Tumours are comprised of a highly heterogeneous population of cells, of which only a small subset of stem-like cells possess the ability to regenerate tumours in vivo. These cancer stem cells (CSCs) ...represent a significant clinical challenge as they are resistant to conventional cancer therapies and play essential roles in metastasis and tumour relapse. Despite this realization and great interest in CSCs, it has been difficult to develop CSC-targeted treatments due to our limited understanding of CSC biology. Here, we present evidence that specific histone deacetylases (HDACs) play essential roles in the CSC phenotype. Utilizing a novel CSC model, we discovered that the HDACs, HDAC1 and HDAC7, are specifically over-expressed in CSCs when compared to non-stem-tumour-cells (nsTCs). Furthermore, we determine that HDAC1 and HDAC7 are necessary to maintain CSCs, and that over-expression of HDAC7 is sufficient to augment the CSC phenotype. We also demonstrate that clinically available HDAC inhibitors (HDACi) targeting HDAC1 and HDAC7 can be used to preferentially target CSCs. These results provide actionable insights that can be rapidly translated into CSC-specific therapies.
Guidelines currently recommend targeting light sedation with dexmedetomidine or propofol for adults receiving mechanical ventilation. Differences exist between these sedatives in arousability, ...immunity, and inflammation. Whether they affect outcomes differentially in mechanically ventilated adults with sepsis undergoing light sedation is unknown.
In a multicenter, double-blind trial, we randomly assigned mechanically ventilated adults with sepsis to receive dexmedetomidine (0.2 to 1.5 μg per kilogram of body weight per hour) or propofol (5 to 50 μg per kilogram per minute), with doses adjusted by bedside nurses to achieve target sedation goals set by clinicians according to the Richmond Agitation-Sedation Scale (RASS, on which scores range from -5 unresponsive to +4 combative). The primary end point was days alive without delirium or coma during the 14-day intervention period. Secondary end points were ventilator-free days at 28 days, death at 90 days, and age-adjusted total score on the Telephone Interview for Cognitive Status questionnaire (TICS-T; scores range from 0 to 100, with a mean of 50±10 and lower scores indicating worse cognition) at 6 months.
Of 432 patients who underwent randomization, 422 were assigned to receive a trial drug and were included in the analyses - 214 patients received dexmedetomidine at a median dose of 0.27 μg per kilogram per hour, and 208 received propofol at a median dose of 10.21 μg per kilogram per minute. The median duration of receipt of the trial drugs was 3.0 days (interquartile range, 2.0 to 6.0), and the median RASS score was -2.0 (interquartile range, -3.0 to -1.0). We found no difference between dexmedetomidine and propofol in the number of days alive without delirium or coma (adjusted median, 10.7 vs. 10.8 days; odds ratio, 0.96; 95% confidence interval CI, 0.74 to 1.26), ventilator-free days (adjusted median, 23.7 vs. 24.0 days; odds ratio, 0.98; 95% CI, 0.63 to 1.51), death at 90 days (38% vs. 39%; hazard ratio, 1.06; 95% CI, 0.74 to 1.52), or TICS-T score at 6 months (adjusted median score, 40.9 vs. 41.4; odds ratio, 0.94; 95% CI, 0.66 to 1.33). Safety end points were similar in the two groups.
Among mechanically ventilated adults with sepsis who were being treated with recommended light-sedation approaches, outcomes in patients who received dexmedetomidine did not differ from outcomes in those who received propofol. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01739933.).
Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related mortality. To determine TRALI incidence by prospective, active surveillance and to identify risk factors by a ...case-control study, 2 academic medical centers enrolled 89 cases and 164 transfused controls. Recipient risk factors identified by multivariate analysis were higher IL-8 levels, liver surgery, chronic alcohol abuse, shock, higher peak airway pressure while being mechanically ventilated, current smoking, and positive fluid balance. Transfusion risk factors were receipt of plasma or whole blood from female donors (odds ratio = 4.5, 95% confidence interval CI, 1.85-11.2, P = .001), volume of HLA class II antibody with normalized background ratio more than 27.5 (OR = 1.92/100 mL, 95% CI, 1.08-3.4, P = .03), and volume of anti–human neutrophil antigen positive by granulocyte immunofluoresence test (OR = 1.71/100 mL, 95% CI, 1.18-2.5, P = .004). Little or no risk was associated with older red blood cell units, noncognate or weak cognate class II antibody, or class I antibody. Reduced transfusion of plasma from female donors was concurrent with reduced TRALI incidence: 2.57 (95% CI, 1.72-3.86) in 2006 versus 0.81 (95% CI, 0.44-1.49) in 2009 per 10 000 transfused units (P = .002). The identified risk factors provide potential targets for reducing residual TRALI.
