Genetic variants in microRNA genes and targets associated with cardiovascular disease risk factors in the African-American population

Abstract

The purpose of this study is to identify microRNA (miRNA) related polymorphism, including single nucleotide variants (SNVs) in mature miRNA-encoding sequences or in miRNA-target sites, and their association with cardiovascular disease (CVD) risk factors in African-American population. To achieve our objective, we examined 1900 African-Americans from the Atherosclerosis Risk in Communities study using SNVs identified from whole-genome sequencing data. A total of 971 SNVs found in 726 different mature miRNA-encoding sequences and 16,057 SNVs found in the three prime untranslated region (3′UTR) of 3647 protein-coding genes were identified and interrogated their associations with 17 CVD risk factors. Using single-variant-based approach, we found 5 SNVs in miRNA-encoding sequences to be associated with serum Lipoprotein(a) [Lp(a)], high-density lipoprotein (HDL) or triglycerides, and 2 SNVs in miRNA-target sites to be associated with Lp(a) and HDL, all with false discovery rates of 5%. Using a gene-based approach, we identified 3 pairs of associations between gene NSD1 and platelet count, gene HSPA4L and cardiac troponin T, and gene AHSA2 and magnesium. We successfully validated the association between a variant specific to African-American population, NR_039880.1:n.18A>C, in mature hsa-miR-4727-5p encoding sequence and serum HDL level in an independent sample of 2135 African-Americans. Our study provided candidate miRNAs and their targets for further investigation of their potential contribution to ethnic disparities in CVD risk factors.

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“…in every…art, fundamental matters are perennially being discovered, discredited, forgotten, rediscovered and reaffirmed”

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Prostate-induced orgasms: A concise review illustrated with a highly relevant case study

Current medical literature does not describe precisely the activation and mechanisms of prostate orgasms. This brief review describes what we know about the anatomy and physiology of the prostate and its involvement in reproduction and especially its stimulation for sexual recreation. It is illustrated with a highly relevant case history. Clin. Anat. 31:81–85, 2018. © 2017 Wiley Periodicals, Inc.

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Hydrophilicity of Graphene in Water through Transparency to Polar and Dispersive Interactions

Abstract

Establishing contact angles on graphene-on-water has been a long-standing challenge as droplet deposition causes free-floating graphene to rupture. The current work presents ice and hydrogels as substrates mimicking water while offering a stable support for graphene. The lowest water contact angles on graphene ever measured, namely on graphene-on-ice and graphene-on-hydrogel, are recorded. The contact angle measurements of liquids with a range of polarities allow the transparency of graphene toward polar and dispersive interactions to be quantified demonstrating that graphene in water is hydrophilic. These findings are anticipated to shed light on the inconsistencies reported so far on the wetting properties of graphene, and most particularly on their implications toward rationalizing how molecules interact with graphene in water.

Graphene manifests hydrophilicity and wetting transparency in an aqueous environment. The determining factors for the wetting transparency are the adhesion and the conformational match between graphene and the substrate. Graphene transmits all types of interactions as long as a clean noncorrugated graphene–substrate interface can be achieved. If not, the graphene screens fully the polar interactions while transmitting the dispersive interactions.

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Giant Magnetic Heat Induction of Magnesium-Doped γ-Fe2O3 Superparamagnetic Nanoparticles for Completely Killing Tumors

Abstract

Magnetic fluid hyperthermia has been recently considered as a Renaissance of cancer treatment modality due to its remarkably low side effects and high treatment efficacy compared to conventional chemotheraphy or radiotheraphy. However, insufficient AC induction heating power at a biological safe range of AC magnetic field (H_appl·f_appl < 3.0–5.0 × 10⁹ A m⁻¹ s⁻¹), and highly required biocompatibility of superparamagnetic nanoparticle (SPNP) hyperthermia agents are still remained as critical challenges for successful clinical hyperthermia applications. Here, newly developed highly biocompatible magnesium shallow doped γ-Fe₂O₃ (Mg_0.13-γFe₂O₃) SPNPs with exceptionally high intrinsic loss power (ILP) in a range of 14 nH m² kg⁻¹, which is an ≈100 times higher than that of commercial Fe₃O₄ (Feridex, ILP = 0.15 nH m² kg⁻¹) at H_appl·f_appl = 1.23 × 10⁹ A m⁻¹ s⁻¹ are reported. The significantly enhanced heat induction characteristics of Mg_0.13-γFe₂O₃ are primarily due to the dramatically enhanced out-of-phase magnetic susceptibility and magnetically tailored AC/DC magnetic softness resulted from the systematically controlled Mg²⁺ cations distribution and concentrations in octahedral site Fe vacancies of γ-Fe₂O₃ instead of well-known Fe₃O₄ SPNPs. In vitro and in vivo magnetic hyperthermia studies using Mg_0.13-γFe₂O₃ nanofluids are conducted to estimate bioavailability and biofeasibility. Mg_0.13-γFe₂O₃ nanofluids show promising hyperthermia effects to completely kill the tumors.

Magnesium-doped γ-Fe₂O₃ (Mg_0.13-γFe₂O₃) superparamagnetic nanoparticles with exceptionally high intrinsic loss power of 14 nH m² kg⁻¹ which is ≈100 times higher than that of commercial Fe₃O₄ at a physiologically safe range of AC magnetic field (H_appl·f_appl = 1.23 × 10⁹ A m⁻¹ s⁻¹) are developed. The hyperthermia effect using Mg_0.13-γFe₂O₃ nanofluids is revealed to be promising for completely killing tumors.

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Siglec-1 inhibits RSV-induced interferon gamma production by adult T Cells in contrast to newborn T cells

Abstract

Interferon gamma (IFN-γ) plays an important role in the antiviral immune response during respiratory syncytial virus (RSV) infections. Monocytes and T cells are recruited to the site of RSV infection, but it is unclear whether cell-cell interactions between monocytes and T cells regulate IFN-γ production. In this study, micro-array data identified the upregulation of sialic acid-binding immunoglobulin-type lectin 1 (Siglec-1) in human RSV-infected infants. In vitro, RSV increased expression of Siglec-1 on healthy newborn and adult monocytes. RSV-induced Siglec-1 on monocytes inhibited IFN-γ production by adult CD4⁺ T cells. In contrast, IFN-γ production by RSV in newborns was not affected by Siglec-1. The ligand for Siglec-1, CD43, is highly expressed on adult CD4⁺ T cells compared to newborns. Our data show that Siglec-1 reduces IFN-γ release by adult T cells possibly by binding to the highly expressed CD43. The Siglec-1-dependent inhibition of IFN-γ in adults and the low expression of CD43 on newborn T cells provides a better understanding of the immune response against RSV in early life and adulthood.

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No abstract is available for this article.

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Diagnostic exome sequencing in children: A survey of parental understanding, experience and psychological impact

ABSTRACT

Clinical exome sequencing (CES) is increasingly being used as an effective diagnostic tool in the field of pediatric genetics. We sought to evaluate the parental experience, understanding and psychological impact of CES by conducting a survey study of English-speaking parents of children who had diagnostic CES. Parents of 192 unique patients participated. The parent's interpretation of the child's result agreed with the clinician's interpretation in 79% of cases, with more frequent discordance when the clinician's interpretation was uncertain. The majority (79%) reported no regret with the decision to have CES. Most (65%) reported complete satisfaction with the genetic counseling experience, and satisfaction was positively associated with years of genetic counselor (GC) experience. The psychological impact of CES was greatest for parents of children with positive results and for parents with anxiety or depression. The results of this study are important for helping clinicians prepare families for the possible results and variable psychological impact of CES. The frequency of parental misinterpretation of test results indicates the need for additional clarity in the communication of results. Finally, while the majority of patients were satisfied with their genetic counseling, satisfaction was lower for new GCs, suggesting a need for targeted GC training for genomic testing.

The aMICRA score was used to assess impact, including distress, uncertainty and positivity (reversed scored) of the genetic test results on the parents. On average, the aMICRA was 12 points higher (more negative impact) in parents who interpreted the results as positive and seven points higher for those who interpreted the results as uncertain compared to those who interpreted the results as negative (p<0.0001, p=0.02). Overall the majority of parents correctly interpreted their child's exome sequencing results. Parental misinterpretation occurred most frequently when the clinician interpreted the results as uncertain.

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Cognitive sequelae of endocrine therapy in women treated for breast cancer: a meta-analysis

Abstract

Purpose

Evidence suggests anti-estrogen endocrine therapy (ET) is associated with adverse cognitive effects; however, findings are based on small samples and vary in the cognitive abilities affected. We conducted a meta-analysis to quantitatively synthesize the evidence.

Methods

Electronic databases were searched in November 2016. Fourteen studies totaling 911 BC patients on aromatase inhibitors (AIs) or tamoxifen (TAM) and 911 controls (i.e., non-cancer controls and BC controls not using ET) were included. Neuropsychological tests were categorized into six domains. Effect sizes were computed to compare (1) ET patients versus controls and (2) TAM patients versus AI patients.

Results

In cross-sectional comparisons, ET patients performed worse than control groups on verbal learning/memory, visual learning/memory, frontal executive function, and processing speed, but did not differ on psychomotor efficiency or visuospatial function. Subgroup analyses revealed that verbal learning/memory was the only domain where ET patients performed worse than both non-cancer and BC controls. In other domains, ET patients and BC controls performed equivalently. Regarding change from pre-treatment performance, ET patients did not differ from controls on any domain. TAM and AI patients did not from one another differ overall; however, subgroup analyses indicated that TAM patients performed better than non-steroidal AI patients on several domains, but showed few performance differences relative to steroidal AI patients.

Conclusions

Verbal learning/memory was the only domain where ET patients performed worse than both non-cancer and BC controls, suggesting specific adverse effects on this domain. Additional studies assessing change from pre-treatment performance and differences between steroidal and non-steroidal AIs are warranted.

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FLNa negatively regulated proliferation and metastasis in lung adenocarcinoma A549 cells via suppression of EGFR

Abstract

Filamin A (FLNa) is a ubiquitously expressed cytoplasmic protein, which composes of an N-terminal actin binding domain (ABD) followed by 24 Ig-like repeats. FLNa functions as a cytoskeletal protein that links transmembrane receptors, including integrins, to F-actin and serves as a signaling intermediate. Recent studies have identified FLNa as a scaffold protein that interacts with over 90 proteins and plays vital roles in cellular signaling transduction. Mutations or defects in human FLNa gene have been shown to cause numerous developmental defects. Moreover, aberrant expression of FLNa has been observed in many cancers, such as parathyroid tumor, cervical cancer, and breast cancer. However, its role in lung adenocarcinoma has seldom been discussed. In the present study, our in vitro and in vivo studies demonstrated that silencing FLNa expression in lung cancer cell line A549 cells promoted proliferation, migration, and invasiveness of A549 cells by enhancing the activation of epidermal growth factor receptor and ERK signaling pathway. These results shed light on novel functions of FLNa in lung cancer and uncovered novel mechanisms, these results provided possible targets for the prediction and treatment for lung adenocarcinoma.

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Artificial neural network model to distinguish follicular adenoma from follicular carcinoma on fine needle aspiration of thyroid

Background

To distinguish follicular adenoma (FA) and follicular carcinoma (FC) of thyroid in fine needle aspiration cytology (FNAC) is a challenging problem.

