Monogenic lupus: it's all new!

Patricia Costa-Reis | Kathleen E Sullivan

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Quality of Care during Neonatal Resuscitation in Kakamega County General Hospital, Kenya: A Direct Observation Study

Background. Birth asphyxia is the leading cause of neonatal mortality in Kenya. Quality care during neonatal resuscitation (NR) can contribute to a reduction in neonatal mortality related to birth asphyxia by 30 percent. This study assessed the quality of care (QoC) during NR for newborns with birth asphyxia. Methods. Direct observations of 138 newborn resuscitations were done in labor ward and maternity theatre. Twenty-eight healthcare providers were observed 3–5 times using a structured checklist. Descriptive and inferential statistics were calculated and quality of care scores computed. Ordered logistic regression model identified HCPs characteristics associated with the QoC scores during NR. Results. Overall QoC scores were good for airway clearance (83%). Suctioning in meconium presence (40%) was poorly performed. Years of experience working in maternity were associated with good drying/stimulation (β = 1.86, , CI = 0.626–3.093) and airway maintenance (β = 1.887, , CI = 0.469–3.305); nurses were poor compared to doctors during initial bag and mask ventilation (β = −2.338, , CI = −4.732–0.056). Conclusion. Key steps in NR are poorly performed during drying and warmth, airway maintenance in meconium presence, and ventilation. Mentorship with periodic refresher training can improve the care provided during NR.

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Evaluating Swine Injection Technologies as a Workplace Musculoskeletal Injury Intervention: A Study Protocol

Intensification of modern swine production has led to many new technologies, including needleless injectors. Although needleless injectors may increase productivity (by reducing injection time) and reduce needlestick injuries, the effect on risk for musculoskeletal disorders is not clear. This project will compare conventional needles with needleless injectors in terms of cost, productivity, injury rates, biomechanical exposures, and worker preference. Muscle activity (EMG) and hand/wrist posture will be measured on swine workers performing injection tasks with both injection methods. Video recordings during the exposure assessments will compare the duration and productivity for each injection method using time-and-motion methods. Injury claim data from up to 60 pig barns will be analyzed for needlestick and musculoskeletal injuries before/after needleless injector adoption. Workers and managers will be asked about what they like and dislike about each method and what helps and hinders successful implementation. The information above will be input into a cost-benefit model to determine the incremental effects of needleless injectors in terms of occupational health, worker preference, and the financial "bottom line" of the farm. Findings will be relevant to the swine industry and are intended to be transferable to other new technologies in animal production.

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Linked Registries: Connecting Rare Diseases Patient Registries through a Semantic Web Layer

Patient registries are an essential tool to increase current knowledge regarding rare diseases. Understanding these data is a vital step to improve patient treatments and to create the most adequate tools for personalized medicine. However, the growing number of disease-specific patient registries brings also new technical challenges. Usually, these systems are developed as closed data silos, with independent formats and models, lacking comprehensive mechanisms to enable data sharing. To tackle these challenges, we developed a Semantic Web based solution that allows connecting distributed and heterogeneous registries, enabling the federation of knowledge between multiple independent environments. This semantic layer creates a holistic view over a set of anonymised registries, supporting semantic data representation, integrated access, and querying. The implemented system gave us the opportunity to answer challenging questions across disperse rare disease patient registries. The interconnection between those registries using Semantic Web technologies benefits our final solution in a way that we can query single or multiple instances according to our needs. The outcome is a unique semantic layer, connecting miscellaneous registries and delivering a lightweight holistic perspective over the wealth of knowledge stemming from linked rare disease patient registries.

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Human Gut Microbiota Associated with Obesity in Chinese Children and Adolescents

Objective. To investigate the gut microbiota differences of obese children compared with the control healthy cohort to result in further understanding of the mechanism of obesity development. Methods. We evaluated the 16S rRNA gene, the enterotypes, and quantity of the gut microbiota among obese children and the control cohort and learned the differences of the gut microbiota during the process of weight reduction in obese children. Results. In the present study, we learned that the gut microbiota composition was significantly different between obese children and the healthy cohort. Next we found that functional changes, including the phosphotransferase system, ATP-binding cassette transporters, flagellar assembly, and bacterial chemotaxis were overrepresented, while glycan biosynthesis and metabolism were underrepresented in case samples. Moreover, we learned that the amount of Bifidobacterium and Lactobacillus increased among the obese children during the process of weight reduction. Conclusion. Our results might enrich the research between gut microbiota and obesity and further provide a clinical basis for therapy for obesity. We recommend that Bifidobacterium and Lactobacillus might be used as indicators of healthy conditions among obese children, as well as a kind of prebiotic and probiotic supplement in the diet to be an auxiliary treatment for obesity.

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Eruption of lymphocyte recovery with atypical lymphocytes mimicking a primary cutaneous T-cell lymphoma: a series of 12 patients

Eruption of lymphocyte recovery (ELR) may occur during bone marrow aplasia after chemotherapies. We reviewed the clinical and pathologic features of 12 patients (male/female: 7/5, median age: 61years) with an atypical ELR histologically mimicking a primary cutaneous T-cell lymphoma (CTCL) such as Sézary Syndrome or CD30+ T-cell lymphoproliferative disorder (LPD). All the patients displayed an erythematous maculopapular eruption on the trunk and the limbs, associated with fever. All but one had received a polychemotherapy for an acute myeloid leukemia (n=10) or an urothelial carcinoma (n=1) before the occurrence of the skin eruption.

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Eps8 expression is significantly lower in p16+ head and neck squamous cell carcinomas (HNSCC) compared to p16− HNSCC

In vitro head and neck cancer studies have demonstrated that epidermal growth factor receptor kinase substrate 8 (Eps8) overexpression contributes to squamous carcinogenesis. Oral squamous cell carcinoma studies have correlated Eps8 expression with metastatic disease and poor prognosis. Head and neck squamous cell carcinoma (HNSCC) studies comparing its expression by anatomic site or in in vivo regional metastases have not been performed. In this study, we compared Eps8 expression in HNSCCs arising in the oral cavity (OCSCC) and oropharynx (OPSCC) along with their corresponding regional lymph nodes (LNs) metastases.

