Epo-IGF1R cross talk expands stress-specific progenitors in regenerative erythropoiesis and myeloproliferative neoplasm.

We found that in regenerative erythropoiesis, the erythroid progenitor landscape is reshaped, and a previously undescribed progenitor population with colony-forming unit-erythroid (CFU-E) activity (stress CFU-E [sCFU-E]) is expanded markedly to restore the erythron. sCFU-E cells are targets of erythropoietin (Epo), and sCFU-E expansion requires signaling from the Epo receptor (EpoR) cytoplasmic tyrosines. Molecularly, Epo promotes sCFU-E expansion via JAK2- and STAT5-dependent expression of IRS2, thus engaging the progrowth signaling from the IGF1 receptor (IGF1R). Inhibition of IGF1R and IRS2 signaling impairs sCFU-E cell growth, whereas exogenous IRS2 expression rescues cell growth in sCFU-E expressing truncated EpoR-lacking cytoplasmic tyrosines. This sCFU-E pathway is the major pathway involved in erythrocytosis driven by the oncogenic JAK2 mutant JAK2(V617F) in myeloproliferative neoplasm. Inability to expand sCFU-E cells by truncated EpoR protects against JAK2(V617F)-driven erythrocytosis. In samples from patients with myeloproliferative neoplasm, the number of sCFU-E-like cells increases, and inhibition of IGR1R and IRS2 signaling blocks Epo-hypersensitive erythroid cell colony formation. In summary, we identified a new stress-specific erythroid progenitor cell population that links regenerative erythropoiesis to pathogenic erythrocytosis.

Identifying patients at risk for hereditary myeloid malignancy syndromes incorporating a novel, self-administered questionnaire to an initial screening platform.

INTRODUCTION: Four to 10% of cases of myeloid malignancies are inherited. We report our experience on hereditary myeloid malignancy syndromes (HMMS) incorporating a novel questionnaire in the screening platform for patients with myeloid malignancies and aplastic anemia. METHODS: The questionnaire was sent via electronic patient portal prior to clinic visits. Patients screened positive based on responses to questionnaire items, presence of suspicion disease characteristics (young age, family history, monosomy 7 etc.) and/or presence of signs of HMMS. Those deemed at-risk based on questionnaire responses, clinical features and/or somatic mutation profile were offered germline testing. RESULTS: A total of 408 patients were screened, 141 (35%) were deemed at-risk. Fifty-four (38%) of at-risk patients were seen in the genetics clinic. Forty-one (76%) of the patients seen agreed to germline testing and 13 declined due to cost or personal decision. Twenty pathogenic (P)/likely-pathogenic (LP) germline mutations were identified in 16 (39%) of the tested patients. Five patients also had a variant of uncertain significance (VUS) and an additional 13 had at least 1 VUS without P/LP mutations (total 29 VUS's were found in 18 (44%) of tested patients). The median age of diagnosis for patients with P/LP mutations was 56 years versus 66 years in the entire cohort. CONCLUSION: Incorporating an electronic questionnaire is an effective screening method for HMMS. Many patients declined testing due to cost. These results highlight the importance of germline testing in patients with myeloid malignancies, further research in HMMS, and coverage by healthcare plans.

Ferrofluid drop impacts and Rosensweig peak formation in a non-uniform magnetic field.

Vertical drop impacts of ferrofluids onto glass slides in a non-uniform magnetic field have been studied using high-speed photography. Outcomes have been classified based on the motion of the fluid-surface contact lines, and formation of peaks (Rosensweig instabilities) which affect the height of the spreading drop. The largest peaks are nucleated at the edge of a spreading drop, similarly to crown-rim instabilities in drop impacts with conventional fluids, and remain there for an extended time. Impact Weber numbers ranged from 18.0 to 489, and the vertical component of the B-field was varied between 0 and 0.37 T at the surface by changing the vertical position of a simple disc magnet placed below the surface. The falling drop was aligned with the vertical cylindrical axis of the 25 mm diameter magnet, and the impacts produced Rosensweig instabilities without splashing. At high magnetic flux densities a stationary ring of ferrofluid forms approximately above the outer edge of the magnet.