Microfinance institutions (MFIs) play a key role in many developing countries. Utilizing data from Eastern Europe and Central Asia, MFIs are found to generally operate with lower costs the longer ...they are in operation. Given the differences in operating environments, subsidies, and organizational form, this finding of increasing cost effectiveness may not aptly characterize all MFIs. Estimation of a mixture model reveals that roughly half of the MFIs are able to operate with reduced costs over time, while half do not. Among other things, we find that larger MFIs offering deposits and those receiving lower subsidies operate more cost effectively over time.
As the number of breast cancer survivors increases, a durable model of comprehensive survivor care is needed, incorporating providers and/or visit types both within and outside of oncology. The ...objective of this study was to explore survivors' comfort with different clinician types or with a telephone/Internet-based virtual visit as components of survivorship care.
Breast cancer survivors participating in a general survivorship survey completed an additional breast cancer-specific questionnaire evaluating the self-perceived impact of follow-up visits to various clinician types, or follow-up by a virtual visit, on survival, worrying, and stress related to cancer.
A total of 218 breast cancer survivors completed the questionnaire. Most favored medical oncologist follow-up visits over those with primary care physicians (PCPs) or nurse practitioners (NPs) in terms of reduced worrying about cancer (odds ratio OR, 2.21; P < .001), reduced stress around the visit (OR, 1.40; P = .002), and improved effect on cancer survival (OR, 2.38; P < .001). However, the majority also displayed substantial comfort with both PCPs and NPs in the same domains. Patients rated a virtual visit as having a less favorable impact on cancer survival and cancer-related worrying compared with in-person visits with clinicians.
Breast cancer survivors are comfortable with both PCPs and NPs providing follow-up care, although they indicate a preference for medical oncologists. Given patients' negative impressions of a virtual visit, increased familiarity with and research investigating this emerging concept are needed. The NP-led survivorship clinic model, with increased guidance for PCPs, offers a promising route for improving quality of and satisfaction with survivor care.
We develop a sequential game representing bargaining between a public university and a professor over a vacant administrative position, such as an academic deanship. We find that the administrative ...salary is an increasing function of the job candidate's salary, the prior dean's salary, the price of undergraduate courses, elasticity of the wage differential, and faculty productivity. The game also indicates that if the new dean is female or minority, and if the previous dean's salary is important, then one can conclude that the professor is able to circumvent wage discrimination given that the salaries of public university officials are publicly available.
Essentials
Dabigatran etexilate may provide a new treatment option for pediatric venous thromboembolism.
Children aged 1 to < 12 years were given dabigatran etexilate in an open‐label, single‐arm ...study.
The pharmacokinetic–pharmacodynamic relationship was similar to that seen in adult patients.
There were no serious adverse events, bleeding events or recurrent venous thromboembolism.
Summary
Background
The current standard‐of‐care treatments for pediatric venous thromboembolism (VTE) have limitations. Dabigatran etexilate (DE), a direct thrombin inhibitor, may offer an alternative therapeutic option.
Objectives
To assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of a DE oral liquid formulation (OLF) in pediatric patients with VTE.
Patients/Methods
Patients who had completed planned treatment with low molecular weight heparin or oral anticoagulants for VTE were enrolled in two age groups (2 to < 12 years and 1 to < 2 years), and received a DE OLF based on an age‐adjusted and weight‐adjusted nomogram. Originally, patients were to receive a DE OLF twice daily for 3 days, but the protocol was amended to a single dose on day 1. The primary endpoints were pharmacokinetics/pharmacodynamics‐related: plasma concentrations of DE and its metabolites; activated partial thromboplastin time (APTT), ecarin clotting time (ECT), and dilute thrombin time (dTT); and pharmacokinetic (PK)–pharmacodynamic (PD) correlation. Safety endpoints included incidence rates of bleeding events and all other adverse events (AEs).
Results
Eighteen patients entered the study and received the DE OLF (an exposure equivalent to a dose of 150 mg twice daily in adults). The projected steady‐state dabigatran trough concentrations were largely comparable between pediatric patients and adults. The PK/PD relationship was linear for ECT and dTT, and non‐linear for APTT. No serious or severe AEs, bleeding events, or recurrent VTEs were reported. Mild AEs were reported in three patients in the single‐dose group (screening period) and in one patient in the multiple‐dose group (on‐treatment period).
Conclusion
The current study supports the further evaluation of DE OLFs in pediatric patients with VTE.