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FGFR1 translocation with concurrent myeloproliferative neoplasm, systemic mastocytosis, and lymphoblastic lymphoma: a case report

FGFR1 translocation may cause myeloid or lymphoid neoplasm but rarely systemic mastocytosis (SM). Conversely, SM is associated with myeloproliferative neoplasm (MPN), but rarely lymphoblastic lymphoma (LBL) or FGFR1 translocation. We report the first case of FGFR1 translocation in a patient with concurrent LBL, MPN, and SM. A 21-year-old male patient presented with diffuse lymphadenopathies and leukocytosis. TdT+/cytoCD3+/CD79aweakly+ LBL was identified in the lymph node. Bone marrow had MPN, SM, and TdT+/CD79a+/cytoCD3weakly+ LBL.

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JAK2-mutated langerhans cell histiocytosis associated with primary myelofibrosis treated with ruxolitinib

The pathogenesis and cellular origin of Langerhans cell histiocytosis (LCH) are debated. Recently, mutations on MAPK and PI3K pathways have been linked to disrupted cell proliferation in LCH. Janus Kinase 2 (JAK2) mutations play the same role in Philadelphia-negative chronic myeloproliferative neoplasms. We describe the case of a patient affected by JAK2-positive Primary Myelofibrosis (PMF) who developed a clonally related LCH while in treatment with Ruxolitinib. JAK-inhibitors are well known to affect function and differentiation of different hematological lineages, including mononuclear phagocytes precursors.

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Universal Screening for Lynch Syndrome in Endometrial Cancers: Frequency of Germline Mutations and Identification of Patients with Lynch-Like Syndrome

Lynch syndrome (LS) is an inherited clinical syndrome characterized by a high risk of colorectal, endometrial (lifetime risk of up to 60%), ovarian and urinary tract cancers. The diagnosis is confirmed by identification of germline mutations in the DNA mismatch repair (MMR) genes MLH1, PMS2, MSH2, MSH6, or EPCAM. In 2015, our institution implemented universal screening of endometrial cancer hysterectomy specimens by MMR immunohistochemistry (IHC) with reflex MLH1 promoter hypermethylation analysis for tumors with loss of MLH1/PMS2 expression.

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Corrigendum to “Graph analysis of EEG resting state functional networks in dyslexic readers” [Clin. Neurophysiol. 127(9) (2016) 3165–3175]

We regret to inform you about a calculation error we recently detected in our published article: Fraga González G, Van der Molen MJW, Žarić G, Bonte M, Tijms J, Blomert L, Stam CJ, Van der Molen MW. Graph analysis of EEG resting state functional networks in dyslexic readers. Clin Neurophysiol. 2016 Sep; 127(9):3165–3175. doi:http://ift.tt/2yYuBal. Epub 2016 Jul 4. PubMed PMID: 27476025. We re-analyzed the data after discovering this error to determine the impact it had on the results.

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Contraction response to muscle percussion: a reappraisal of the mechanism of this bedside test

The contraction response to muscle percussion was first described in 1858 by Schiff who called it "idiomuscular contraction" in the belief that it was of muscular origin. Subsequently, it was noted that this response was diminished in patients with primary myopathic disorders (Babinski and Jarkowski, 1911; Patel and Swami, 1969) and in case of denervation (André-Thomas and de Ajuriaguerra, 1949), prolonged in patients with myotonia (Dejerine, 1914), and retained (Guillain et al., 1916) or even enhanced (Ropper et al., 1991) in Guillain-Barré patients.

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Revisiting interhemispheric imbalance in chronic stroke: a tDCS study

The immense burden of stroke-related disability has led to the development of noninvasive brain stimulation (NIBS) as a possible approach to augment neurorehabilitation of the paretic upper limb (Ackerley et al., 2010). Transcranial direct current stimulation (tDCS) is a polarity-dependent neuromodulatory technique that has demonstrated some benefit to motor function at the chronic stage (>6 months) post stroke, but effect sizes have varied (Jacobson et al., 2012; Kang et al., 2015).

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Frontal infraslow activity marks the motor spasms of anti-LGI1 encephalitis

The clinical and electrographic features of seizures in anti-LGI1 encephalitis are distinct from those seen in other autoimmune encephalitides or non-encephalitic epilepsies. The recognition of unusual lateralized motor spasms, which have come to be known as faciobrachial dystonic seizures (FBDS) (Irani et al., 2011a), has greatly facilitated early clinical diagnosis of the condition. Electrographically, a pattern of unusually frequent subclinical temporal lobe seizures in the absence of interictal spikes has been identified as an independent diagnostic marker (Andrade et al., 2011a,b; Steriade et al., 2016).

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Reply to “The insular cortex and QTc interval in HIV+ and HIV- individuals: Is there an effect of sympathetic nervous system activity?”

The correspondence by Nagai et al. (2017a) raised several points regarding our interpretation of the lateralized effects for QTc interval length on resting functional connectivity (rsFC) of the ventromedial prefrontal cortex (VMPFC) (McIntosh et al., 2017). The authors first contend that if some form of sympathetic inhibition accounts for prolongation of the QT interval in a dog model then a similar mechanism, i.e., parasympathetic arousal, would be expected to correspond with longer QTc interval lengths in our sample of HIV+ and HIV-negative men.

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Resident Research Tips: Surviving and Thriving Within the Peer Review Process

Publications serve an important role in academics, allowing dissemination of protocols and research findings and promulgating further research to enhance patient care. However, the information that is released should be accurate and properly represented. The scientific community requires a quality control measure for research. Peer reviewers serve as one of the main arbiters of this process.

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Adenosine Administration With a Stopcock Technique Delivers Lower-Than-Intended Drug Doses

Adenosine administration with a stopcock is the recommended treatment for pediatric patients with acute supraventricular tachycardia. Recent reports suggest that many infants do not respond to the first dose of adenosine administered. Our aim is to determine whether administration of adenosine with a stopcock delivers lower-than-expected drug doses in patients weighing less than 10 kg, corresponding to weights of infants.

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A Randomized, Double-Blind, Placebo-Controlled Trial of Naproxen With or Without Orphenadrine or Methocarbamol for Acute Low Back Pain

In US emergency departments (EDs), patients with low back pain are often treated with nonsteroidal anti-inflammatory drugs and muscle relaxants. We compare functional outcomes among patients randomized to a 1-week course of naproxen+placebo versus naproxen+orphenadrine or naproxen+methocarbamol.