Aims and objectives

In this article, we attempted to build an artificial neural network (ANN) model from the cytological and morphometric features of the FNAC smears of thyroid to distinguish FA from FC.

Material and methods

The cytological features and morphometric analysis were done on the FNAC smears of histology proven cases of FA (26) and FC (31). The cytological features were analysed semi-quantitatively by two independent observers (RS and PD). These data were used to make an ANN model to differentiate FA versus FC on FNAC material. The performance of this ANN model was assessed by analysing the confusion matrix and receiving operator curve.

Result

There were 39 cases in training set, 9 cases each in validation and test sets. In the test group, ANN model successfully distinguished all cases (9/9) of FA and FC. The area under receiver operating curve was 1.

Conclusion

The present ANN model is efficient to diagnose follicular adenoma and carcinoma cases on cytology smears without any error. In future, this ANN model will be able to diagnose follicular adenoma and carcinoma cases on thyroid aspirate. This study has immense potential in future. This is an open ended ANN model and more parameters and more cases can be included to make the model much stronger.

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Inhibition of autophagy delays motoneuron degeneration and extends lifespan in a mouse model of spinal muscular atrophy

Inhibition of autophagy delays motoneuron degeneration and extends lifespan in a mouse model of spinal muscular atrophy

Inhibition of autophagy delays motoneuron degeneration and extends lifespan in a mouse model of spinal muscular atrophy, Published online: 20 December 2017; doi:10.1038/s41419-017-0086-4

Inhibition of autophagy delays motoneuron degeneration and extends lifespan in a mouse model of spinal muscular atrophy

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Boys in a famous choir: Singing and ticcing

This informal observational study on the tic prevalence in 40 young singers was carried out during a public concert of Bach's Christmas Oratorio. Tics were highly prevalent (present in 35% = 14 boys). Given the possibility of an overrepresentation of perioral tics in this group of highly achieving young vocal artists, one might speculate that there is a relationship between the ability of the motor system to produce a surplus of movements (tics) and high performance (exquisite singing). Despite the unusual study design, with all its limitations, our observations strengthen the view that tics may be related to motor learning. However, alternative explanations, for example, that repetitive motor performance or personality traits in singers drive tic development, could also be true. In light of the boys choir's enchantment, the sole perception of tics as a disorder falls short of the properties of the motor system. Ann Neurol 2017;82:1029–1031

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Progression patterns under BRAF inhibitor treatment and treatment beyond progression in patients with metastatic melanoma

Abstract

Despite markedly improved treatment options for metastatic melanoma, resistance to targeted therapies such as BRAF inhibitors (BRAFi) or BRAFi plus MEK inhibitors (MEKi) remains a major problem. Our aim was to characterize progression on BRAFi therapy and outcome of subsequent treatment. One hundred and eighty patients with BRAF-mutant metastatic melanoma who had progressed on treatment with single-agent BRAFi from February 2010 to April 2015 were included in a retrospective data analysis focused on patterns of progression, treatment beyond progression (TBP) and subsequent treatments after BRAFi therapy. Analysis revealed that 51.1% of patients progressed with both new and existing metastases opposed to progression of only preexisting (28.3%) or only new (20.6%) metastases. Exclusive extracranial progression occurred in 50.6% of patients compared to both extra- and intracranial (29.4%) or sole cerebral progression (20%). Multivariable analyses demonstrated that single site progression and primary response to BRAFi were associated with improved progression-free survival. Progression with exclusively new or only existing metastases and a baseline Eastern Cooperative Oncology Group (ECOG) of 0 were associated with prolonged overall survival (OS). TBP had no significant impact on OS. Other subsequent treatments showed low efficacy with the exception of anti-PD-1 antibodies. In conclusion we identified specific patterns of progression which significantly correlate with further prognosis after progression on BRAFi treatment. In contrast to previously published data, we could not demonstrate a significant survival benefit for BRAFi TBP. Subsequent therapies had strikingly low efficacy except for PD-1 inhibitors.

We identified patterns of progression that significantly correlate with further prognosis after progression on BRAF inhibitor (BRAFi) treatment. In contrast to previously published studies, we did not find a significant survival benefit for BRAFi treatment beyond progression, whereas subsequent therapies (ipilimumab, chemotherapy) had strikingly low efficacy except for PD-1 inhibitors.

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Aprepitant and fosaprepitant decrease the effectiveness of hormonal contraceptives

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Pregnancy outcomes in women on metformin for diabetes or other indications among those seeking teratology information services

ABSTRACT

Background

Metformin is used to treat type 2 diabetes, polycystic ovary syndrome associated infertility, and gestational diabetes. Human studies evaluating the safety of metformin in early pregnancy are scarce.

Method

We evaluated the risk of major birth defects and pregnancy losses in a cohort of pregnant women exposed to metformin during first trimester for different indications relative to a matched unexposed reference group.

Results

The risk of major birth defects was 5.1% (20/392) in pregnancies exposed to metformin during the first trimester and 2.1% (9/431) in the reference group (adjusted odds ratio (OR) 1.70; 95%CI 0.70-4.38). Among metformin users, this risk was 7.8% (17/219) in patients with pre-gestational diabetes and 1.7% (3/173) in those without this diagnosis. Compared to the unexposed reference, the OR for metformin user with diabetes was 3.95 (95% CI 1.77-9.41) and for metformin with other indications it was 0.83 (95% CI 0.18-2.81). The risk of pregnancy losses (spontaneous abortions and stillbirths) was 20.8% in women on metformin during the first trimester and 10.8% in the reference group (adjusted hazard ratio (HR) 1.57; 95%CI 0.90-2.74). The risks for women on metformin with and without pre-gestational diabetes were 24.0% and 16.8% respectively, with adjusted HR of 2.51 (95%CI 1.44-4.36) and 1.38 (95%CI 0.74-2.59) when compared to the reference.

Conclusion

Pregnant women with pre-gestational diabetes on metformin are at a higher risk for adverse pregnancy outcomes than the general population. This appears to be due to the underlying diabetes since women on metformin for other indications do not present meaningfully increased risks.

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Spatial versus temporal inhibition in dystonia

Dystonia is a motor disorder characterized by involuntary muscle contractions, frequently causing twisted postures. A pathophysiological hallmark of dystonia is reduced motor inhibition at multiple levels of the central nervous system including the spinal cord, brainstem and cortex. In addition, it is widely accepted that the sensory system is involved in dystonia. A well-known and fascinating phenomenon is the sensory trick. Touching a body part, usually at a location close to where dystonia occurs such as the neck or face in cervical dystonia or blepharospasm, alleviates dystonia symptoms.

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The implant effect after intracranial electrode placement: is transient clinical improvement explained by post-implantation electrophysiological changes?

It has been repeatedly observed that implanting electrodes in the brain or on the brain is occasionally associated with a transient improvement in seizure control. This improvement was observed with responsive neurostimulation (Morrell et al., 2011), deep brain stimulation (Velasco et al., 2006; Fisher et al., 2010; Valentin et al., 2013), and even diagnostic intracranial electrode implantation (Schulze-Bonhage et al., 2010; Roth et al., 2012; Kovac et al., 2014). In the pivotal trial of anterior thalamic stimulation, there was a 21-22% median seizure frequency reduction in the first month after implantation, prior to randomization (Fisher et al., 2010).

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Vedolizumab in the treatment of chronic, antibiotic-dependent or refractory pouchitis

Summary

Background

The most common complication after ileal pouch anal anastomosis in up to 50% of patients is an acute pouchitis. The majority of patients respond to antibiotic treatment. However, 10%-15% develops chronic antibiotic-dependent or refractory pouchitis which is usually hard to treat.

Aim

To evaluate the effectiveness of vedolizumab in patients with chronic pouchitis.

Methods

Patients with chronic antibiotic-dependent or refractory pouchitis were treated with vedolizumab (300 mg at week 0, 2, 6 and 10) in 10 IBD centres and retrospectively registered. Data were recorded until week 14 of vedolizumab treatment. In total 20 patients (12 male, median age 43 years) were included for analysis. The effectiveness was measured using the Oresland Score (OS) at week 2, 6, 10 and 14 and the pouch disease activity index (PDAI) at week 0 and 14.

Results

The mean OS declined from 6.8 (range 2-12) to 3.4 (range 0-11). Concordantly, the mean PDAI after 14 weeks of treatment dropped from 10 (range 5-18) to 3 (range 0-10). Only three patients reported moderate side effects. No serious side effects were recorded. In addition, symptomatic co-medication such as loperamide and tincture of opium could be terminated in 8 out of 12 patients as well as antibiotic treatment could be stopped in 17 out of 19 patients.

Conclusion

Our data indicate that vedolizumab could be an option in the treatment of patients with chronic, antibiotic-dependent or refractory pouchitis.

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The effect of resorbable membranes on one-stage ridge augmentation in anterior single-tooth replacement: A randomized, controlled clinical trial

Abstract

Aim

To evaluate the effect of resorbable membranes on one-stage ridge augmentation procedures in small (2-4 mm) buccal bony dehiscences in anterior maxillary single-tooth replacement.

Materials and methods

Patients with a buccal bony dehiscence after implant placement in the esthetic zone were randomly allocated to one-stage ridge augmentation with (M+) or without a membrane (M−). Second-phase surgery was performed after 8 weeks, and follow-up was performed 1, 6, and ≥12 months after loading. Outcomes included implant survival and success, complications, clinical and radiographic parameters, esthetic results and patient satisfaction.

Results

Fifty-two patients were randomized to one-stage ridge augmentation with (n = 25) or without use of a membrane (n = 27). No significant differences in implant survival and success have been observed. The risk of having a small mucosal dehiscence was more than six times higher in the M+ group than in the M− group (RR 6.24, 95% CI 0.81 to 48.21). At the last follow-up, the bleeding index (BI) was marginally higher in the M+ group (14/9/2/0) compared to the M- group (24/2/0/0) (U = 205, Z = −2.97, p = .003, r = .42). The median change in marginal bone level was statistically lower in the M+ group (0.06 mm) than the M− group (0.60 mm) at last follow-up (U = 120, Z = −2.73 a p = .006 r = .42). Total pink esthetic index (PES) and white esthetic score (WES) and combined PES/WES were not significantly different between treatment groups at more than 12 months after loading. Only the subcategory root convexity/soft tissue color scored significantly lower in the M+ group (1.5) compared to the M− group (2.0) at the last follow-up (U = 172, Z = −2.34, p = .019 r = .34). No differences were found in patient satisfaction.

Conclusion

The use of a resorbable membrane in small buccal bony dehiscences in anterior maxillary single-tooth replacement resulted in less marginal bone loss, but showed more mucosal dehiscences, higher bleeding scores and lower scores on root convexity and soft tissue color after at least one year of loading. No effect was seen on implant survival and success, overall esthetic results, and patient satisfaction.

The research protocol was registered at the Dutch Trial Register (NTR) with ID NTR6137.

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Editorial: non-alcoholic fatty liver disease—it is better to be slender after all

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Editorial: proton pump inhibitor therapy and liver disease progression—more cause for concern?