Outcomes of liver transplant recipients with high MELD scores: an experience from a Canadian centre.

BACKGROUND: The frequency with which patients with high Model for End-Stage Liver Disease (MELD) scores undergo liver transplantation has been increasing. Canadian literature regarding the outcomes of liver transplantation in recipients with high MELD scores is limited. The primary objective of this study was to assess patient and graft survival among recipients with high (> 35) and low (≤ 35) MELD scores. Secondary objectives were to potentially identify independent predictors of graft failure and patient mortality. METHODS: We conducted a retrospective chart review of patients undergoing liver transplantation at a single Canadian centre from 2012 to 2017. RESULTS: A total of 332 patients were included in the study: 280 patients had a MELD score of 35 or lower, and 52 had a MELD score above 35. Patients with high MELD scores had higher rates of pretransplant acute kidney injury and dialysis (p < 0.001), admission to the intensive care unit (ICU) or intubation (p < 0.001), intraoperative blood product transfusions (p < 0.001) and post-transplantation acute kidney injury and dialysis (p < 0.001), as well as longer ICU (p < 0.001) and hospital stays (p = 0.002). One- and 3-year patient survival in recipients with MELD scores of 35 or lower was 93.1% and 84.9% versus 85.0% and 80.0% in recipients with MELD scores above 35 (p = 0.37). One- and 3-year graft survival in recipients with MELD scores of 35 or lower was 91.7% and 90.9% versus 77.2% and 72.8% in recipients with MELD scores above 35 (p < 0.001). Prior liver transplant was an independent predictor of patient mortality, and no independent predictors of graft failure were identified. When MELD was replaced with D-MELD (donor age × recipient MELD), it predicted graft failure but not patient survival. CONCLUSION: No difference in patient mortality was found between MELD groups. Graft survival was significantly lower in recipients with MELD scores above 35. D-MELD may potentially be used as an adjunct in determining risk of graft failure in recipients with high MELD scores.

The association between bacterobilia and the risk of postoperative complications following pancreaticoduodenectomy.

BACKGROUND: Pre-operative biliary bacterial colonisation (bacterobilia) is considered a risk factor for infectious complications after pancreaticoduodenectomy (PD). This study aimed to investigate the role of the PD biliary microbiome grown in the development of post-PD complications. METHODS: In a retrospective study of 162 consecutive patients undergoing PD (2008-2018), intra-operative bile cultures were analyzed and sensitivities compared to pre-anesthetic antibiotics and thirty-day post-surgery complications. RESULTS: Bacterobilia was present in 136 patients (84%). Most bile cultures grew bacteria resistant to pre-operative antibiotics (n = 112, 82%). Patients with bacterobilia had significantly higher rates of major complication than patients without (P = 0.017), as well as higher rates of surgical-site infections (SSI) (P = 0.010). Patients with negative bile cultures (n = 26) had significantly lower rates of major complication and SSI than those growing sensitive (n = 24) or non-sensitive (n = 112) bacteria (major complication P = 0.029 and SSI P = 0.011). CONCLUSION: Positive bile cultures were associated with a higher incidence of major complications and SSI. Patients with sterile bile cultures had the lowest risk of post-operative complications and efforts to reduce rates of bacterobilia, such as limitation of biliary instrumentation, should be considered. Sensitivity to antibiotics had no effect upon the rate of post-operative complications, but this may reflect low cohort numbers.

A critical review on diet-induced microbiota changes and cardiovascular diseases.

Background: Cardiovascular diseases (CVDs) commonly denote the disorders that generally occur as a result of unhealthy food habits. Heart failure, cerebrovascular illness, rheumatic heart disease are the common CVDs. The prevalence of CVD is increased considerably in recent decades upon unhealthy food habits and varied alternative factors such as diabetes, smoking and excessive use of alcohol. A change into a healthy food habit can reverse the strategy during a course of time.Objectives of the study: The objective of this review is to summarize the research findings and elaborate the relationship between the diet, gut microbiota, and CVD.Results: The dietary products containing the least saturated, trans-fat and cholesterol have the tendency to scale back the burden of CVDs, for instance, vegetables and fruits. The potential reason for the cardioprotective activity of the diet ought to be its high-unsaturated fatty acid composition and less saturated fat. Recent studies have found that gut microbiota plays a key role in mediating disease prevention. The metabolism of dietary products into varied bioactive metabolites is regulated by gut microbiota. The contributory role of gut microbiota in dietary metabolism and CVD prevention studies are increasing with promising outcomes.Conclusion: Hence, the review was proposed to reach the researchers within this field of study and share the available knowledge in gut microbiota-mediated CVD prevention. In our current review, we have updated all the research findings within the field of diet-mediated cardiovascular prevention through gut microbiota.