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Preoxygenation With Flush Rate Oxygen: Comparing the Nonrebreather Mask With the Bag-Valve Mask

Nonrebreather masks and bag-valve masks are used for preoxygenation before emergency intubation. Flush rate oxygen delivered with a nonrebreather mask is noninferior to bag-valve mask oxygen at 15 L/min. We seek to compare the nonrebreather mask with flush rate oxygen to a bag-valve mask with flush rate oxygen (with and without inspiratory assistance) and determine whether the efficacy of bag-valve mask with flush rate oxygen is compromised by a simulated mask leak.

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Fast and binary assay for predicting radiosensitivity based on the nucleoshuttling of ATM protein: development, validation and performances

Our recent approach that predicts adverse tissue reactions after radiotherapy has stressed the role of the nucleoshuttling of the ATM protein. However, although very reliable it requires cellular amplification which protracts process up to some weeks. Here, we proposed a predictive assay based on the quantification of the pATM proteins via ELISA technique that renders much faster our previous approach. Such fast assay elicits the highest statistical performance among the fastest predictive approaches available.

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The bias of professional accomplishment: Another important consideration for ethics in clinical research

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PET-Adjusted Intensity-Modulated Radiotherapy for Locally Advanced Non-small Cell Lung Cancer

We performed a prospective trial using dose-painted IMRT based on pre-treatment PET metrics with concurrent chemotherapy for locally advanced NSCLC. We found that this approach yields high rates of metabolic response on post-treatment PET. Use of a relatively low dose for low-risk tumors and lymph nodes does not seem to compromise local control of those lesions. This approach should be pursued to maximize the therapeutic ratio of radiotherapy in this setting.

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Prognostic Value of c-MET Expression in Patients with Pancreatic Cancer Receiving Adjuvant and Neoadjuvant Chemoradiation Therapy

Chemoradiation therapy improves local control for pancreatic cancer, however, its benefit is lessened by the high metastatic potential of this disease. Biomarkers of distant progression could be used to determine the appropriate sequencing of adjuvant therapies.

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Trends in Cardiac Mortality in Patients with Locally Advanced Non-Small Cell Lung Cancer

The present study describes trends in cardiac specific mortality (CSM) for patients with stage IIIA/ IIIB non-small cell lung cancer (NSCLC) undergoing definitive radiation therapy (RT) between the years of 1988-2012 and comparing CSM between patients undergoing RT to the left lung to those undergoing to the right lung. On multivariate analysis, between 1993-2008, patients with left sided lung cancer had worse CSM than patients with right sided disease.

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Treatment Course Interruption/Delay Due to Weekend Breaks: Acknowledging and Confronting Personal and Professional Biases

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Tumor control and toxicity for common SBRT dose-fractionation regimens in Stage I NSCLC

In this retrospective review of 662 T1-T3 non-small cell lung cancer lesions treated with definitive intent SBRT between 2003-2012 we found that the higher biologically equivalent SBRT dose regimen of 60 Gy in 3 fractions was associated with a statistically significant lower rate of local failure, though also slightly increased (primarily low-grade) chest wall and pulmonary toxicity. Other patterns of failure (lobar, nodal, distant) and overall survival were similar across all SBRT dose regimens.

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“Caught in the act”

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Adalimumab trough levels predict Crohn’s disease clinical course

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iSepsis – Death by Fluid, Part 3

The CLASSIC trial is a exploratory RCT comparing a fluid "restrictive" with a more liberal approach to fluid management in patients with septic shock

EMCrit by Paul Marik.

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A New Approach for Sampling Ordered Parameters in Probabilistic Sensitivity Analysis

Abstract

Background

Probabilistic sensitivity analysis (PSA) in cost-effectiveness analysis involves sampling a large number of realisations of an economic model. For some parameters, we may be uncertain around the true mean values of the variables, but the ordering of the values is known. Typical sampling approaches lack either statistical or clinical validity. For example, sampling using a common number generator results in extreme dependence, and independent sampling can lead to realisations with incorrect ordering.

Methods

We propose a new sampling approach for ordered parameters, the difference method (DM) approach, which samples the parameters of interest via a difference parameter. If the parameters of interest are bounded, it involves transforming the variables so that they are unbounded and then sampling via the difference parameter. We have provided a Microsoft Excel workbook to implement the method. The proposed approach is illustrated with an example sampling ordered parameters for utility and cost.

Results

The DM approach has a number of advantages when comparing with the typical approaches used in practice. It generates PSA samples that have similar summary statistics as the given values in our examples, while maintaining the constraint that one value was greater than another. The method also implies plausible positive correlation between the two ordered variables.

Conclusions

Both clinical and statistical validity should be checked when producing PSA samples. The DM approach should be considered as a solution to potential problems in generating PSA samples for ordered parameters.

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A Computational Method to Quantify Fly Circadian Activity

A method to quantify the main temporal features seen in fly circadian locomotor rhythms is presented. The quantification is achieved by fitting fly activity with a multi-parametric model waveform. The model parameters describe the shape and size of the morning and evening peaks of daily activity.

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VEGF/BMP-2 Loaded Three-Dimensional Model for Enhanced Angiogenic and Odontogenic Potential of Dental Pulp Stem Cells

Abstract

Aim

To investigate the proliferation and differentiation potential of human dental pulp stem cells (DPSCs) in a three-dimensional culture model (TDM) by incorporation of VEGF and BMP-2.

Methodology

TDM was established using fibrin gel (fg) as a soft tissue matrix and demineralized dentine disc (dd) as a hard tissue matrix. DPSCs and vascular endothelial growth factor (VEGF) were encapsulated in fibrin gel (fg-VEGF) and then inserted into bone morphogenetic protein (BMP-2) coated demineralized dentine discs (dd-BMP-2). DPSCs were incubated for 28 days in various fg/dd combinations in the absence or presence of VEGF and BMP-2. Proliferation and morphology of DPSCs in fibrin gel were analysed using MTT and Live&Dead assays. Release profiles of VEGF and BMP-2 from fibrin gel and dentine discs were quantified using ELISA, and the expressions of angiogenic and odontogenic differentiation markers were determined with RT-qPCR analysis. Data were analysed statistically using Wilcoxon signed rank tests, Kruskal-Wallis tests with Mann Whitney U tests and Bonferroni adjustment. The level of significance was set at p<0.05.

Results

DPSCs were able to proliferate and showed interconnected cellular elongations in fibrin gel depending on fibrinogen concentration while monolayer control group showed typical fibroblast-like cell morphology. Encapsulating of VEGF in fibrin gel and BMP-2 in gelatin that was used to coat dentine discs allowed the controlled releases of growth factors, which induced angiogenic and odontogenic gene expressions by DPSCs. Higher expressions of PECAM as an angiogenic factor, and BSP, DMP-1, OCN and CBFA as odontogenic factors were observed in TDM as compared to the other fg/dd combinations and the monolayer control group (p<0.05).