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Editorial: rifaximin—a kick in the gut for spontaneous bacterial peritonitis? Authors’ reply

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Editorial: the influence of genetic factors in mediating the effects of tobacco smoke in IBD—Authors’ reply

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Editorial: hepatocellular carcinoma risk in the era of direct-acting anti-virals—is the case closed?

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This article is linked to Ogawa et al paper. To view this article visit http://ift.tt/2BhBRjZ.

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Editorial: there is trouble ahead, but just how much? The troubling reality of America's excesses and NAFLD

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ConsensusDriver Improves upon Individual Algorithms for Predicting Driver Alterations in Different Cancer Types and Individual Patients

Existing cancer driver prediction methods are based on very different assumptions and each of them can detect only a particular subset of driver genes. Here we perform a comprehensive assessment of 18 driver prediction methods on more than 3,400 tumor samples from 15 cancer types, all to determine their suitability in guiding precision medicine efforts. We categorized these methods into five groups: functional impact on proteins in general (FI) or specific to cancer (FIC), cohort-based analysis for recurrent mutations (CBA), mutations with expression correlation (MEC), and methods that use gene interaction network-based analysis (INA). The performance of driver prediction methods varied considerably, with concordance with a gold standard varying from 9% to 68%. FI methods showed relatively poor performance (concordance <22%), while CBA methods provided conservative results but required large sample sizes for high sensitivity. INA methods, through the integration of genomic and transcriptomic data, and FIC methods, by training cancer-specific models, provided the best trade-off between sensitivity and specificity. As the methods were found to predict different subsets of driver genes, we propose a novel consensus-based approach, ConsensusDriver, which significantly improves the quality of predictions (20% increase in sensitivity) in patient subgroups or even individual patients. Consensus-based methods like ConsensusDriver promise to harness the strengths of different driver prediction paradigms.Significance: These findings assess state-of-the-art cancer driver prediction methods and develop a new and improved consensus-based approach for use in precision oncology. Cancer Res; 78(1); 1–12. ©2017 AACR.

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Tenascin-C promotes tumor cell migration and metastasis through integrin {alpha}9{beta}1 -mediated YAP inhibition

Tenascin-C is an extracellular matrix molecule that drives progression of many types of human cancer but the basis for its actions remain obscure. In this study, we describe a cell-autonomous signaling mechanism explaining how tenascin-C promotes cancer cell migration in the tumor microenvironment. In a murine xenograft model of advanced human osteosarcoma, tenascin-C and its receptor integrin α9β1 were determined to be essential for lung metastasis of tumor cells. We determined that activation of this pathway also reduced tumor cell-autonomous expression of target genes for the transcription factor YAP. In clinical specimens, a genetic signature comprising four YAP target genes represents prognostic impact. Taken together, our results illuminate how tumor cell deposition of tenascin-C in the tumor microenvironment promotes invasive migration and metastatic progression. 

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Oncogenic RAS-Induced Perinuclear Signaling Complexes Requiring KSR1 Regulate Signal Transmission to Downstream Targets

The precise characteristics that distinguish normal and oncogenic RAS signaling remain obscure. Here we show that oncogenic RAS and BRAF induce perinuclear re-localization of several RAS pathway proteins, including the kinases CK2 and p-ERK1/2 and the signaling scaffold KSR1. This spatial reorganization requires endocytosis, the kinase activities of MEK-ERK and CK2, and the presence of KSR1. CK2α co-localizes with KSR1 and Rab11, a marker of recycling endosomes, whereas p-ERK associates predominantly with a distinct KSR1-positive endosomal population. Notably, these perinuclear signaling complexes (PSCs) are present in tumor cell lines, mouse lung tumors and mouse embryonic fibroblasts undergoing RAS-induced senescence. PSCs are also transiently induced by growth factors (GFs) in non-transformed cells with delayed kinetics (4-6 hr), establishing a novel late phase of GF signaling that appears to be constitutively activated in tumor cells. PSCs provide an essential platform for RAS-induced phosphorylation and activation of the pro-senescence transcription factor C/EBPβ in primary MEFs undergoing senescence. Conversely, in tumor cells C/EBPβ activation is suppressed by 3'UTR-mediated localization of Cebpb transcripts to a peripheral cytoplasmic domain distinct from the PSC region. Collectively, our findings indicate that sustained PSC formation is a critical feature of oncogenic RAS/BRAF signaling in cancer cells that controls signal transmission to downstream targets by regulating selective access of effector kinases to substrates such as C/EBPβ.

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Inactivation of cancer-associated-fibroblasts (CAF) disrupts oncogenic signaling in pancreatic cancer cells and promotes its regression

Resident fibroblasts that contact tumor epithelial cells (TEC) can become irreversibly activated as cancer-associated-fibroblasts (CAF) which stimulate oncogenic signaling in TEC. In this study, we evaluated the crosstalk between CAF and TEC isolated from tumors generated in a mouse model of KRAS/mutp53-induced pancreatic cancer (KPC mice). Transcriptomic profiling conducted after treatment with the anticancer compound Minnelide revealed deregulation of the TGF-β signaling pathway in CAF, resulting in an apparent reversal of their activated state to a quiescent, non-proliferative state. TEC exposed to media conditioned by drug-treated CAF exhibited a decrease in oncogenic signaling as manifested by downregulation of the transcription factor Sp1. This inhibition was rescued by treating TEC with TGF-β. Given promising early clinical studies with minnelide, our findings suggest that approaches to inactivate CAF and prevent tumor-stroma crosstalk may offer a viable strategy to treat pancreatic cancer. 

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ER stress signaling promotes the survival of cancer 'persister cells' tolerant to EGFR tyrosine kinase inhibitors

An increasingly recognized component of resistance to tyrosine kinase inhibitors (TKI) involves persistence of a drug-tolerant subpopulation of cancer cells which survive despite effective eradication of the majority of the cell population. Multiple groups have demonstrated that these drug-tolerant persister cells undergo transcriptional adaptation via an epigenetic state change that promotes cell survival. Because this mode of TKI drug tolerance appears to involve transcriptional addiction to specific genes and pathways, we hypothesized that systematic functional screening of EGFR TKI/transcriptional inhibitor combination therapy would yield important mechanistic insights and alternative drug escape pathways. We therefore performed a genome-wide CRISPR/Cas9 enhancer/suppressor screen in EGFR-dependent lung cancer PC9 cells treated with erlotinib + THZ1 (CDK7/12 inhibitor) combination therapy,a combination previously shown to suppress drug tolerant cells in this setting. As expected, suppression of multiple genes associated with transcriptional complexes (EP300, CREBBP and MED1) enhanced erlotinib/THZ1 synergy. Unexpectedly, we uncovered nearly every component of the recently described ufmylation pathway in the synergy suppressor group. Loss of ufmylation did not affect canonical downstream EGFR signaling. Instead, absence of this pathway triggered a protective unfolded protein response (UPR) associated with STING upregulation, promoting pro-tumorigenic inflammatory signaling but also unique dependence on Bcl-xL. These data reveal that dysregulation of ufmylation and ER stress comprise a previously unrecognized TKI drug tolerance pathway that engages survival signaling, with potentially important therapeutic implications.

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The CARMA3-Bcl10-MALT1 Signalosome Drives NF-{kappa}B Activation and Promotes Aggressiveness in Angiotensin II Receptor-positive Breast Cancer.

The angiotensin II receptor AGTR1, which mediates vasoconstrictive and inflammatory signaling in vascular disease, is overexpressed aberrantly in some breast cancers. In this study, we established the significance of an AGTR1-responsive NF-κB signaling pathway in this breast cancer subset. We documented that AGTR1 overexpression occurred in the luminal A and B subtypes of breast cancer, was mutually exclusive of HER2 expression, and correlated with aggressive features that include increased lymph node metastasis, reduced responsiveness to neoadjuvant therapy, and reduced overall survival. Mechanistically, AGTR1 overexpression directed both ligand-independent and ligand-dependent activation of NF-κB, mediated by a signaling pathway that requires the triad of CARMA3, Bcl10, and MALT1 (CBM signalosome). Activation of this pathway drove cancer cell-intrinsic responses that include proliferation, migration and invasion. In addition, CBM-dependent activation of NF-κB elicited cancer cell-extrinsic effects, impacting endothelial cells of the tumor microenvironment to promote tumor angiogenesis. CBM/NF-κB signaling in AGTR1+ breast cancer therefore conspires to promote aggressive behavior through pleiotropic effects. Overall, our results point to the prognostic and therapeutic value of identifying AGTR1 overexpression in a subset of HER2-negative breast cancers, and they provide a mechanistic rationale to explore the repurposing of drugs that target angiotensin II-dependent NF-κB signaling pathways to improve the treatment of this breast cancer subset.

http://ift.tt/2kn3ihS

FIH is an oxygen sensor in ovarian cancer for G9a/GLP-driven epigenetic regulation of metastasis-related genes

The prolyl hydroxlyases PHD1-3 and the asparaginly hydroxlyase FIH are oxygen sensors for HIF-driven transcription of hypoxia-induced genes, but whether these sensors affect oxygen-dependent epigenetic regulation more broadly is not known. Here we show that FIH exerts an additional role as an oxygen sensor in epigenetic control by the histone lysine methyltransferases G9a and GLP. FIH hydroxylated and inhibited G9a and GLP under normoxia. When the FIH reaction was limited under hypoxia, G9a and GLP were activated and repressed metastasis suppressor genes, thereby triggering cancer cell migration and peritoneal dissemination of ovarian cancer xenografts. In clinical specimens of ovarian cancer, expression of FIH and G9a were reciprocally associated with patient outcomes. We also identified mutations of FIH target motifs in G9a and GLP, which exhibited excessive H3K9 methylation and facilitated cell invasion. This study provides insight into a new function of FIH as an upstream regulator of oxygen-dependent chromatin remodeling. It also implies that the FIH-G9a/GLP pathway could be a potential target for inhibiting hypoxia-induced cancer metastasis.

http://ift.tt/2kMLGvn

Inhibition of translesion DNA synthesis as a novel therapeutic strategy to treat brain cancer

Temozolomide is a DNA alkylating agent used to treat brain tumors but resistance to this drug is common. In this study, we provide evidence that efficacious responses to this drug can be heightened significantly by co-administration of an artificial nucleoside (5-NIdR) that efficiently and selectively inhibits the replication of DNA lesions generated by temozolomide. Conversion of this compound to the corresponding nucleoside triphosphate 5-NITP in vivo creates a potent inhibitor of several human DNA polymerases that can replicate damaged DNA. Accordingly, 5-NIdR synergized with temozolomide to increase apoptosis of tumor cells. In a murine xenograft model of glioblastoma, whereas temozolomide only delayed tumor growth its co-administration with 5-NIdR caused complete tumor regression. Exploratory toxicology investigations showed that high doses of 5-NIdR did not produce the side effects commonly seen with conventional nucleoside analogs. Collectively, our results offer a preclinical pharmacological proof of concept for the coordinate inhibition of translesion DNA synthesis as a strategy to improve chemotherapeutic responses in aggressive brain tumors.

http://ift.tt/2knhXcW

LSD1 stimulates cancer-associated fibrobasts to drive Notch3-dependent self-renewal of liver cancer stem-like cells

Cancer stem-like cells (CSC) in hepatocellular carcinoma (HCC) are thought to mediate therapeutic resistance and poor survival outcomes, but their intrinsic and extrinsic control is not well understood. In this study, we found that the chromatin modification factor LSD1 is highly expressed in HCC CSC where it decreases during differentiation. LSD1 was responsible for maintaining CSC self-renewal and tumorigenicity in HCC and its overexpression was sufficient to drive self-renewal of non-CSC.Levels of acetylated LSD1 were low in CSC with high LSD1 activity, and these CSC were capable of self-renewal. Notch signaling activated LSD1 through induction of the sirtuin SIRT1, leading to deacetylation and activation of LSD1 and CSC self-renewal. Notably, we found that LSD1 expression was increased in cancer-associated fibroblasts (CAF) as an upstream driver of Notch3-mediated CSC self-renewal. In clinical specimens of HCC, the presence of CAF, LSD1 and Notch3 strongly associated with poor patient survival. Overall, our results reveal that CAF-induced expression of Notch3 is responsible for LSD1 activation in CSC, driving their self-renewal in HCC.