A critical review of the relationship between dietary components, the gut microbe Akkermansia muciniphila, and human health.

The human gut contains trillions of microorganisms with a great diversity that are associated with various health benefits. Recent studies have reported an increasing correlation between diet, gut microbiota, and human health, indicating rapid development in the field of gut health. Diet is an important factor that determines the gut microbiota composition. The gut comprises great diversities of microbes involved in immune modulation and other functions. In particular, Akkermansia muciniphila is a mucin-degrading bacterium is believed to have several health benefits in humans. Several studies have evaluated the prebiotic effects of various dietary components on A. muciniphila and their association with various ailments, such as diabetes mellitus, atherosclerosis, and cancer. Hence, this review aims to provide a plausible mechanistic basis for the interactions between dietary components, and A. muciniphila and for the therapeutic benefits of this interaction on various illnesses.

Minimally invasive hepatectomy is associated with decreased morbidity and resource utilization in the elderly.

BACKGROUND: The aim of this study was to evaluate whether elderly patients undergoing elective hepatectomy experience increased morbidity/mortality and whether these outcomes could be mitigated by minimally invasive hepatectomy (MIH). METHODS: 15,612 patients from 2014 to 2017 were identified in the Hepatectomy Targeted Procedure Participant Use File of the American College of Surgeons National Surgical Quality Improvement Program. Multivariable logistic regression models were constructed to examine the effect of elderly status (age ≥ 75 years, N = 1769) on outcomes with a subgroup analysis of elderly only patients by open (OH) versus MIH (robotic, laparoscopic, and hybrid, N = 4044). Propensity score matching was conducted comparing the effect of MIH to OH in elderly patients to ensure that results are not the artifact of imbalance in baseline characteristics. RESULTS: Overall, elderly patients had increased risk for 30-day mortality, major morbidity, prolonged length of hospital stay, and discharge to destination other than home. In the elderly subgroup, MIH was associated with decreased major morbidity (OR 0.71, P = 0.031), invasive intervention (OR 0.61, P = 0.032), liver failure (OR 0.15, P = 0.011), bleeding (OR 0.46, P < 0.001), and prolonged length of stay (OR 0.46, P < 0.001). Propensity score-matched analyses successfully matched 4021 pairs of patients treated by MIH vs. OH, and logistic regression analyses on this matched sample found that MIH was associated with decreased major complications (OR 0.69, P = 0.023), liver failure (OR 0.14, P = 0.010), bile leak (OR 0.46, P = 0.009), bleeding requiring transfusion (OR 0.46, P < 0.001), prolonged length of stay (OR 0.46, P < 0.001), and discharge to destination other than home (OR 0.691, P = 0.035) compared to OH. CONCLUSION: MIH is associated with decreased risk of major morbidity, liver failure, bile leak, bleeding, prolonged length of stay, and discharge to destination other than home among elderly patients in this retrospective study. However, MIH in elderly patients does not protect against postoperative mortality.

Impact of surgical wait times on oncologic outcomes in resectable pancreas adenocarcinoma.