Conclusions

TDM consisting of fibrin gel and dentine matrix allowed cell-cell interactions. TDM was highly effective in delivering both VEGF and BMP-2 that enhanced the angiogenic and odontogenic potential of DPSCs.

This article is protected by copyright. All rights reserved.

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Primary High-Grade Non-Muscle-Invasive Bladder Cancer: High NFκB Expression in Tumor Specimens Distinguishes Patients Who are at Risk for Disease Progression

Abstract

To investigate the potential prognostic role of NFκB expression in primary high-grade non-muscle-invasive bladder cancer. Patients with primary high-grade non-muscle-invasive bladder cancer who received induction and maintenance BCG therapy were retrospectively included. Recurrence and progression were histologically proven. Intensity and extent of immunochemistry were assessed. The final evaluation of the NFκB staining was done by combining intensity and extent as ΄΄product΄΄ and expressing it as ΄΄low NFκΒ expression΄΄ or ΄΄high NFκB expression΄΄. Epidemiological, pathological, clinical parameters and NFκB expression were statistically analyzed for recurrence (REC), progression (PR), recurrence-free survival (RFS) and progression-free survival (PFS). NFκB is significantly associated with disease progression (p < 0,001 in univariate analysis and p = 0,001, Odds Ratio = 14,484, 95% Confidence Interval = 3187-65,821 in multivariate analysis), but not with recurrence. The median value of NFκB expression as ΄΄product΄΄ is significantly higher for the patients with progression in comparison to patients with recurrence only (p = 0,003) and patients without recurrence or progression (p = 0,001). Patients' age is significantly associated (p = 0,001 in univariate analysis and p = 0,003, Odds Ratio = 1273, 95% Confidence Interval = 1086–1492 in multivariate analysis) with disease recurrence. High NFκB expression in primary high-grade non-muscle-invasive bladder cancer, treated with postoperative intravesical BCG immunotherapy, could represent an unfavorable prognostic factor.

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MicroRNA Expression in Laser Micro-dissected Breast Cancer Tissue Samples – a Pilot Study

Abstract

Breast cancer continues to represent a significant public health burden despite outstanding research advances regarding the molecular mechanisms of cancer biology, biomarkers for diagnostics and prognostic and therapeutic management of this disease. The studies of micro RNAs in breast cancer have underlined their potential as biomarkers and therapeutic targets; however most of these studies are still done on largely heterogeneous whole breast tissue samples. In this pilot study we have investigated the expression of four micro RNAs (miR-21, 145, 155, 92) known to be involved in breast cancer, in homogenous cell populations collected by laser capture microdissection from breast tissue section slides. Micro RNA expression was assessed by real time PCR, and associations with clinical and pathological characteristics were also explored. Our results have confirmed previous associations of miR-21 expression with poor prognosis characteristics of breast cancers such as high stage, large and highly proliferative tumors. No statistically significant associations were found with the other micro RNAs investigated, possibly due to the small sample size of our study. Our results also suggest that miR-484 could be a suitable endogenous control for data normalization in breast tissues, these results needing further confirmation by future studies. In summary, our pilot study showed the feasibility of detecting micro RNAs expression in homogenous laser captured microdissected invasive breast cancer samples, and confirmed some of the previously reported associations with poor prognostic characteristics of breast tumors.

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Clinical significance of tryptophan catabolism in Hodgkin lymphoma

Summary

Indoleamine 2,3-dioxygenase 1 (IDO) is an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway. The purpose of the present study was to determine the clinical significance of Trp catabolism in newly-diagnosed Hodgkin Lymphoma (HL) patients. We quantified serum Trp and Kyn in 52 HL patients, and analyzed their associations with different clinical parameters including serum soluble CD30 (sCD30) concentration. IDO expression was evaluated in the patients′ affected lymph nodes. The enrolled patients comprised 22 males and 30 females (age range 15-81, median 45 years), with a 5-year overall survival (OS) of 88.6%. The OS was significantly shorter for patients with a high Kyn/Trp ratio (OS at 5 years, 60.0%-vs-92.2%), for those with stage IV disease, and for those with lymphocytopenia (< 600/mm³ and/or < 8% of the white blood cell [WBC] count). The latter two parameters are components of the international prognostic score for advanced HL. In contrast, there were no significant differences in OS according to age, serum albumin, hemoglobin, sex, WBC count, or serum sCD30 (≥ or < 285.6 ng/mL). Multivariate analysis using the three variables stage, lymphocytopenia and serum Kyn/Trp ratio demonstrated that only the latter significantly affected OS. IDO was produced by macrophages/dendritic cells, but not by HL tumor cells, and IDO levels determined by immunohistochemistry had a significant positive correlation with the serum Kyn/Trp ratio. In conclusion, quantification of serum Kyn and Trp is useful for predicting prognosis of individual HL patients.

This article is protected by copyright. All rights reserved.

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Integrin {alpha}6 variants and colorectal cancer

I read with interest the study by De Archangelis et al1 on the protective role of hemidesmosomes against colitis and colorectal cancer using genetically modified mouse integrin α6 subunit mutant models. I was however surprised to read that, based on their observations with these α6 mutant mice, the authors concluded that the α6β4 integrin can be classified as a tumour suppressor in the colon. Indeed, earlier studies have reported that in carcinomas, α6β4 can be released from hemidesmosomes to become associated with microfilament-associated cell motility adhesomes and, consequently, engage in various signal transduction pathways that contribute to tumour progression.2 3 While it is recognised that the roles of α6β4 may be dependent on the tissue-context as underlined by the authors, it remains increasingly evident that the alternative messenger RNA splicing of the α6 subunit constitutes a key-contributing factor for the definition of the function of...

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Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer

Objective

Extensive molecular heterogeneity of pancreatic ductal adenocarcinoma (PDA), few effective therapies and high mortality make this disease a prime model for advancing development of tailored therapies. The p16-cyclin D-cyclin-dependent kinase 4/6-retinoblastoma (RB) protein (CDK4) pathway, regulator of cell proliferation, is deregulated in PDA. Our aim was to develop a novel personalised treatment strategy for PDA based on targeting CDK4.