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Loss of RASSF4 expression in multiple myeloma promotes RAS-driven malignant progression.

RAS mutations occur frequently in multiple myeloma (MM), but apart from driving progression they can also stimulate antitumor effects by activating tumor suppressive RASSF proteins. While this family of death effector molecules are often silenced in cancers, functional data about RASSF proteins in MM are lacking. Here we report that RASSF4 is downregulated during MM progression and correlates with a poor prognosis. Promoter methylation analysis in human cell lines revealed an inverse correlation between RASSF4 mRNA levels and methylation status. Epigenetic modulating agents restored RASSF4 expression. Enforced expression of RASSF4 induced G2 phase cell cycle arrest and apoptosis in human cell lines, reduced primary MM cell viability, and blocked MM growth in vivo. Mechanistic investigations showed that RASSF4 linked RAS to several pro-death pathways including those regulated by the kinases MST1, JNK and p38. By activating MST1 and the JNK/c-Jun pathway, RASSF4 sensitized MM cells to bortezomib. Genetic or pharmacological elevation of RASSF4 levels increased the anti-MM effects of the clinical relevant MEK1/2 inhibitor trametinib. Kinome analysis revealed this effect was mediated by concomitant activation of the JNK/c-Jun pathway along with inactivation of the MEK/ERK and PI3K/mTOR/Akt pathways. Overall, our findings establish RASSF4 as a tumor suppressive hub in MM and provide a mechanistic rationale for combining trametinib with HDAC inhibitors or bortezomib to treat patients with tumors exhibiting low RASSF4 expression.

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CXCR4 promotes neuroblastoma growth and therapeutic resistance through miR-15a/16-1 mediated ERK and BCL2/cyclin D1 pathways

CXCR4 expression in neuroblastoma (NB) tumors correlates with disease severity. In this study, we describe mechanisms by which CXCR4 signaling controls NB tumor growth and response to therapy. We found that overexpression of CXCR4 or stimulation with CXCL12 supports NB tumorigenesis. Moreover, CXCR4 inhibition with the high affinity CXCR4 antagonist, BL-8040 prevented tumor growth and reduced survival of tumor cells. These effects were mediated by the upregulation of miR-15a/16-1, which resulted in downregulation of their target genes BCL-2 and cyclin D1, as well as inhibition of ERK. Overexpression of miR-15a/16-1 in cells increased cell death, whereas antagomirs to miR-15a/16-1 abolished the pro-apoptotic effects of BL-8040. CXCR4 overexpression also increased miR-15a/16-1 shifting their oncogenic dependency from the BCL-2 to the ERK signaling pathway. Overall, our results demonstrate the therapeutic potential of CXCR4 inhibition in neuroblastoma treatment and provide a rationale to test combination therapies employing CXCR4 and BCL-2 inhibitors to increase the efficacy of these agents.

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Amplification of oncolytic vaccinia virus widespread tumor cell killing by sunitinib through multiple mechanisms

Oncolytic viruses pose many questions in their use in cancer therapy. In this study, we assessed the potential of mpJX-594 (mouse-prototype JX-594), a replication-competent vaccinia virus administered by intravenous injection, to target the tumor vasculature, produce immune activation and tumor cell killing more widespread than the infection, and suppress invasion and metastasis. These actions were examined in RIP-Tag2 transgenic mice with pancreatic neuroendocrine tumors (PNET) that developed spontaneously and progress as in humans. mpJX-594 initially infected tumor vascular endothelial cells, leading to vascular pruning and prolonged leakage in tumors but not in normal organs; parallel effects were observed in U87 gliomas. Viral infection spread to tumor cells, where tumor cell killing was much more widespread than the infection. Widespread tumor cell killing at 5 days was prevented by depletion of CD8+ T lymphocytes and did not require GM-CSF, as mpJX-594 variants that expressed human, mouse, or no GM-CSF produced equivalent amounts of killing. The antivascular, antitumor, and antimetastatic effects of mpJX-594 were amplified by concurrent or sequential administration of sunitinib, a multi-targeted receptor tyrosine kinase inhibitor (TKI). These effects were not mimicked by selective inhibition of VEGFR-2 despite equivalent vascular pruning, but were accompanied by suppression of regulatory T cells (Tregs) and greater influx of activated CD8+ T cells. Together, our results showed that mpJX-594 targets tumor blood vessels, spreads secondarily to tumor cells, and produces widespread CD8+ T-cell-dependent tumor cell killing in primary tumors and metastases, and that these effects can be amplified by co-administration of sunitinib.

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Optical analysis of glioma: Fourier-transform infrared spectroscopy reveals the IDH1 mutation status.

Purpose: Somatic mutations in human cytosolic isocitrate dehydrogenase 1 (IDH1) gene cause profound changes in cell metabolism and are a common feature of gliomas with unprecedented predictive and prognostic impact. Fourier-transform infrared (FT-IR) spectroscopy addresses the molecular composition of cells and tissue and was investigated to deduct the IDH1-mutation status. Experimental Design: We tested the technique on human cell lines that were transduced with IDH1 wild-type or mutated IDH1 and on 34 human glioma samples. IR spectra were acquired at 256 positions from cell pellets or tissue cryosections. Moreover, IR spectra were obtained from fresh, unprocessed biopsies of 64 glioma patients. Results: IDH1 mutation was linked to changes in spectral bands assigned to molecular groups of lipids and proteins in cell lines and human glioma. The spectra of cryosections of brain tumor samples showed high inter-patient variability, for example bands related to calcifications at 1113 cm-1. However, supervised classification recognized relevant spectral regions at 1103, 1362, 1441, 1485 and 1553 cm-1 and assigned 88% of the tumor samples to the correct group. Similar spectral positions allowed the classification of spectra of fresh biopsies with an accuracy of 86%.  Conclusions: Here, we show that vibrational spectroscopy reveals the IDH1 genotype of glioma. Because it can provide information in seconds, an implementation into the intraoperative workflow might allow simple and rapid online diagnosis of IDH1 genotype. The intraoperative confirmation of IDH1 mutation status might guide the decision to pursue definitive neurosurgical resection and guide future in situ therapies of infiltrative gliomas.

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Minimally Invasive Anterior Pelvic Internal Fixation: An Anatomic Study Comparing Pelvic Bridge to INFIXu

Publication date: Available online 19 December 2017
Source:Injury
Author(s): Lee M. Reichel, Lauren MacCormick, Anthony Dugarte, Amir Rizkala, Sara Graves, Peter A. Cole
ObjectivesAnterior external fixation for pelvic ring fractures has shown to effectively improve stability and reduce mortality. However, these fixators can be associated with substantial morbidity such as pin tract infection, premature loss of fixation, and decreased quality of life in patients. Recently, two new methods of subcutaneous anterior pelvic internal fixation have been developed; the INFIX and the Pelvic Bridge. These methods have the purported advantages of lower wound complications, less surgical site pain, and improved quality of life.We sought to investigate the measured distances to critical anatomic structures, as well as the qualitative and topographic differences notable during implantation of both devices in the same cadaveric specimen.Materials and MethodsThe Pelvic Bridge and INFIX were implanted in eleven fresh cadavers. Distances were then measured to: the superficial inguinal ring, round ligament, spermatic cord, lateral femoral cutaneous nerve (LFCN), femoral nerve, femoral artery, and femoral vein. Observations regarding implantation and topography were also recorded.ResultsThe INFIX had greater measured distances from all structures except for the LFCN, in which its proximity placed this structure at risk. Neither device appears to put other critical structures at risk in the supine position. Significant implantation and topographic differences exist between the devices. The INFIX application lacked "safety margins" concerning the LFCN in 10/11 (90.9%) specimens, while Pelvic Bridge placement lacked "safety margins" with regard to the right superficial ring (1/11, 9%) and the right spermatic cord (1/11, 9%).ConclusionsBoth the Pelvic Bridge and INFIX lie at safe distances from most critical pelvic structures in the supine position, though INFIX application places the LFCN at risk.



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Defibrillation Electrodes for Lifepak AEDs by Physio-Control: Class I Recall - Incorrect Placement Instructions for Infants Depicted on Artwork

Audience: Risk Manager, Critical Care Medicine, Emergency Medicine Includes electrodes for LIFEPAK EXPRESS AED, LIFEPAK CR Plus AED, LIFEPAK 1000 defibrillator, or LIFEPAK 500 Biphasic AED with a pink connector [Posted 12/19/2017] ISSUE:...

http://ift.tt/2kmxEkE

Effectiveness of Acupuncture for Early Recovery of Bowel Function in Cancer: A Systematic Review and Meta-Analysis

Objectives. The aim of this study was to evaluate the effects of acupuncture therapy to reduce the duration of postoperative ileus (POI) and to enhance bowel function in cancer patients. Methods. A systematic search of electronic databases for studies published from inception until January 2017 was carried out from six databases. Randomized controlled trials (RCTs) involving the use of acupuncture and acupressure for POI and bowel function in cancer patients were identified. Outcomes were extracted from each study and pooled to determine the risk ratio and standardized mean difference. Results. 10 RCTs involving 776 cancer patients were included. Compared with control groups (no acupuncture, sham acupuncture, and other active therapies), acupuncture was associated with shorter time to first flatus and time to first defecation. A subgroup analysis revealed that manual acupuncture was more effective on the time to first flatus and the time to first defecation; electroacupuncture was better in reducing the length of hospital stay. Compared with control groups (sham or no acupressure), acupressure was associated with shorter time to first flatus. However, GRADE approach indicated a low quality of evidence. Conclusions. Acupuncture and acupressure showed large effect size with significantly poor or inferior quality of included trials for enhancing bowel function in cancer patients after surgery. Further well-powered evidence is needed.