BACKGROUND: Timely surgical resection in patients with suspected or diagnosed pancreas adenocarcinoma is an essential part of care. We hypothesized that longer surgical wait time was associated with worse oncologic outcomes. METHODS: A retrospective cohort of patients (N = 144) with resectable pancreas adenocarcinoma was divided into four wait time groups (<4, 4-8, 8-12, and >12 weeks), defined from the time of diagnosis on cross-sectional imaging. Overall and recurrence-free survival were analyzed using the Kaplan-Meier method and Cox proportional hazards regression. A higher rate of conversion to palliative bypass in patients waiting over 4 weeks was observed and further analyzed using post-hoc multivariate regression. RESULTS: On multivariable analysis, longer wait time was associated with improved overall (HR 0.49, 95% CI: 0.28-0.85) and recurrence-free survival (HR 0.29, 95% CI: 0.15-0.56) in >12 weeks compared to <4 weeks group. On post-hoc analysis, longer wait time over 8 weeks was positively associated with palliative bypass (OR 5.33, 95% CI: 1.32-27.88). CONCLUSION: Wait time over 8 weeks was associated with a higher rate of palliative bypass. There was an improvement in overall and recurrence-free survival in patients who waited over 12 weeks, likely due to selection bias.

Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations.

Classical hairy cell leukemia (cHCL) is characterized by a near 100% frequency of the BRAFV600E mutation, whereas ∼30% of variant HCLs (vHCLs) have MAP2K1 mutations. However, recurrent genetic alterations cooperating with BRAFV600E or MAP2K1 mutations in HCL, as well as those in MAP2K1 wild-type vHCL, are not well defined. We therefore performed deep targeted mutational and copy number analysis of cHCL (n = 53) and vHCL (n = 8). The most common genetic alteration in cHCL apart from BRAFV600E was heterozygous loss of chromosome 7q, the minimally deleted region of which targeted wild-type BRAF, subdividing cHCL into those hemizygous versus heterozygous for the BRAFV600E mutation. In addition to CDKN1B mutations in cHCL, recurrent inactivating mutations in KMT2C (MLL3) were identified in 15% and 25% of cHCLs and vHCLs, respectively. Moreover, 13% of vHCLs harbored predicted activating mutations in CCND3 A change-of-function mutation in the splicing factor U2AF1 was also present in 13% of vHCLs. Genomic analysis of de novo vemurafenib-resistant cHCL identified a novel gain-of-function mutation in IRS1 and losses of NF1 and NF2, each of which contributed to resistance. These data provide further insight into the genetic bases of cHCL and vHCL and mechanisms of RAF inhibitor resistance encountered clinically.

Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia.

BACKGROUND: BRAF V600E is the genetic lesion underlying hairy-cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy-cell leukemia that had relapsed after treatment with a purine analogue or who had disease that was refractory to purine analogues. METHODS: We conducted two phase 2, single-group, multicenter studies of vemurafenib (at a dose of 960 mg twice daily)--one in Italy and one in the United States. The therapy was administered for a median of 16 weeks in the Italian study and 18 weeks in the U.S. study. Primary end points were the complete response rate (in the Italian trial) and the overall response rate (in the U.S. trial). Enrollment was completed (28 patients) in the Italian trial in April 2013 and is still open (26 of 36 planned patients) in the U.S. trial. RESULTS: The overall response rates were 96% (25 of 26 patients who could be evaluated) after a median of 8 weeks in the Italian study and 100% (24 of 24) after a median of 12 weeks in the U.S. study. The rates of complete response were 35% (9 of 26 patients) and 42% (10 of 24) in the two trials, respectively. In the Italian trial, after a median follow-up of 23 months, the median relapse-free survival was 19 months among patients with a complete response and 6 months among those with a partial response; the median treatment-free survival was 25 months and 18 months, respectively. In the U.S. trial, at 1 year, the progression-free survival rate was 73% and the overall survival rate was 91%. Drug-related adverse events were usually of grade 1 or 2, and the events most frequently leading to dose reductions were rash and arthralgia or arthritis. Secondary cutaneous tumors (treated with simple excision) developed in 7 of 50 patients. The frequent persistence of phosphorylated ERK-positive leukemic cells in bone marrow at the end of treatment suggests bypass reactivation of MEK and ERK as a resistance mechanism. CONCLUSIONS: A short oral course of vemurafenib was highly effective in patients with relapsed or refractory hairy-cell leukemia. (Funded by the Associazione Italiana per la Ricerca sul Cancro and others; EudraCT number, 2011-005487-13; ClinicalTrials.gov number NCT01711632.).