Background
Sentinel lymph node biopsy (SNB) in pregnant women with breast cancer is uncommonly pursued given concern for fetal harm. This study evaluated efficacy and safety outcomes in pregnant ...breast cancer patients undergoing SNB.
Methods
Patients who underwent SNB while pregnant were identified from a retrospective parent cohort of women diagnosed with breast cancer during pregnancy. Chart review was performed to tabulate patient/tumor characteristics, method/outcome of SNB, and short-term maternal/fetal outcomes.
Results
Within a cohort of 81, 47 clinically node-negative patients had surgery while pregnant: 25 (53.2 %) SNB, 20 (42.6 %) upfront axillary lymph node dissection, and 2 (4.3 %) no lymph node surgery. Of SNB patients, 8, 9, and 8 had SNB in the first, second, and third trimesters, respectively. 99 m-Technetium (99-Tc) alone was used in 16 patients, methylene blue dye alone in 7 patients, and 2 patients had unknown mapping method. Mapping was successful in all patients. There were no SNB-associated complications. At a median of 2.5 years from diagnosis, there was one locoregional recurrence, one new primary contralateral tumor, three distant recurrences, and one breast cancer death. Among patients who underwent SNB, there were 25 liveborn infants, of whom 24 were healthy, and 1 had cleft palate (in the setting of other maternal risk factors).
Conclusions
SNB in pregnant breast cancer patients appears to be safe and accurate using either methylene blue or 99-Tc. This is one of the largest reported experiences of SNB during pregnancy; however, numbers remain limited. SNB rates in this cohort were lower than in non-pregnant breast cancer patients.
The purpose of this investigation was to examine oxidative markers after exercise in a hyperthermic environment (35 degrees C, 70 % RH) (Hot) versus a neutral environment (25 degrees C, 40 % RH) ...(Con). Hyperthermia may exacerbate oxidative stress by uncoupling the mitochondrial respiratory chain or by inhibiting antioxidant defense mechanisms, but this has not been assessed in vivo. Six male subjects performed low-intensity exercise (50 % VO(2max)) on a treadmill in Hot until a core temperature of 39.5 degrees C was reached, and for an equivalent time in Con. Blood samples were drawn before and immediately after exercise and at 8 min and 15 min following exercise. Samples were analyzed for F2 isoprostanes (FIP), lipid hydroperoxides (LPO), and lactate. A 2 x 4 repeated measures ANOVA was used to test for treatment, time, and interaction effects for FIP, LPO, and lactate. Differences in VO(2) were tested with Student's t-test. Significance was set at p < 0.05. Oxygen consumption was not significantly different between Hot and Con. The pattern of change of FIP and lactate in Hot was significant versus exercise in Con. LPO was significantly elevated over time in both Hot and Con, but the pattern of change was not significantly different. Ending core temperatures and heart rates were significantly elevated in Hot versus Con. These data indicate that hyperthermia increases oxidative stress and selectively affects specific lipid markers, independent of oxygen consumption.
Transfusion-related acute lung injury incidence remains the leading cause of posttransfusion mortality. The etiology may be related to leukocyte antibodies or biologically active compounds in ...transfused plasma, injuring susceptible recipient's lungs. The authors have hypothesized that transfusion could have less severe effects that are not always appreciated clinically and have shown subtly decreased pulmonary oxygen gas transfer in healthy volunteers after transfusion of fresh and 21-day stored erythrocytes. In this study, the authors tested the same hypothesis in surgical patients.
Ninety-one patients undergoing elective major spine surgery with anticipated need for erythrocyte transfusion were randomly allocated to receive their first transfusion of erythrocytes as cell salvage (CS), washed stored, or unwashed stored. Clinicians were not blinded to group assignment. Pulmonary gas transfer and mechanics were measured 5 min before and 30 min after erythrocyte transfusion.
The primary outcome variable, gas transfer, as assessed by change of PaO2/FIO2, with erythrocyte transfusion was not significant in any group (mean ± SD; CS: 9 ± 59; washed: 10 ± 26; and unwashed: 15 ± 1) and did not differ among groups (P = 0.92). Pulmonary dead space (VD/VT) decreased with CS transfusion (-0.01 ± 0.04; P = 0.034) but did not change with other erythrocytes; the change from before to after erythrocyte transfusion did not differ among groups (-0.01 to +0.01; P = 0.28).
The authors did not find impaired gas exchange as assessed by PaO2/FIO2 with transfused erythrocytes that did or did not contain nonautologous plasma. This clinical trial did not support the hypothesis of erythrocyte transfusion-induced gas exchange deficit that had been found in healthy volunteers.
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