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The Influence of Suprascapular Notch Shape on the Visualization of Structures in the Suprascapular Notch Region: Studies Based on a New Four-Stage Ultrasonographic Protocol

Evaluation of the morphology of the suprascapular notch region is important from a clinical point of view because it is the most common site of suprascapular nerve compression and injury. A group of 120 patients underwent ultrasound examination of the suprascapular notch region according to our original four-stage "step-by-step" protocol. The notches were classified based on their morphology and measurements like maximal depth (MD) and superior transverse diameter (STD) as follows: type I-MD is longer than STD, type II-MD and STD are equal, type III-STD is longer than MD, and in type IV/V-notches only the bony margin was visualized without depression. Both suprascapular notches were fully visualized in 115 of 120 patients. The type III suprascapular notch was the most prevalent (64.2%), followed by type IV/V (18.7%), type I (11.1%), and type II (6.0%). Color Doppler analysis allowed the suprascapular artery to be recognized in all visualized notches. The suprascapular vein was visible in 176 notches and the suprascapular nerve in 150. Notches containing both suprascapular nerve and vein were significantly wider and shallower than average. As the suprascapular artery is the most easily recognised structure in the area, it may serve as a useful landmark of the suprascapular notch.

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Endothelial Glycocalyx Layer: A Possible Therapeutic Target for Acute Lung Injury during Lung Resection

Background. Shedding of the endothelial glycocalyx layer (EGL) is known to occur during major surgery, but its degradation associated with minimally invasive video-assisted thoracoscopy (VATS) remains unclear. We investigated if serum biomarkers of EGL disruption were elevated during VATS lobectomy, and whether the urinary trypsin inhibitor (UTI) ulinastatin exerted a protective effect during this procedure. Materials and Methods. Sixty ASA II-III lung cancer patients undergoing elective VATS lobectomy were divided equally into UTI and control groups. UTI group patients received intravenous UTI during surgery. Serum levels of syndecan-1 and heparan sulfate were examined before (T0) and at the end of surgery (T1). Serum albumin and hemoglobin were measured before surgery (BOD) and on the first postoperative day (POD1). Results. In control group, syndecan-1 levels were significantly elevated at T1 compared with T0 ( versus , ) and increased even more significantly in patients whose surgery lasted >3 h ( versus , ). Serum albumin levels on POD1 were significantly lower in control group compared with UTI group ( versus , ). Conclusion. EGL degradation occurs following VATS lobectomy. UTI can alleviate this shedding, thus helping preserve normal vascular permeability. Trail Registration. This trial is registered with ChiCTR-IOC-17010416 (January 13, 2017).

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Quantitative Assessment of Blood Pressure Measurement Accuracy and Variability from Visual Auscultation Method by Observers without Receiving Medical Training

This study aimed to quantify blood pressure (BP) measurement accuracy and variability with different techniques. Thirty video clips of BP recordings from the BHS training database were converted to Korotkoff sound waveforms. Ten observers without receiving medical training were asked to determine BPs using (a) traditional manual auscultatory method and (b) visual auscultation method by visualizing the Korotkoff sound waveform, which was repeated three times on different days. The measurement error was calculated against the reference answers, and the measurement variability was calculated from the SD of the three repeats. Statistical analysis showed that, in comparison with the auscultatory method, visual method significantly reduced overall variability from 2.2 to 1.1 mmHg for SBP and from 1.9 to 0.9 mmHg for DBP (both ). It also showed that BP measurement errors were significant for both techniques (all , except DBP from the traditional method). Although significant, the overall mean errors were small (−1.5 and −1.2 mmHg for SBP and −0.7 and 2.6 mmHg for DBP, resp., from the traditional auscultatory and visual auscultation methods). In conclusion, the visual auscultation method had the ability to achieve an acceptable degree of BP measurement accuracy, with smaller variability in comparison with the traditional auscultatory method.

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Defibrillation Electrodes for Lifepak AEDs by Physio-Control: Class I Recall - Incorrect Placement Instructions for Infants Depicted on Artwork

Audience: Risk Manager, Critical Care Medicine, Emergency Medicine Includes electrodes for LIFEPAK EXPRESS AED, LIFEPAK CR Plus AED, LIFEPAK 1000 defibrillator, or LIFEPAK 500 Biphasic AED with a pink connector [Posted 12/19/2017] ISSUE:...

http://ift.tt/2kmxEkE

Editorial Note

We are sad to say farewell to our co-editor, Professor Graham Mooney. We would like to express our gratitude to Graham for his outstanding contribution to Social History of Medicine for almost a decade.  He has been a meticulous, considerate and innovative editor of the journal and has set an inspirational example for all of us. Throughout his tenure, Graham has worked with different co-editors whom he has welcomed, and occasionally mentored, with his characteristically friendly and caring demeanour. During his editorship, the journal went through major changes; it increased from three to four issues per year, migrated to the online submission system, adopted a new house-style, increased the length of its research papers and started publishing virtual special issues. The changes have been possible primarily because of Graham's vision, initiative and dedication to the journal.  In many ways, what Social History of Medicine is today, is because of Graham. We wish him the very best for his future endeavours.

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The Recovery Revolution: The Battle over Addiction Treatment in the United States

ClarkClaire D., The Recovery Revolution: The Battle over Addiction Treatment in the United States,New York: Columbia University Press, 2017. Pp. 336. £27.95. ISBN 978 0 231 17638 5.

http://ift.tt/2oP4e3j

Sabine Arnaud, On Hysteria: The Invention of a Medical Category between 1670 and 1720

ArnaudSabine, On Hysteria: The Invention of a Medical Category between 1670 and 1720,Chicago: The University of Chicago Press, 2015. Pp. 376. £38. ISBN 978 0 2262 7554 3.

http://ift.tt/2D867Lq

David Gentilcore, Food and Health in Early Modern Europe: Diet, Medicine and Society, 1450–1800

GentilcoreDavid, Food and Health in Early Modern Europe: Diet, Medicine and Society, 1450–1800,London: Bloomsbury, 2016. Pp. 249. $35.95. ISBN 978 1 4725 3497 2.

http://ift.tt/2oRgOyK

Aya Homei and Michael Worboys, Fungal Disease in Britain and the United States, 1850–2000. Mycoses and Modernity

HomeiAya and WorboysMichael, Fungal Disease in Britain and the United States, 1850–2000. Mycoses and Modernity,Basingstoke, UK: Palgrave Macmillan, 2013. xiii + 225 pages. $31. ISBN: 978 1 137 39263 3.

http://ift.tt/2D5BWV8

David Wright, SickKids: The History of The Hospital for Sick Children

WrightDavid, SickKids: The History of The Hospital for Sick Children.Toronto: University of Toronto Press, 2016. Pp. 480. $39.95. ISBN: 978 1 4426 4723 7.

http://ift.tt/2oRgG2e

Andreas-Holger Maehle, Contesting Medical Confidentiality. Origins of the Debate in the United States, Britain, and Germany

MaehleAndreas-Holger, Contesting Medical Confidentiality. Origins of the Debate in the United States, Britain, and Germany,Chicago: University of Chicago Press, 2016. Pp. 168. $40. ISBN: 978 0 2264 0482 0.

http://ift.tt/2D6cOxz

William Feindel and Richard Leblanc, The Wounded Brain Healed: The Golden Age of the Montreal Neurological Institute, 1934–1984

FeindelWilliam and LeblancRichard, The Wounded Brain Healed: The Golden Age of the Montreal Neurological Institute, 1934–1984,Montreal & Kingston: McGill-Queen's University Press, 2016. Pp. 648. CAD$100. ISBN 978 0 7735 4637 0.

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Where the Wild Things Were: Victor of Aveyron and the Pre-Emptive Critique of Developmental Disability in the Early Modern Novel

Summary

The history of psychology, with its notions of 'development', has returned regularly to Victor of Aveyron. He has become a test case for the emerging mind-sciences' ability to tame, civilise, educate, and cure. Historians have established first his idiotism, then his mental retardation, and most recently his autism, in various retrospective explanations à la mode as to why he failed to become a fully rational and therefore perfect adult being. Literary and cultural historians, meanwhile, have noted his subsequent influence on the wild monsters of Romantic fiction. What has not been noted is that he has some deficient fictional predecessors too. The present article looks closely at these and sets him in their context. Alongside Victor, as a paradigm case for the early history of psychiatry, three seminal early modern novels are considered, two German and one English: Simplicius Simplicissimus, Wilhelm Meister's Years of Apprenticeship and Tristram Shandy.

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Anna Winterbottom and Facil Tesfaye (eds), Histories of Medicine and Healing in the Indian Ocean World, Volume One: The Medieval and Early Modern Period

WinterbottomAnna and TesfayeFacil (eds), Histories of Medicine and Healing in the Indian Ocean World, Volume One: The Medieval and Early Modern Period,Basingstoke: Palgrave Macmillan, 2016. Pp. 220. $95. ISBN 978 1 137 56760 4.

http://ift.tt/2oRctM4

Fay Bound Alberti, This Mortal Coil: The Human Body in History and Culture

AlbertiFay Bound, This Mortal Coil: The Human Body in History and Culture,Oxford, Oxford University Press, 2016. Pp. 304. £20. ISBN 978 0 1995 9903 5.

http://ift.tt/2D7FA0Q

Tracy Penny Light, Barbara Brookes and Wendy Mitchinson (eds), Essays on Gender and Health, 1800–2000

LightTracy Penny, BrookesBarbara and MitchinsonWendy (eds), Essays on Gender and Health, 1800–2000,Montreal: McGill-Queen's University Press, 2015. Pp. 408. CAN$31.46. ISBN 978 0 7735 4414 7.

http://ift.tt/2D69nHn

Iain Hutchison, Malcolm Nicolson and Lawrence Weaver (eds), Child Health in Scotland: A History of Glasgow’s Royal Hospital for Sick Children

HutchisonIain, NicolsonMalcolm and WeaverLawrence (eds), Child Health in Scotland: A History of Glasgow's Royal Hospital for Sick Children,Renfrewshire: Scottish History Press, 2016. Pp. 322. £24.95. ISBN 978 0 9564 4773 9.

http://ift.tt/2oRcsru

Elizabeth Hallam, Anatomy Museum: Death and the Body Displayed

HallamElizabeth, Anatomy Museum: Death and the Body Displayed,London: Reaktion Books, 2016. Pp. 448. £35. ISBN 978 1 8618 9375 8.

http://ift.tt/2D6EAtT

Waltraud Ernst (ed.), Work, Psychiatry and Society, c.1750–2015

ErnstWaltraud (ed), Work, Psychiatry and Society, c.1750–2015,Manchester: Manchester University Press, 2016. Pp. 392. £75. ISBN 978 0 7190 9769 0.

http://ift.tt/2oNBZBP

Susanne M. Klausen, Abortion under Apartheid. Nationalism, Sexuality and Women’s Reproductive Rights in South Africa

KlausenSusanne M., Abortion under Apartheid. Nationalism, Sexuality and Women's Reproductive Rights in South Africa,Oxford, Oxford University Press, 2015. Pp. 344. £35.99. ISBN 978 0 19 984449 4.

http://ift.tt/2D862aA

Jessica Van Horssen, A Town Called Asbestos: Environmental Contamination, Health and Resilience in a Resource Community

Van HorssenJessica, A Town Called Asbestos: Environmental Contamination, Health and Resilience in a Resource Community,Vancouver: University of British Columbia Press, 2016. Pp. 256. $32.95. ISBN 978 0 7748 2842 0.

http://ift.tt/2oPb9t1

James G. Hanley, Healthy Boundaries: Property, Law and Public Health in England and Wales, 1815–1872

HanleyJames G., Healthy Boundaries: Property, Law and Public Health in England and Wales, 1815–1872,Rochester: University of Rochester Press, 2016. Pp. 270. £95. ISBN 978 1 5804 6556 4.

http://ift.tt/2D8tSTN

Selection of an Anticalin® against the membrane form of Hsp70 via bacterial surface display and its theranostic application in tumour models

Journal Name: Biological Chemistry
Issue: Ahead of print


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Comparative Effectiveness of Preoperative Paravertebral Block for Post-Mastectomy Reconstruction: A Systematic Review of the Literature

Abstract

Introduction

Paravertebral block (PVB) has emerged as a viable strategy for improving postoperative outcomes in breast surgery; however, it is unclear whether these benefits extend to recipients of post-mastectomy reconstruction (PMR).