How effective are common household preparations on removing pesticide residues from fruit and vegetables? A review.

Nowadays, the use of pesticides is inevitable for pest control in crops, especially for fruit and vegetables. After the harvest from raw agricultural commodities, the amount of pesticide residues in food is mainly influenced by the storage, handling and processing that follow. If good agricultural and good manufacturing practices are enforced effectively, the amount of pesticide residues would be brought below the corresponding maximum residue level. Thus, the consumption of raw and/or prepared fruit and vegetables would be safe. Nonetheless, reports regarding pesticide residues in fruit or vegetables on mass media have been worrying consumers, who are concerned about the adverse effects of pesticide residues. As a result, consumers perform household processing before consumption to reduce any related risks. However, can these preparations effectively remove pesticide residues? Reviewing the extensive literature, it showed that, in most cases, washing and soaking can only lead to a certain degree of reduction in residue level, while other processing such as peeling, soaking in chemical baths and blanching can reduce pesticide residues more effectively. In general, the behaviour of residues during processing can be rationalised in terms of the physico-chemical properties of the pesticide and the nature of the process. In contrast, the reported studies are diversified and some areas still lack sufficient studies to draw any remarks. Recommendations are provided with respect to the available information that aims to formulate an environmental friendly, cost-effective and efficient household processing of fruit and vegetables to reduce pesticide residues. © 2017 Society of Chemical Industry.

miR-29a maintains mouse hematopoietic stem cell self-renewal by regulating Dnmt3a.

Hematopoietic stem cells (HSCs) possess the ability to generate all hematopoietic cell types and to self-renew over long periods, but the mechanisms that regulate their unique properties are incompletely understood. Herein, we show that homozygous deletion of the miR-29a/b-1 bicistron results in decreased numbers of hematopoietic stem and progenitor cells (HSPCs), decreased HSC self-renewal, and increased HSC cell cycling and apoptosis. The HSPC phenotype is specifically due to loss of miR-29a, because miR-29b expression is unaltered in miR-29a/b-1-null HSCs, and only ectopic expression of miR-29a restores HSPC function both in vitro and in vivo. HSCs lacking miR-29a/b-1 exhibit widespread transcriptional dysregulation and adopt gene expression patterns similar to normal committed progenitors. A number of predicted miR-29 target genes, including Dnmt3a, are significantly upregulated in miR-29a/b-1-null HSCs. The loss of negative regulation of Dnmt3a by miR-29a is a major contributor to the miR-29a/b-1-null HSPC phenotype, as both in vitro Dnmt3a short hairpin RNA knockdown assays and a genetic haploinsufficiency model of Dnmt3a restored the frequency and long-term reconstitution capacity of HSCs from miR-29a/b-1-deficient mice. Overall, these data demonstrate that miR-29a is critical for maintaining HSC function through its negative regulation of Dnmt3a.

Novel therapeutic strategies in myelodysplastic syndromes: do molecular genetics help?

PURPOSE OF REVIEW: Many studies over the past decade have together identified genes that are recurrently mutated in the myelodysplastic syndromes (MDS). We will summarize how this information has informed our understanding of disease pathogenesis and behavior, with an emphasis on how this information may inform therapeutic strategies. RECENT FINDINGS: Genomic sequencing techniques have allowed for the identification of many recurrently mutated genes in MDS, with the most common mutations being found in epigenetic modifiers and components of the splicing machinery. Although many mutations are associated with clinical outcomes and disease phenotypes, at the current time they add relatively little to already robust clinical prognostic algorithms. However, as molecular genetic data are accumulated in larger numbers of patients, it is likely that the clinical significance of co-occurring mutations and less common mutations will come to light. Finally, mutated genes may identify biologically distinct subgroups of MDS that may benefit from novel therapies, and a subset of these genes may themselves serve as therapeutic targets. SUMMARY: Advances in our knowledge of the molecular genetics of MDS have significantly improved our understanding of disease biology and promise to improve tools for clinical decision-making and identify new therapies for patients.

The differential effects of metronomic gemcitabine and antiangiogenic treatment in patient-derived xenografts of pancreatic cancer: treatment effects on metabolism, vascular function, cell proliferation, and tumor growth.