Design

Sensitivity to potent CDK4/6 inhibitor PD-0332991 (palbociclib) was correlated to protein and genomic data in 19 primary patient-derived PDA lines to identify biomarkers of response. In vivo efficacy of PD-0332991 and combination therapies was determined in subcutaneous, intrasplenic and orthotopic tumour models derived from genome-sequenced patient specimens and genetically engineered model. Mechanistically, monotherapy and combination therapy were investigated in the context of tumour cell and extracellular matrix (ECM) signalling. Prognostic relevance of companion biomarker, RB protein, was evaluated and validated in independent PDA patient cohorts (>500 specimens).

Results

Subtype-specific in vivo efficacy of PD-0332991-based therapy was for the first time observed at multiple stages of PDA progression: primary tumour growth, recurrence (second-line therapy) and metastatic setting and may potentially be guided by a simple biomarker (RB protein). PD-0332991 significantly disrupted surrounding ECM organisation, leading to increased quiescence, apoptosis, improved chemosensitivity, decreased invasion, metastatic spread and PDA progression in vivo. RB protein is prevalent in primary operable and metastatic PDA and may present a promising predictive biomarker to guide this therapeutic approach.

Conclusion

This study demonstrates the promise of CDK4 inhibition in PDA over standard therapy when applied in a molecular subtype-specific context.

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Enterochromaffin cells in the gut: a distant regulator of brain function?

We read with great interest the recent excellent work by Stevens et al,1 in which the authors showed that zonulin and fatty acid-binding protein 2 have a relationship with the increase in lipopolysaccharide (LPS) and abnormal composition of gut microbiota in patients with anxiety or depression. We appreciate these findings and would like to discuss the role of enterochromaffin cells (ECs) in brain function in this context.

Accumulating evidence has shown that neuropsychiatric diseases are frequently associated with gut microbiota disorders.2 It has been widely recognised that toxins within the human body mainly stem from the gut.3 The opening of intercellular tight junctions in the gut allow many toxins into the bloodstream that then have a deleterious effect on the brain, finally resulting in a series of neuropsychiatric symptoms.3 In their study, Stevens and colleagues suggested that overexpression of the tight junction protein...

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The Presence of ALK Alterations and Clinical Relevance of Crizotinib Treatment in Pediatric Solid Tumors

Abstract

Soft tissue sarcomas (STS) and neuroblastomas (NBL), are childhood malignancies still associated with poor prognoses despite the overall improvement in childhood tumor survival of the past decades. Anaplastic lymphoma kinase (ALK) inhibition is promising new strategy to improve the outcome of these pediatric tumors. Eighteen histologic samples of pediatric STS and 19 NBL patients were analyzed for ALK abnormalities using fluorescent in situ hybridization (FISH) with break-apart probes and immunohistochemistry (IHC). ALK alterations were presented in 20 of the 37 sections. The presence of ALK alteration in NBL samples were detected using IHC in 84,2% of all cases compared to 21,1% FISH positivity. In STS cases the results were less different (IHC 16,7% vs FISH 22,2%). The difference can be explained by the different type of molecular alterations. FISH method detected translocation and amplification, but not the point mutation of ALK gene. IHC confirmed the diagnosis by detecting the expression of ALK protein.After ALK positivity was proven, the effectiveness and safety of the crizotinib therapy was examined in 4 patients (1 alveolar rhabdomyosarcoma (RMA), 1 embryonal rhabdomyosarcoma (RME), 1 inflammatory myofibroblastic tumor (IMT), 1 NBL). We observed continuous remission of the IMT patient, all other cases the inhibitor treatment was not curative.Our findings underline the importance of screening the ALK status parallel with both IHC and FISH. Crizotinib treatment had a long-term effect in ALK positive IMT patients, however itwas only temporary efficient in relapsed, progressive STS and NBL.

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Combination chemotherapy with irinotecan and gemcitabine for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancer: a multicenter phase I/II trial (GOGO-Ov 6)

Abstract

Purpose

To develop a new therapeutic strategy for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancers, we evaluated the feasibility and efficacy of irinotecan and gemcitabine combination chemotherapy.

Methods

Patients with taxane/platinum-resistant/refractory cancer received escalating doses of irinotecan and gemcitabine (level 1: 80 and 800 mg/m², respectively; level 2: 100 and 1000 mg/m²) on days 1 and 8 on a 21-day cycle. Genotyping for UGT1A1*6 and *28 polymorphisms was performed for possible adverse irinotecan sensitivity.

Results

A total of 35 patients were enrolled. The recommended dose was defined as 100 mg/m² irinotecan and 1000 mg/m² gemcitabine (level 2). The observed common grade 3/4 toxicities were neutropenia (60%), anemia (17.1%), diarrhea (8.6%), thrombocytopenia (5.7%) and nausea (5.7%). Groups homozygous for UGT1A1*6 or *28 were associated with grade 3/4 neutropenia and diarrhea. Objective responses were 20%, including one complete response and six partial responses. In 29 patients treated with the recommended dose, the median progression-free survival and overall survival were 3.8 months (95% CI 2.1–6.0 months) and 17.4 months (95% CI 9.9–21.9 months), respectively, while the 1-year survival rate was 58.6%.

Conclusions

Combination chemotherapy with irinotecan and gemcitabine represents a safe and effective treatment combination for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancers.

http://ift.tt/2yUrDSd

Ibrutinib does not prolong the corrected QT interval in healthy subjects: results from a thorough QT study

Abstract

Purpose

Ibrutinib is an orally administered, irreversible Bruton's tyrosine kinase inhibitor for treatment of B-cell malignancy. This study evaluated the effects of single-dose ibrutinib at therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects.

Methods

Part 1 used an open-label, two-period sequential design to assess the safety and pharmacokinetics of single doses of ibrutinib 840 and 1680 mg in eight subjects. Part 2 was a randomized, placebo- and positive (moxifloxacin)-controlled, double-blind, single dose, four-way cross-over study to assess the effect of ibrutinib (840 and 1680 mg) on QT/QTc interval. 64 healthy subjects were planned to be enrolled. Baseline-adjusted QT (QTc) intervals for ibrutinib and moxifloxacin (assay sensitivity) were compared to placebo using linear mixed-effect model. A concentration-QTc analysis was also conducted.