Methods

A systematic search of the PubMed, EMBASE, Web of Science and Cochrane Library electronic databases was conducted for all studies matching the a priori inclusion criteria (inception to 1 March 2017). Independent assessment by two reviewers, in stages, of the title/abstract and full text was performed. Data relating to study design, patient characteristics, PVB medications and technique, and outcomes, including pain, opioid consumption, length of stay (LOS), postoperative nausea and vomiting (PONV), and PVB-related complications was abstracted.

Results

Of the 1243 identified articles, nine met the inclusion criteria, accounting for 936 patients (PVB, n = 518; non-PVB, n = 418) in two randomized controlled trials (RCT) and seven retrospective cohort studies. Of these studies, six described PVB for prosthetic PMR, and three described PVB for autologous PMR. Overall, there is a subtle trend towards improved pain control, less opioid requirement and shorter LOS, while PONV was largely unchanged in patients receiving PVB for PMR. In two studies, technical failure was reported at 7.4 and 10%, although no study reported a PVB-related complication. Study quality varied, and risk of bias in the included studies was high. Heterogeneity precluded a meta-analysis.

Conclusions

Although recent reports and RCTs advocate for PVB use in PMR, our review highlights significant heterogeneity and knowledge gaps that must be addressed in order for PVB to become part of the optimal anesthetic protocol in PMR.

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Cost Effectiveness of New Biomarkers for Colorectal Cancer Screening – Futility or Call for Innovation?

http://ift.tt/2Bfvu0y

Gene Expression Profiling of Bronchoalveolar Lavage Cells during Aspergillus Colonization of the Lung Allograft

AbstractBackgroundAspergillus colonization after lung transplant is associated with an increased risk of chronic lung allograft dysfunction (CLAD). We hypothesized that gene expression during Aspergillus colonization could provide clues to CLAD pathogenesis.MethodsWe examined transcriptional profiles in 3 or 6-month surveillance bronchoalveolar lavage fluid cell pellets from recipients with A. fumigatus colonization (n=12) and without colonization (n=10). Among the Aspergillus colonized, we also explored profiles in those who developed CLAD (n=6) or remained CLAD free (n=6). Transcription profiles were assayed with the HG-U133 Plus 2.0 microarray (Affymetrix). Differential gene expression was based upon an absolute fold difference ≥2.0, and unadjusted P-value

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Hepatology Highlights

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Notices

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Table of contents

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Masthead

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Instructions to authors and Information for readers

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Application of “Omics” and Systems Biology to Sarcoidosis Research

Annals of the American Thoracic Society, Volume 14, Issue Supplement_6, Page S445-S451, December 2017.


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Executive Summary of the NHLBI Workshop Report: Leveraging Current Scientific Advancements to Understand Sarcoidosis Variability and Improve Outcomes

Annals of the American Thoracic Society, Volume 14, Issue Supplement_6, Page S415-S420, December 2017.


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Disease Burden and Variability in Sarcoidosis

Annals of the American Thoracic Society, Volume 14, Issue Supplement_6, Page S421-S428, December 2017.


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Genetic, Immunologic, and Environmental Basis of Sarcoidosis

Annals of the American Thoracic Society, Volume 14, Issue Supplement_6, Page S429-S436, December 2017.


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High-Risk Sarcoidosis. Current Concepts and Research Imperatives

Annals of the American Thoracic Society, Volume 14, Issue Supplement_6, Page S437-S444, December 2017.


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Effect of postoperative radiotherapy on survival in duodenal adenocarcinoma: a propensity score-adjusted analysis of Surveillance, Epidemiology, and End Results database

Abstract

Purpose

The use of adjuvant treatment has not been sufficiently investigated in duodenal adenocarcinoma. This study evaluated the effect of postoperative radiotherapy (PORT) on survival outcomes in this rare malignancy.

Methods

We identified patients who were diagnosed between 2004 and 2013 in the Surveillance, Epidemiology, and End Results database. Overall survival (OS) and disease-specific survival (DSS) were analyzed before and after propensity score matching.

Results

Among the 701 eligible patients, 116 (17%) underwent PORT. There were no significant differences in OS and DSS according to receipt of PORT in the unmatched population (P = 0.982 and 0.496, respectively), whereas the propensity-matched analysis showed improved OS and DSS with PORT (P = 0.053 and 0.019, respectively). No receipt of PORT was an independent poor prognostic factor in multivariate analysis of both OS (P = 0.022) and DSS (P = 0.005). The potential survival benefits of PORT were observed in subgroups of T4 stage, larger tumor size, higher lymph node ratio, and total/radical resection.

Conclusions

We provide useful insights into the therapeutic role of PORT in adenocarcinoma of the duodenum. Adjuvant strategy with PORT needs to be considered in locally advanced tumors.

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Chronological Age and Risk of Chemotherapy Nonfeasibility: A Real-Life Cohort Study of 153 Stage II or III Colorectal Cancer Patients Given Adjuvant-modified FOLFOX6

Objectives: To assess nonfeasibility of adjuvant-modified FOLFOX6 chemotherapy in patients with stage II or III colorectal cancer. Methods: Consecutive patients managed between 2009 and 2013 in 2 teaching hospitals in the Paris urban area were included in the CORSAGE (COlorectal canceR, AGe, and chemotherapy fEasability study) cohort study. Nonfeasibility was defined by the frequencies of empirical first-cycle dose reduction (>15%), early discontinuation (

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Modifiable and Nonmodifiable Factors Associated With Perioperative Failure of Extraglottic Airway Devices

BACKGROUND: Extraglottic airway device (EGA) failure can be associated with severe complications and adverse patient outcomes. Prior research has identified patient- and procedure-related predictors of EGA failure. In this retrospective study, we assessed the incidence of perioperative EGA failure at our institution and identified modifiable factors associated with this complication that may be the target of preventative or mitigating interventions. METHODS: We performed a 5-year retrospective analysis of adult general anesthesia cases managed with EGAs in a single academic center. Univariable and multivariable logistic regressions were used to identify clinically modifiable and nonmodifiable factors significantly associated with 3 different types of perioperative EGA failure: (1) "EGA placement failure," (2) "EGA failure before procedure start," and (3) "EGA failure after procedure start." RESULTS: A total of 19,693 cases involving an EGA were included in the analysis dataset. EGA failure occurred in 383 (1.9%) of the cases. EGA placement failure occurred in 222 (1.13%) of the cases. EGA failure before procedure start occurred in 76 (0.39%) of the cases. EGA failure after procedure start occurred in 85 (0.43%) of the cases. Factors significantly associated with each type of failure and controllable by the anesthesia team were as follows: (1) EGA placement failure: use of desflurane (odds ratio [OR], 1.67; 95% confidence interval [CI], 1.23–2.25) and EGA size 4 or 5 vs 2 or 3 (OR, 0.07; 95% CI, 0.05–0.10); (2) EGA failure before procedure start: use of desflurane (OR, 2.05; 95% CI, 1.23–3.40) and 3 or more placement attempts (OR, 4.69; 95% CI, 2.57–8.56); and (3) EGA failure after procedure start: 3 or more placement attempts (OR, 2.06; 95% CI, 1.02–4.16) and increasing anesthesia time (OR, 1.35; 95% CI, 1.17–1.55). CONCLUSIONS: The overall incidence of EGA failure was 1.9%, and EGA placement failure was the most common type of failure. We also found that use of desflurane and use of smaller EGA sizes in adult patients were factors under the direct control of anesthesia clinicians associated with EGA failure. An increasing number of attempts at EGA placement was associated with later device failures. Our findings also confirm the association of EGA failure with previously identified patient- and procedure-related factors such as increased body mass index, male sex, and position other than supine. Accepted for publication September 29, 2017. Funding: None. The authors declare no conflicts of interest. This study was entirely conducted at Barnes Jewish Hospital and the School of Medicine of Washington University in St Louis. Reprints will not be available from the authors. Address correspondence to Andrea Vannucci, MD, DEAA, Department of Anesthesiology, University of Mississippi Medical Center-School of Medicine, 2500 N State St, Jackson, MS 39216. Address e-mail to avannucci@umc.edu. © 2017 International Anesthesia Research Society

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Surveying the Literature

No abstract available

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Differential Effects of Anesthetics and Opioid Receptor Activation on Cardioprotection Elicited by Reactive Oxygen Species–Mediated Postconditioning in Sprague-Dawley Rat Hearts

BACKGROUND: Despite an array of cardioprotective interventions identified in preclinical models of ischemia–reperfusion (IR) injury, successful clinical translation has not been achieved. This study investigated whether drugs routinely used in clinical anesthesia influence cardioprotective effectiveness by reducing effects of reactive oxygen species (ROS), upstream triggers of cardioprotective signaling. Effects of propofol, sevoflurane, or remifentanil were compared on postischemic functional recovery induced by ROS-mediated postconditioning with Intralipid. METHODS: Recovery of left ventricular (LV) work, an index of IR injury, was measured in isolated Sprague-Dawley rat hearts subjected to global ischemia (20 minutes) and reperfusion (30 minutes). Hearts were either untreated or were treated with postconditioning with Intralipid (1%, throughout reperfusion). Propofol (10 μM), sevoflurane (2 vol%), remifentanil (3 nM), or combinations thereof were administered peri-ischemically (before and during IR). The effects of anesthetics on ROS production were measured in LV cardiac fibers by Amplex Red assay under phosphorylating and nonphosphorylating conditions. RESULTS: Recovery of LV work (expressed as percentage of the preischemic value ± standard deviation) in untreated hearts was poor (20% ± 7%) and was improved by Intralipid postconditioning (58% ± 8%, P = .001). In the absence of Intralipid postconditioning, recovery of LV work was enhanced by propofol (28% ± 9%, P = .049), sevoflurane (49% ± 5%, P

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You’re Wrong, I’m Right: Dueling Authors Reexamine Classic Teachings in Anesthesia

No abstract available

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Macintosh Blade Videolaryngoscopy Combined With Rigid Bonfils Intubation Endoscope Offers a Suitable Alternative for Patients With Difficult Airways