BACKGROUND: Metronomic chemotherapy has shown promising activity against solid tumors and is believed to act in an antiangiogenic manner. The current study describes and quantifies the therapeutic efficacy, and mode of activity, of metronomic gemcitabine and a dedicated antiangiogenic agent (DC101) in patient-derived xenografts of pancreatic cancer. METHODS: Two primary human pancreatic cancer xenograft lines were dosed metronomically with gemcitabine or DC101 weekly. Changes in tumor growth, vascular function, and metabolism over time were measured with magnetic resonance imaging, positron emission tomography, and immunofluorescence microscopy to determine the anti-tumor effects of the respective treatments. RESULTS: Tumors treated with metronomic gemcitabine were 10-fold smaller than those in the control and DC101 groups. Metronomic gemcitabine, but not DC101, reduced the tumors' avidity for glucose, proliferation, and apoptosis. Metronomic gemcitabine-treated tumors had higher perfusion rates and uniformly distributed blood flow within the tumor, whereas perfusion rates in DC101-treated tumors were lower and confined to the periphery. DC101 treatment reduced the tumor's vascular density, but did not change their function. In contrast, metronomic gemcitabine increased vessel density, improved tumor perfusion transiently, and decreased hypoxia. CONCLUSION: The aggregate data suggest that metronomic gemcitabine treatment affects both tumor vasculature and tumor cells continuously, and the overall effect is to significantly slow tumor growth. The observed increase in tumor perfusion induced by metronomic gemcitabine may be used as a therapeutic window for the administration of a second drug or radiation therapy. Non-invasive imaging could be used to detect early changes in tumor physiology before reductions in tumor volume were evident.

CD34-Selected Hematopoietic Stem Cell Transplants Conditioned with Myeloablative Regimens and Antithymocyte Globulin for Advanced Myelodysplastic Syndrome: Limited Graft-versus-Host Disease without Increased Relapse.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for patients with myelodysplastic syndrome (MDS). Donor T cells are critical for the graft-versus-tumor effect but carry the risk of graft-versus-host disease (GVHD). CD34 selection with immunomagnetic beads has been an effective method of depleting alloreactive donor T cells from the peripheral blood graft and has been shown to result in significant reduction in acute and chronic GVHD. We analyzed the outcomes of 102 adults (median age, 57.6 years) with advanced MDS who received a CD34-selected allo-HSCT between January 1997 and April 2012 at Memorial Sloan Kettering Cancer Center. The cumulative incidences of grades II to IV acute GVHD were 9.8% at day 100 (95% confidence interval [CI], 5.0% to 16.5%) and 15.7% at day 180 (95% CI, 9.4% to 23.4%). The cumulative incidence of chronic GVHD at 1 year was 3.9% (95% CI, 1.3% to 9.0%). The cumulative incidences of relapse were 11.8% at 1 year (95% CI, 6.4% to 18.9%) and 15.7% at 2 years (95% CI, 9.4% to 23.4%). Forty-eight patients were alive with a median follow-up of 71.7 months. Rates of overall survival (OS) were 56.9% at 2 years (95% CI, 48% to 67.3%) and 49.3% at 5 years (95% CI, 40.4% to 60.2%). Rates of relapse-free survival (RFS) were 52.0% at 2 years (95% CI, 41.9% to 61.1%) and 47.6% at 5 years (95% CI, 37.5% to 56.9%). The cumulative incidences of nonrelapse mortality were 7.8% at day 100 (95% CI, 3.7% to 14.1%), 22.5% at 1 year (95% CI, 15.0% to 31.1%), and 33.4% at 5 years (95% CI, 24.2% to 42.6%) post-transplant. The incidence of chronic GVHD/RFS overlapped with RFS. These findings demonstrate that ex vivo T cell-depleted allo-HSCT by CD34 selection offers long-term OS and RFS with low incidences of acute and chronic GVHD and without an increased risk of relapse.

The Role of Contrast-enhanced Ultrasound in Guiding Radiofrequency Ablation of Hepatocellular Carcinoma: A Retrospective Study.