Results

No clinically relevant safety observations were noted in Part 1. During Part 2, one subject experienced Grade 4 ALT/AST elevations with ibrutinib 1680 mg, leading to study termination and limiting the enrollment to 20 subjects. Ibrutinib demonstrated dose-dependent increases in exposure. The upper bounds of the 90% CIs for the mean difference in change from baseline in QTc between ibrutinib and placebo were < 10 ms at all timepoints and at supratherapeutic C _max. Moxifloxacin showed the anticipated QTc effect, confirming assay sensitivity despite the early study termination. Ibrutinib caused a concentration-dependent mild shortening of QTc and mild PR prolongation, but these effects were not considered clinically meaningful.

Conclusions

Therapeutic and supratherapeutic concentrations of ibrutinib do not prolong the QTc interval.

Clinicaltrials.gov

NCT02271438.

http://ift.tt/2hhOC20

Prematurity and perinatal adversity effects hypothalamic-pituitary-adrenal axis reactivity to social evaluative threat in adulthood

Abstract

This study examined the long-term effects of prematurity and perinatal adversity on individual differences in stress-related reactivity and regulation of the HPA axis. A prospective sample of 155 infants born preterm and healthy (n = 20), medical illness (n = 48), neurological illness (n = 26), and small for gestational age (n = 24) and full-term (n = 37) were recruited between 1985 and 1989. At age 23 years, multiple saliva samples were collected before and after participation in the Trier Social Stress Test and later assayed for cortisol. Results reveal that at age 23 years, infants born premature with neurological complications showed higher cortisol reactivity to social evaluative threat compared to either their full-term, small for gestation age, medically ill, or healthy preterm peers. Findings are discussed in terms of implications for contemporary theories that propose effects of early adversity on biological sensitivities and susceptibilities, which translate experience into developmental outcomes related to poor health and risk for disease.

http://ift.tt/2xuxjk9

Rapid facial reactions in response to happy and angry expressions in 7-month-old infants

Abstract

Humans rapidly and spontaneously activate muscles in the face when viewing emotional facial expressions in others. These rapid facial reactions (RFRs) are thought to reflect low-level, bottom-up processes, and are theorized to assist an observer to experience and share the affect of another individual. It has been assumed that RFRs are present from birth; however to date, no study has investigated this response in children younger than 3 years of age. In the present study, we used facial electromyography (EMG) to measure corrugator supercilii (brow) and zygomaticus major (cheek) muscle activity in 7-month-old infants while they viewed happy and angry facial expressions. The results showed that 7-month olds exhibited greater zygomaticus activity in response to happy expressions than angry expressions, however, we found no evidence of differential corrugator muscle activity.

http://ift.tt/2zTP5zb

Comment on: “Non-Small-Cell Lung Cancer (NSCLC) Harboring ALK Translocations: Clinical Characteristics and Management in a Real-Life Setting: a French Retrospective Analysis (GFPC 02–14 Study)”

http://ift.tt/2hgNziD

Author’s Reply to Arnaud Uguen: “Non-Small-Cell Lung Cancer (NSCLC) Harboring ALK Translocations: Clinical Characteristics and Management in a Real-Life Setting: a French Retrospective Analysis (GFPC 02–14 Study)”

http://ift.tt/2hhmQ5K

Emerging Technologies in Flow Diverters and Stents for Cerebrovascular Diseases

Abstract

Purpose of Review

Stents and flow diverters have revolutionized the treatment of cerebrovascular disease. Guglielmi coils, flexible microcatheters, and first-generation intracranial stents, such as Neuroform (Stryker Neurovascular) and Enterprise stents (Codman/DePuy-Synthes), have paved the way for the development of the Pipeline Embolization Device (PED) (ev3/Covidien/Medtronic) and other endovascular approaches.

Recent Findings

This review discusses the historical development of flow diverter technologies from the PED to similar devices, such as the Surpass stent (Stryker Neurovascular), the Flow-Redirection Endoluminal Device (FRED; MicroVention, Inc.), the SILK stent (Balt Extrusion), and the p64 Flow Modulation Device (Phenox). In addition, the potential use of drug-eluting stents and various bioresorbable scaffolds (e.g., poly-l-lactic acid, magnesium), new developments in stent material (e.g., thin-film nitinol), design (e.g., biocompatible polymers, embedded microcircuitry, flow models), and potential applications for flow diverters will be considered.

Summary

Endovascular treatment of cerebrovascular disease is rapidly advancing via continued development of new technology.

http://ift.tt/2xu0oMP

Cancers, Vol. 9, Pages 148: Novel Molecular Challenges in Targeting Anaplastic Lymphoma Kinase in ALK-Expressing Human Cancers

Cancers, Vol. 9, Pages 148: Novel Molecular Challenges in Targeting Anaplastic Lymphoma Kinase in ALK-Expressing Human Cancers

Cancers doi: 10.3390/cancers9110148

Authors: Abdulraheem Alshareef

Targeting anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase receptor initially identified as a potent oncogenic driver in anaplastic large-cell lymphoma (ALCL) in the form of nucleophosmin (NPM)-ALK fusion protein, using tyrosine kinase inhibitors has shown to be a promising therapeutic approach for ALK-expressing tumors. However, clinical resistance to ALK inhibitors invariably occurs, and the molecular mechanisms are incompletely understood. Recent studies have clearly shown that clinical resistance to ALK inhibitors is a multifactorial and complex mechanism. While few of the mechanisms of clinical resistance to ALK inhibitors such as gene mutation are well known, there are others that are not well covered. In this review, the molecular mechanisms of cancer stem cells in mediating resistance to ALK inhibitors as well as the current understanding of the molecular challenges in targeting ALK in ALK-expressing human cancers will be discussed.

http://ift.tt/2zN9oNF

Parents' views on their children's use of eye drops and willingness to accept a new sustained-release subconjunctival injection

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Aneurysmal bone cysts and pathologic fracture associated with supernumerary ring chromosome 6 in two unrelated patients