BACKGROUND: In the armamentarium of an anesthesiologist, videolaryngoscopy is a valuable addition to secure the airway. However, when the videolaryngoscope (VLS) offers no solution, few options remain. Earlier, we presented an intubation technique combining Macintosh blade VLS and Bonfils intubation endoscope (BIE) for a patient with a history of very difficult intubation. In the present study, we evaluated this technique to establish whether it is a valuable alternative. METHODS: In this single-blinded nonrandomized study, 38 patients with a history of difficult intubation or 1 or more predictors of difficult intubation, scoring a Cormack & Lehane (C&L) grade III or IV using Macintosh blade VLS, were included. Patients were intubated combining the VLS with the BIE. The C&L grade was scored 3 times during (1) direct laryngoscopy; (2) indirect videolaryngoscopy; and (3) using the combined technique (VLS + BIE). Afterward, 2 blinded anesthesiologists assessed the C&L grade using the pictures taken during the procedure. RESULTS: Data of 38 patients were analyzed. An improvement of the C&L grade with the combined technique occurred in 33 of 38 patients (86.8%; 95% confidence interval, 71.9%–95.6%). Reviewer 1 reported an improvement of the C&L grade with the combined technique in 37 of 38 patients. Reviewer 2 reported improvement in 33 and deterioration in 2 of the patients. No complications occurred. CONCLUSIONS: The combined use of a VLS with Macintosh blade and BIE gives the anesthesiologist a valuable alternative intubation option in patients with extremely difficult airways. Accepted for publication November 2, 2017. Funding: None of the study members has received funding from the device manufacturer of the Bonfils intubation endoscope. All devices used for the study were readily available from the department. No funding was obtained from the device manufacturers. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). Clinical trial registration: ClinicalTrials.gov—NCT01691703. Reprints will not be available from the authors. Address correspondence to Barbe M. Pieters, MD, PhD, Department of Anesthesiology, University Medical Centre Utrecht, Postbus 85090, 3508 AB Utrecht, the Netherlands. Address e-mail to bmapieters@gmail.com. © 2017 International Anesthesia Research Society

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Impact of Inhalational Anesthetics on Liver Regeneration After Living Donor Hepatectomy: A Propensity Score-Matched Analysis

BACKGROUND: Although desflurane and sevoflurane, the most commonly used inhalational anesthetics, have been linked to postoperative liver injury, their impact on liver regeneration remains unclear. We compared the influence of these anesthetics on the postoperative liver regeneration index (LRI) after living donor hepatectomy (LDH). METHODS: We conducted a retrospective chart review of 1629 living donors who underwent right hepatectomy for LDH between January 2008 and August 2016. The patients were divided into sevoflurane (n = 1206) and desflurane (n = 423) groups. Factors associated with LRI were investigated using multivariable logistic regression analysis. Propensity score matching analysis compared early (1 postoperative week) and late (within 1–2 months) LRIs and delayed recovery of hepatic function between the 2 groups. RESULTS: The mean early and late LRIs in the 1629 patients were 63.3% ± 41.5% and 93.7% ± 48.1%, respectively. After propensity score matching (n = 403 pairs), there were no significant differences in early and late LRIs between the sevoflurane and desflurane groups (early LRI: 61.2% ± 41.5% vs 58.9% ± 42.4%, P = .438; late LRI: 88.3% ± 44.3% vs 94.6% ± 52.4%, P = .168). Male sex (regression coefficient [β], 4.6; confidence interval, 1.6–7.6; P = .003) and remnant liver volume (β, –4.92; confidence interval, –5.2 to –4.7; P

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Promoting a Restrictive Intraoperative Transfusion Strategy: The Influence of a Transfusion Guideline and a Novel Software Tool

BACKGROUND: The effect of neither transfusion guidelines nor decision support tools on intraoperative transfusion has been previously evaluated. The University of Michigan introduced a transfusion guideline in 2009, and in 2011, the Department of Anesthesiology developed a transfusion decision support tool. The primary aim of this study was to assess the associations of the transfusion guideline and the optional use of the software transfusion tool with intraoperative behaviors; pretransfusion hematocrit assessment (whether or not a hematocrit was checked before each red cell unit) and restrictive red cell use (withholding transfusion unless the hematocrit was ≤21%). METHODS: This was a before–after retrospective study without a concurrent control group of patients transfused 1–3 units of red cells intraoperatively. Three phases were studied to provide data both before and after the implementation of the transfusion guideline and the intraoperative software tool. Within each phase, trends of checking hematocrits before transfusion and restrictive transfusion were charted against time. F tests were used to measure differences of slopes. The difference between means of each phase was measured using Mann-Whitney U tests. Independent associations were measured using mixed-effects multivariable logistic regression. A secondary outcome analysis was conducted for 30-day mortality, myocardial infarction, renal injury, and their combination. RESULTS: The transfusion guideline was associated with increased pretransfusion hematocrit evaluation (67.4%, standard deviation [SD] 3.9 vs 76.5%, SD 2.7; P

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An Environment Is More Than a Climate

No abstract available

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Predictors of Hematologic Toxicity and Chemotherapy Dose Intensity in Patients Undergoing Chemoradiation for Pancreatic Cancer

Objectives: Intensity-modulated radiation therapy (IMRT) has been shown to decrease abdominal toxicity in patients undergoing chemoradiation (CRT) for pancreatic cancer. We evaluated whether IMRT impacts the rates of hematologic toxicity and chemotherapy dose intensity in patients undergoing CRT. Methods: We retrospectively reviewed patients with borderline resectable or locally advanced pancreatic cancer undergoing CRT between 2006 and 2012. Exclusion criteria included receipt of non-gemcitabine therapy, chemotherapy before CRT, or abnormal baseline hematologic indices. Endpoints included total gemcitabine dose received, dose intensity, unplanned dose reductions, and hematologic toxicity (WBC, ANC, platelet, and hemoglobin). Patient/treatment factors were evaluated for their relationship to the above endpoints during CRT and within the first 3 months post-CRT. Statistical analysis was performed using the Fisher exact test and regression models. Because of the multiple comparisons in the presented analysis, a false discovery rate adjustment was performed at the 5% false discovery rate level. Results: Eighty-five patients met the inclusion criteria. Fifty-eight (68.2%) patients received treatment with IMRT, and 27 (31.8%) patients were treated with 3D-conformal radiation. During CRT, there was no relationship between radiation technique and gemcitabine dose received, dose intensity, or hematologic grade 3+ toxicity. Post-CRT, there was no relationship between radiation technique and total gemcitabine dose received, dose intensity, or dose reduction. Patients receiving IMRT were more likely to have ANC grade 3+ toxicity (P=0.007) post-CRT, although this was no longer statistically significant after correction. There were no other relationships between treatment technique and hematologic toxicity. Conclusions: IMRT technique may be associated with higher hematologic toxicity in patients undergoing CRT for pancreatic cancer. Given the expanding use of CRT, additional study is needed to identify the impact of IMRT on myelosuppression in these patients.

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Self-reported Conflicts of Interest and Trial Sponsorship of Clinical Trials in Prostate Cancer Involving Radiotherapy

Objectives: To examine the association between trial sponsorship and conflicts of interest (COI) with clinical trial conclusions for prostate cancer trials related to radiotherapy. Materials and Methods: The MEDLINE database was searched for all prostate cancer clinical trials published between 2004 and 2013 and identified 1396 studies. Two investigators independently identified trials published in the English language of ≥30 patients, and extracted relevant data. Clinical trials were classified according to trial characteristics, sponsorship source and type, COI, and study conclusion, and analyzed by univariable and multivariable logistic regression. Results: Of 240 eligible trials, 160 (67.5%) evaluated drugs without radiotherapy, 60 (25%) involved radiotherapy, and 18 (7.5%) involved procedures without radiotherapy. Of the 60 radiotherapy trials eligible for analysis, positive sponsorship and potential COI were present in 58.3% and 20% of trials, respectively. Study conclusions were positive, negative, or neutral in 78.3%, 5%, and 16.7% of trials, respectively. No association was found between positive conclusions and either industry support of potential COI. Positive conclusions were reported in 86.7% and 83.3% of trials with sponsorship and COI, respectively, as compared with 75.6% and 77.1% of those without sponsorship (P=0.37) and COI (P=0.64). Sponsorship was significantly associated with radiotherapy trials combined with drugs (odds ratio 5.5, P=0.01) and higher-risk disease (odds ratio 4.71, P=0.01). Conclusions: The presence of sponsorship was associated with radiotherapy trials involving drugs or studying higher-risk prostate cancer. However, there were no identified associations between study conclusion and sponsorship type or COI.

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Wrong to be Right: Margin Laterality is an Independent Predictor of Biochemical Failure After Radical Prostatectomy

Objectives: To examine the impact of positive surgical margin (PSM) laterality on failure after radical prostatectomy (RP). A PSM can influence local recurrence and outcomes after salvage radiation. Unlike intrinsic risk factors, a PSM is caused by intervention and thus iatrogenic failures may be elucidated by analyzing margin laterality as surgical approach is itself lateralized. Patients and Methods: We reviewed 226 RP patients between 1991 and 2013 with PSM. Data includes operation type, pre/postoperative PSA, surgical pathology, and margin type (location, focality, laterality). The median follow-up was 47 months. Biochemical recurrence after RP was defined as PSA≥0.1 ng/mL or 2 consecutive rises above nadir. Ninety-two patients received salvage radiation therapy (SRT). Failure after SRT was defined as any PSA≥0.2 ng/mL or greater than presalvage. Kaplan-Meier and Cox multivariate analyses compared relapse rates. Results: The majority of PSM were iatrogenic (58%). Laterality was associated with differences in median relapse: right 20 versus left 51 versus bilateral 14 months (P

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Fractionated Radiation Therapy for Benign Nonacoustic Schwannomas

Objectives: We analyzed the outcomes of patients with benign nonacoustic schwannomas treated with fractionated radiation therapy (RT). Methods: Between October 1987 and March 2013, 11 patients with benign nonacoustic schwannomas diagnosed radiographically (n=3) or pathologically (n=8) were treated with fractionated RT with curative intent at the University of Florida. We reviewed patients' medical records to assess outcomes and toxicities from treatment. Results: The median follow-up for all patients was 8.2 years (range, 2.2 to 22.7 y) and 8 years for all living patients (range, 2.2 to 22.7 y). Of the 11 patients included in the analysis, 8 (73%) were treated solely with RT, 1 (9%) was treated with postoperative RT after subtotal resection, and 2 (18%) were treated with postoperative RT after recurrence following initial surgical resection. The 5-year overall survival, disease-free survival, and local control rates were 100%. There were no grade 2 to 5 treatment toxicities. Conclusions: RT for benign nonacoustic schwannoma may be effective when used alone or in addition to surgery. Irradiation should be considered in patients for whom resection is likely to result in one or more neurological deficits. Fractionated RT to a total dose of 50 Gy provides excellent local control and minimal morbidity.

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Prognostic Value of Ki-67 Labeling Index and Postoperative Radiotherapy in WHO Grade II Meningioma

Objective: This study was performed to determine the clinical significance of the Ki-67 labeling index (LI) for local control (LC) in patients with World Health Organization (WHO) grade II meningioma. We also tried to discern the effect of postoperative radiotherapy (PORT) on LC depending upon the Ki-67 LI value. Materials and Methods: The medical records and values of Ki-67 LIs were retrospectively reviewed for 50 patients who underwent surgical resection of intracranial WHO grade II meningiomas at Samsung Medical Center from May 2001 to December 2012. Forty-three patients (86%) were treated with immediate PORT. The median total radiation dose was 60 Gy (range, 54 to 60 Gy). Results: The median follow-up was 47.4 months. The mean Ki-67 LI was 13% (range, 1% to 47%). Twelve patients (24.0%) showed local failure, and 8 patients (16.0%) experienced local failure even after PORT. The mean Ki-67 LI was 15% in patients with local failure (n=12) and 12% in patients without local failure (n=38). The 3-year actuarial LC was 80.5%. The 3-year overall survival was 89.5%. Ki-67 LI>13% and PORT were significant prognostic factors for LC (P=0.015 and 0.009, respectively). In patients with Ki-67 LI>13% (n=17), PORT (n=14) improved LC (P13%, PORT should be recommended to improve LC.

