as well as stem cell antigen-1 (Sca-1). Interestingly, some GFP(-) cells also were stained for CD117 and A6, suggesting that both extrahepatic and intrahepatic stem cells were present and may have contributed to the regenerative response under these conditions. Reduced-size liver transplantation using GFP(+) transgenic mice supports the hypothesis that recipient-derived progenitor cells are present and may contribute to liver regeneration following transplantation.

Presentation and outcomes among patients with isolated myeloid sarcoma: a Surveillance, Epidemiology, and End Results database analysis.

Isolated myeloid sarcoma (MS) is a rare extramedullary presentation of acute myeloid leukemia (AML). Little is known about MS outcomes due to its rarity. A population-based analysis of MS using the Survival, Epidemiology, and End Results (SEER) database was performed. We identified 345 patients, aged 15 or older, diagnosed with isolated MS between 1973 and 2010. Overall survival (OS) was calculated and compared between MS and non-MS AML using the log-rank test. Survival was also evaluated based upon the primary site of disease presentation. The 3-year survival rate for MS (0.319; 95% confidence interval [CI]: 0.267-0.371) was greater than for non-MS AML (0.172; 95% CI: 0.168-0.175). There was variation in survival based on the site of involvement. The survival rates for isolated MS involving the pelvis/genitourinary organs, eyes/gonads and gastrointestinal mucosa appeared to be slightly improved when compared to primary sites of soft tissues, lymphatic/hematopoietic tissues or nervous system.