Small supernumerary ring chromosome 6 (sSRC[6]) is a rare chromosomal abnormality characterized by a broad clinical phenotype. The spectrum of this disorder can range from phenotypically normal to severe developmental delay and congenital anomalies. We describe two unrelated patients with small SRCs derived from chromosome 6 with a novel bone phenotype. Both patients presented with a complex bone disorder characterized by severe osteopenia, pathologic fractures, and cyst-like lesions within the bone. Imaging revealed decreased bone mineral density, mutiple multiloculated cysts and cortical thinning. Lesion pathology in both patients demonstrated a bland cyst wall with woven dysplastic appearing bone entrapped within it. In patient 1, array comparative genomic hybridization (CGH) detected a tandem duplication of region 6p12.3 to 6q12 per marker chromosome. Cytogenetic analysis further revealed a complex patient of mosaicism with some cell lines displaying either one or two copies of the marker indicative of both tetrasomy and hexasomy of this region. Patient 2 was mosaic for a sSRC that encompassed a 26.8 Mb gain from 6p21.2 to 6q12. We performed an in-depth clinical analysis of a phenotype not previously observed in sSRC(6) patients and discuss the potential influence of genes located within this region on the skeletal presentation observed.

http://ift.tt/2llgOFu

Fatal acute retropharyngeal hemorrhage in neurofibromatosis type 1

Abstract

We report the sudden death of a woman with neurofibromatosis type 1 (NF1). The decedent developed acute respiratory distress and died rapidly despite an emergent cricothyroidotomy. An autopsy with postmortem CT scan was performed to determine the cause of the fatal respiratory collapse and to determine if death was related to neurofibromatosis. Postmortem examination revealed the classical external hallmarks of neurofibromatosis, including innumerable cutaneous neurofibromas. In addition, there was a massive retropharyngeal hematoma with fatal extrinsic compression of the airway. On macroscopic examination A localized 3 cm diameter tumor nodule was found in the soft tissues of the neck. Histologic examination of the nodule revealed a neurofibroma. In addition, histologic sections of the hematoma and surrounding soft tissues revealed plexiform neurofibroma with infiltration of the walls of small blood vessels and of the right vertebral artery. The fatal retropharyngeal hemorrhage was caused by diffuse infiltration of the blood vessels of the neck by plexiform neurofibroma. We concluded that the underlying cause of death was NF1. This case underscores the protean nature of neurofibroma, particularly when diffuse interstitial hemorrhage is present. Infiltration of soft tissues by neurofibroma may only be detectable on histologic examination.

http://ift.tt/2lmtfRI

Ringing up about breastfeeding: A random controlled trial exploring early telephone peer support for breastfeeding (RUBY) – Primary outcomes

Publication date: October 2017
Source:Women and Birth, Volume 30, Supplement 1
Author(s): Della Forster, Fiona McLardie-Hore, Helen McLachlan, Mary-Ann Davey, Lisa H. Amir, Lisa Gold, Kate Mortensen, Anita M. Moorhead, Heather Grimes, Touran Shaifei




http://ift.tt/2xv6BrJ

Private midwives and collaboration: What are their experiences?

Publication date: October 2017
Source:Women and Birth, Volume 30, Supplement 1
Author(s): Rachele Meredith, Caroline S.E. Homer, Christine Catling




http://ift.tt/2zXjcFN

Australia's New Perinatal Mental Health Guidelines: A sneak peak into what's new and the implications for practice

Publication date: October 2017
Source:Women and Birth, Volume 30, Supplement 1
Author(s): Nicole Highet, Jan Taylor




http://ift.tt/2xuQMBq

Midwives knowledge and understanding of vasa praevia: A qualitative descriptive study

Publication date: October 2017
Source:Women and Birth, Volume 30, Supplement 1
Author(s): Nasrin Javid, Jon Hyett, Caroline S.E. Homer




http://ift.tt/2zVTkKm

The Perfect Storm of Trauma: The experiences of women who have experienced birth trauma and subsequently accessed residential parenting services in Australia

Publication date: October 2017
Source:Women and Birth, Volume 30, Supplement 1
Author(s): Holly Priddis, Hannah Dahlen, Hazel Keedle




http://ift.tt/2xv6sVd

Exploring the use of Virtual Reality technology in neonatal resuscitation simulation for midwifery students

Publication date: October 2017
Source:Women and Birth, Volume 30, Supplement 1
Author(s): Jessica Williams, Donovan Jones, Lyn Ebert, Craig Williams




http://ift.tt/2zVTeT0

Promoting early expression of breast milk in mothers of preterm infants in a Neonatal Unit: A best practice implementation project

Publication date: October 2017
Source:Women and Birth, Volume 30, Supplement 1
Author(s): Louise Goodchild, L. Hussey, A. McPhee, L. Lizarondo, J. Gillis, C. Collins




http://ift.tt/2xv6pZx

The birth unit practice development project

Publication date: October 2017
Source:Women and Birth, Volume 30, Supplement 1
Author(s): Sarah Winter, Louise Luscri, Maralyn Foureur




http://ift.tt/2zWklO2

The Maternity Care Classification System – A validated system for classifying models of care

Publication date: October 2017
Source:Women and Birth, Volume 30, Supplement 1
Author(s): Natasha Donnolley, Georgina Chambers, Kerryn Butler-Henderson, Michael Chapman, Elizabeth Sullivan




http://ift.tt/2xuNKgF

Hypertension in pregnancy: Gaining insight into women's mental health and birth experience 6–12 months postpartum

Publication date: October 2017
Source:Women and Birth, Volume 30, Supplement 1
Author(s): Lynne M. Roberts, Samuel B. Harvey, Caroline S.E. Homer, Gregory K. Davis




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Aims and scope

Publication date: October 2017
Source:Women and Birth, Volume 30, Supplement 1





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The politics of midwifery practice: The quest to extend the boundaries by advocating for women and midwifery through political engagement

Publication date: October 2017
Source:Women and Birth, Volume 30, Supplement 1
Author(s): Paula Medway, Annabel Digance




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Is merely surviving childbirth enough?: The importance of respectful maternity care

Publication date: October 2017
Source:Women and Birth, Volume 30, Supplement 1
Author(s): Frances Boothroyd




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From ‘homebirth sceptics’ to ‘homebirth champions’: The influence of Australian publicly-funded homebirth programs on care provider's attitudes

Publication date: October 2017
Source:Women and Birth, Volume 30, Supplement 1
Author(s): Rebecca Coddington, Caroline S.E. Homer, Christine Catling




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“This poor woman, it's her first birth and this is her experience. And I’m a part of it!” Reconciling advocacy in the face of disrespectful maternity care

Publication date: October 2017
Source:Women and Birth, Volume 30, Supplement 1
Author(s): Izabella McFarlane




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The journey from pain to power: A meta-ethnography on women's experiences of vaginal birth after caesarean

Publication date: October 2017
Source:Women and Birth, Volume 30, Supplement 1
Author(s): Hazel Keedle, Virginia Schmied, Elaine Burns, Hannah Dahlen