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Concurrent Radiotherapy With Cetuximab or Platinum-based Chemotherapy for Locally Advanced Cutaneous Squamous Cell Carcinoma of the Head and Neck

Objectives: The management of high-risk cutaneous squamous cell carcinoma of the head and neck (SCCHN) is not well defined. We review outcomes in patients with locally advanced cutaneous SCCHN treated with radiation and concomitant platinum (Pt)-based chemotherapy or cetuximab (Cx). Methods: We identified 23 patients treated at our institution from 2007 to 2014. Systemic therapy consisted of Pt-based chemotherapy for 15 (65%) patients and Cx for 8 (35%) patients. Treatment intent was definitive for 48% and adjuvant for 52% of the cases. Results: The majority (87%) of patients had stage III/IV disease and 9 (39%) patients had unresectable disease. All patients were being treated for recurrent disease. Aside from median age (59 Pt vs. 71 Cx, P=0.04), there were no significant differences in patient and tumor characteristics between those receiving Pt versus Cx therapy. At mean follow-up of 24 months, locoregional recurrence and distant failure were observed in 52% and 17% of all patients, respectively. Estimated 2-year disease-free survival and overall survival in the Cx versus Pt groups were: 50% versus 30% (P=0.25), and 73% versus 40% (P=0.32), respectively. Conclusions: Radiotherapy with either concurrent Pt or Cx appears to offer similar clinical outcomes in patients with locally advanced cutaneous SCCHN.

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Primary Pulmonary Carcinoid Tumor: A Long-term Single Institution Experience

Objectives: Primary carcinoid tumors of the lung are rare tumors which comprise approximately 0.5% to 5% of all lung malignancies in adults and roughly 20% to 30% of all carcinoid tumors. The purpose of this retrospective, descriptive study was to describe the incidence, characteristics, and outcomes of patients treated for primary pulmonary carcinoid tumor at a single institution. Materials and Methods: All patients with a diagnosis of primary pulmonary carcinoid tumor treated from 1989 to 2009 were reviewed. Data collected included demographics, pathology, tobacco use, clinical presentation, tumor location, tumor spread, treatment, and survival. Results: There were 59 cases of pulmonary carcinoid tumors: 47 typical (80%) and 12 atypical (20%). All but 4 patients underwent surgery, including 54 (92%) lung-sparing resections and 1 pneumonectomy. Five of 55 patients received concurrent adjuvant chemoradiation therapy; 4 patients with atypical and 1 with typical histology. Three additional patients with atypical carcinoid were treated only with adjuvant radiotherapy, palliative radiotherapy, or palliative chemotherapy, respectively. The Kaplan-Meier 5- and 10-year overall survivals were both 80% within the entire population. In the 88% of patients who achieved complete remission, disease-free survival was 98%. A review of a large series from the literature is also presented. Conclusions: Surgical resection was primary and adequate therapy for most typical carcinoid tumors with high overall survival and disease-free survival. Adjuvant chemotherapy or radiotherapy might be considered for patients with atypical carcinoid tumors who present with adverse pathologic findings.

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Is Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy Justified for Biphasic Variants of Peritoneal Mesothelioma? Outcomes from the Peritoneal Surface Oncology Group International Registry

Abstract

Background

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has dramatically improved the survival of patients with epithelioid peritoneal mesothelioma. It is unknown if CRS/HIPEC is indicated for the more aggressive biphasic mesothelioma variant.

Methods

A retrospective analysis of the Peritoneal Surface Oncology Group International (PSOGI) registry including data from 33 centers was performed. Survival was reviewed based on mesothelioma type, completion of cytoreduction, and volume of disease.

Results

Overall, 484 of 1165 (41.5%) CRS/HIPEC procedures with complete CC0 and CC1 cytoreductions were analyzed; 450 (93%) procedures were performed for epithelioid mesotheliomas, while 34 (7%) were performed for biphasic mesotheliomas. For patients with CC0 resection, 5-year survival was 64.5 and 50.2% (median 7.8 and 6.8 years; p = 0.015) for epithelioid and biphasic mesotheliomas, respectively, while inclusion of CC1 resections in the analysis resulted in inferior 5-year survival of 62.9% and 41.6% (median 7.8 and 2.8 years; p = 0.0012), respectively. Incomplete CC2 resections for biphasic primaries resulted in a median survival of 4.3 months. Univariate analysis of the biphasic cohort indicated Peritoneal Cancer Index (PCI; p = 0.015), CC status of resection (p < 0.0001), and Ki67 (p = 0.04) as predictors of survival. Systemic chemotherapy before (p = 0.55) or after (p = 0.7) CRS/HIPEC did not influence survival. In multivariate analysis, only PCI (p = 0.03) and CC (p = 0.04) remained significant.

Conclusions

Long-term survival is achievable in patients with low-volume biphasic mesothelioma after complete macroscopic cytoreduction. Biphasic peritoneal mesotheliomas should not be considered as an absolute contraindication for CRS/HIPEC if there is low-volume disease and if complete cytoreduction can be achieved.

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Investigation of red blood cell mechanical properties using AFM indentation and coarse-grained particle method

Red blood cells (RBCs) deform significantly and repeatedly when passing through narrow capillaries and delivering dioxygen throughout the body. Deformability of RBCs is a key characteristic, largely governed b...

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Whole-body PET/MRI of Pediatric Patients: The Details That Matter

This article provides comprehensive step-by-step instructions for the acquisition of whole-body 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) PET/MRI scans for cancer staging of pediatric patients. The protocol was developed for children above 6 years, or old enough to comply with breath-hold instructions, but can be used for general anesthesia patients as well.

http://ift.tt/2kn7mPk

Critical Care Organizations: Building and Integrating Academic Programs

Objective: Academic medical centers in North America are expanding their missions from the traditional triad of patient care, research, and education to include the broader issue of healthcare delivery improvement. In recent years, integrated Critical Care Organizations have developed within academic centers to better meet the challenges of this broadening mission. The goal of this article was to provide interested administrators and intensivists with the proper resources, lines of communication, and organizational approach to accomplish integration and Critical Care Organization formation effectively. Design: The Academic Critical Care Organization Building section workgroup of the taskforce established regular monthly conference calls to reach consensus on the development of a toolkit utilizing methods proven to advance the development of their own academic Critical Care Organizations. Relevant medical literature was reviewed by literature search. Materials from federal agencies and other national organizations were accessed through the Internet. Setting: The Society of Critical Care Medicine convened a taskforce entitled "Academic Leaders in Critical Care Medicine" on February 22, 2016 at the 45th Critical Care Congress using the expertise of successful leaders of advanced governance Critical Care Organizations in North America to develop a toolkit for advancing Critical Care Organizations. Measurements and Main Results: Key elements of an academic Critical Care Organization are outlined. The vital missions of multidisciplinary patient care, safety, and quality are linked to the research, education, and professional development missions that enhance the value of such organizations. Core features, benefits, barriers, and recommendations for integration of academic programs within Critical Care Organizations are described. Selected readings and resources to successfully implement the recommendations are provided. Communication with medical school and hospital leadership is discussed. Conclusions: We present the rationale for critical care programs to transition to integrated Critical Care Organizations within academic medical centers and provide recommendations and resources to facilitate this transition and foster Critical Care Organization effectiveness and future success. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/29S62lw). Dr. Masur received support for article research from the National Institutes of Health, and he disclosed government work. Dr. Coopersmith's institution received funding from the Society of Critical Care Medicine (SCCM) as the president-elect of SCCM in 2014 and president in 2015. An honorarium for time spent in this role was paid to Emory University. Dr. Pastores received funding from Winthrop University Hospital, NY (Medical Grand Rounds) and New York Hospital Queens (Medical Grand Rounds), and he received other support from Theravanxe (Advisory Board Meeting). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: moorje@ccm.upmc.edu Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Extracellular expression of a novel β-agarase from Microbulbifer sp. Q7, isolated from the gut of sea cucumber

A novel endo-type β-agarase was cloned from an agar-degrading bacterium, Microbulbifer sp. Q7 (CGMCC No. 14061), that was isolated from sea cucumber gut. The agarase-encoding gene, ID2563, consisted of 1800 bp th...

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Methodology for Biomimetic Chemical Neuromodulation of Rat Retinas with the Neurotransmitter Glutamate In Vitro

This protocol describes a novel method for investigating a form of chemical neurostimulation of wholemount rat retinas in vitro with the neurotransmitter glutamate. Chemical neurostimulation is a promising alternative to the conventional electrical neurostimulation of retinal neurons for treating irreversible blindness caused by photoreceptor degenerative diseases.

http://ift.tt/2CFxHi0

Factors contributing to anaemia after uncomplicated falciparum malaria in under five year-old Nigerian children ten years following adoption of artemisinin-based combination therapies as first-line antimalarials

Artemisinin-based combination therapies (ACTs) have remained efficacious treatments of acute falciparum malaria in many endemic areas but there is little evaluation of factors contributing to the anaemia of ac...

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The diagnostic value of FNA biopsy in grading pancreatic neuroendocrine tumors

BACKGROUND

There has been much controversy regarding the accuracy of grading pancreatic neuroendocrine tumors (PNETs) on fine-needle aspiration (FNA) biopsy. The objectives of this study were to evaluate whether grading according to the fraction of Ki-67–positive tumor cells (the Ki-67 proliferation index) on material from endoscopic ultrasound-guided FNA biopsies correlated with grading on surgical resection specimens and to evaluate the minimum amount of FNA material needed.

METHODS

A case series of 27 PNETs with FNA biopsies and corresponding surgical resection specimens at the authors' institution were evaluated. Tumors were graded on FNA and surgical specimens with an evaluation of Ki-67 index according to 2010 World Health Organization criteria. Chart reviews were conducted to evaluate recurrence or clinical progression in patients who were being managed conservatively with observation.

RESULTS

The evaluation of grading between FNA and tumor resection specimens revealed that 22 of 26 FNA specimens (84.6%) had Ki-67 results comparable to those in the corresponding surgical resection specimens, thus allowing for accurate grading. Correct FNA diagnosis with the ability to distinguish between grade 1 and 2 tumors had a positive predictive value of 88.9%, with 72.7% sensitivity, 93.3% specificity, and a P value of .00081. In addition, 24 of 26 cases contained less than 2000 cells, of which 20 were correctly graded on FNA material. Seven of 26 FNA samples had less than 1000 cells, of which 6 were correctly graded, including 2 that had only 50 cells.

CONCLUSIONS

The current results exhibit good correlation between FNA grade and final grade on surgical resection specimens using Ki-67 index, even in samples with less than the recommended total cell count. Therefore, grading of PNETs on FNA with the Ki-67 proliferation index should be assessed and is a practical parameter to report to clinicians. Cancer Cytopathol 2017. © 2017 American Cancer Society.

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