PURPOSE: The objective of the study was to determine the efficacy of contrast-enhanced ultrasound (CEUS) using ultrasound (US)-specific microbubbles in guiding radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). METHODS: A retrospective analysis of 50 patients with HCC treated with CEUS guided RFA using perflutren at our institution was performed. CEUS images were first compared to B-mode US images performed at the same RFA session to determine the ability of CEUS to increase the conspicuity of lesions. A qualitative score (1 = poor, 2 = fair, 3 = excellent) was used to grade the ability to visualize the lesions. The preprocedure CEUS images were then evaluated using the most recent prior contrast enhanced computed tomography (CT) or magnetic resonance imaging (MRI). The efficacy of the treatment was evaluated with short-term follow-up imaging (median 1 month) for presence of residual or recurrent disease. RESULTS: CEUS allows at least fair visualization (score ≥2) in 78% (reader 1) and 80% (reader 2) of the lesions not visualized by B-mode US, and 50% (reader 1) and 42% (reader 2) of the lesions poorly visualized by B-mode US. Lesion appearances on CEUS are largely concordant with those on CT or MRI: 88% for reader 1, 96% for reader 2. With CEUS-guided RFA, complete response was achieved in the vast majority of the lesions at short-term follow-up: 82% for reader 1, 94% for reader 2. CONCLUSIONS: CEUS increases the conspicuity and provides better characterization of hypervascular HCC that are either not seen or poorly seen on B-mode US, and CEUS provides real-time guidance of RFA with good short-term treatment responses.

Genetic mutations in acute myeloid leukemia that influence clinical decisions.

PURPOSE OF REVIEW: A plethora of studies over the past two decades have identified many genes that are recurrently mutated in acute myeloid leukemia (AML). Although great advances have been made in understanding the role of these mutated genes in AML disease pathogenesis, to date relatively few have been demonstrated to have direct clinical relevance. RECENT FINDINGS: Genomic techniques have allowed for the identification of many mutated genes that appear to drive disease pathogenesis and prognosis in AML. Integrated analyses examining the co-occurrence of these genes in well annotated AML patient cohorts has helped to significantly refine prognostic models, allowing for a more nuanced selection of patients for optimal postremission therapies. Furthermore, there are emerging data that gene mutations may be useful to select patients for optimal doses and/or modalities of upfront AML therapy. Finally, mutated genes themselves hold promise as therapeutic targets, as supported by strong preclinical studies. SUMMARY: Recent advances in our knowledge of the molecular genetics of AML have significantly improved our tools for clinical decision-making and promise to identify new therapies for patients.

Exchange protein activated by cAMP 1 (Epac1)-deficient mice develop ß-cell dysfunction and metabolic syndrome.

Previously, exchange protein directly activated by cAMP 2 (Epac2) and PKA were known to play a role in glucose-stimulated insulin secretion (GSIS) by pancreatic ß cells. The present study shows that Epac1 mRNA is also expressed by ß cells. Therefore, we generated mice and embryonic stem (ES) cells with deletion of the Epac1 gene to define its role in ß-cell biology and metabolism. The homozygous Epac1-knockout (Epac1(-/-)) mice developed impaired glucose tolerance and GSIS with deranged islet cytoarchitecture, which was confirmed by isolated islets from adult Epac1(-/-) mice. Moreover, Epac1(-/-) mice developed more severe hyperglycemia with increased ß-cell apoptosis and insulitis after multiple low-dose streptozotocin (MLDS; 40 mg/kg) treatment than Epac1(+/+) mice. Interestingly, Epac1(-/-) mice also showed metabolic defects, including increased respiratory exchange ratio (RER) and plasma triglyceride (TG), and more severe diet-induced obesity with insulin resistance, which may contributed to ß-cell dysfunction. However, islets differentiated from Epac1(-/-) ES cells showed insulin secretion defect, reduced Glut2 and PDX-1 expression, and abolished GLP-1-stimulated PCNA induction, suggesting a role of Epac1 in ß-cell function. The current study provides in vitro and in vivo evidence that Epac1 has an important role in GSIS of ß cells and phenotype resembling metabolic syndrome.