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Extending the boundaries of midwifery through collaborative autonomy

Publication date: October 2017
Source:Women and Birth, Volume 30, Supplement 1
Author(s): Jaunita Landéesse




http://ift.tt/2xuNpup

Implementing the evidence: Intranasal and subcutaneous fentanyl for labour analgesia

Publication date: October 2017
Source:Women and Birth, Volume 30, Supplement 1
Author(s): Julie Fleet, Ingrid Belan, Meril Jones, Allan Cyna




http://ift.tt/2zUR0TY

Racism in practice—A student's perspective

Publication date: October 2017
Source:Women and Birth, Volume 30, Supplement 1
Author(s): Stephanie Archibald




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From the Ground Up: Creating spaces for breastfeeding in the community

Publication date: October 2017
Source:Women and Birth, Volume 30, Supplement 1
Author(s): Virginia Schmied, Elaine Burns, Athena Sheehan




http://ift.tt/2zW7fAg

Dysfunction of GABAergic neurons in the parafacial zone mediates sleep disturbances in a streptozotocin-induced rat model of sporadic Alzheimer’s disease

Abstract

Sleep disturbances are prevalent among patients with Alzheimer's disease (AD) and often precede the onset and progression of dementia. However, there are no reliable animal models for investigating sleep disturbances in patients with sporadic AD (sAD), which accounts for more than 90% of all AD cases. In the present study, we characterize the sleep/wake cycles and explore a potential mechanism underlying sleep disturbance in a rat model of sAD induced via intracerebroventricular (icv) injection of streptozotocin (STZ). STZ-icv rats exhibited progressive decreases in slow wave sleep (SWS) during the light phase and throughout the light/dark cycle beginning from 7 days after STZ-icv. Additionally, increased wakefulness and decreased rapid-eye-movement (REM) and non-REM (NREM) sleep were observed from 14 days after STZ-icv. Beginning on day 7, STZ-icv rats exhibited significant decreases in delta (0.5–4.0 Hz) power accompanied by increased power in the beta (12–30 Hz) and low gamma bands (30–50 Hz) during NREM sleep, resembling deficits in sleep quality observed in patients with AD. Immunohistochemical staining revealed a significant reduction in the ratio of c-Fos-positive GABAergic neurons in the parafacial zone (PZ) beginning from day 7 after STZ-icv. These results suggest that the STZ-icv rat model is useful for evaluating sleep disturbances associated with AD, and implicate the dysregulation of GABAergic neuronal activity in the PZ is associated with sleep disturbance induced by STZ.

http://ift.tt/2zMSWgH

Reirradiation of Skull Base Tumors With Advanced Highly Conformal Techniques

Abstract

Purpose of Review

Skull base reirradiation is challenging due to complex anatomy, enrichment of treatment-resistant clonogens, and increased risk of severe treatment complications. Without local therapy, early mortality is certain and tumor progression can result in debilitating symptoms. Modern radiotherapy advancements, such as image-guided radiation therapy (IGRT), intensity-modulated radiation therapy (IMRT), particle therapy, and stereotactic radiation therapy (SRT), are attractive for skull base reirradiation.

Recent Findings

Although limited by their retrospective nature and heterogeneous patient populations, several studies have demonstrated that reirradiation with these highly conformal techniques is feasible. Compared to IMRT or particle therapy reirradiation, SRT reirradiation appears promising with lower toxicity and increased convenience.

Summary

Here, we provide thorough explanations for each technology and summarize the most relevant and recent studies, with particular attention to efficacy and toxicity. Skull base reirradiation using these extremely conformal therapy techniques requires meticulous treatment planning and should be delivered by experienced teams.

http://ift.tt/2zM6fhk

Treatment for Malignant Pheochromocytomas and Paragangliomas: 5 Years of Progress

Abstract

Purpose of Review

The purpose of this manuscript is to review the progress in the field of therapeutics for malignant pheochromocytomas and sympathetic paraganglioma (MPPG) over the past 5 years.

Recent Findings

The manuscript will describe the clinical predictors of survivorship and their influence on the first TNM staging classification for pheochromocytomas and sympathetic paragangliomas, the treatment of hormonal complications, and the rationale that supports the resection of the primary tumor and metastases in patients with otherwise incurable disease. Therapeutic options for patients with bone metastasis to the spine will be presented. The manuscript will also review chemotherapy and propose a maintenance regimen with dacarbazine for patients initially treated with cyclophosphamide, vincristine, and dacarbazine. Finally, the manuscript will review preliminary results of several phase 2 clinical trials of novel radiopharmaceutical agents and tyrosine kinase inhibitors.

Summary

MPPGs are very rare neuroendocrine tumors. MPPGs are usually characterized by a large tumor burden, excessive secretion of catecholamines, and decreased overall survival. Recent discoveries have enhanced our knowledge of the pathogenesis and phenotypes of MPPG. This knowledge is leading to a better understanding of the indications and limitations of the currently available localized and systemic therapies as well as the development of phase 2 clinical trials for novel medications.

http://ift.tt/2hi4mSy

Relationships of depressive behavior and sertraline treatment with walking speed and activity in older female nonhuman primates

Abstract

Depression is the most common mental health problem in aging persons and is a leading risk factor for physical disability, especially in women. Though antidepressant drugs such as serotonin reuptake inhibitors (SSRI) are commonly prescribed, epidemiological evidence reveals mixed effects of long-term antidepressant use on physical function and activity, possibly depending on depressive status. The purpose of this preclinical trial was to determine the relationships of depressive behavior and the potential for an SSRI treatment to modulate walking speed and activity patterns in older adult female cynomolgus monkeys (Macaca fascicularis). We evaluated the effects of depression and a commonly prescribed SSRI, sertraline HCl (20 mg/kg/day p.o.), on (a) walking speed, (b) accelerometry-derived activity (counts) and sedentariness (daytime 60-s sedentary epochs), and (c) observed locomotor and sedentary behaviors (% time) in adult female depressed and nondepressed monkeys (n = 42; 17.2 ± 1.8 years) during an 18 month pre-treatment phase and an 18 month treatment phase using a longitudinal, stratified placebo–control study design. Monkeys that were depressed prior to treatment (19/42) subsequently had slower walking speeds (F _D [1, 38] = 4.14; p ≤ 0.05) and tended to be more sedentary during the daytime (F _D [1, 38] = 3.63; p ≤ 0.06). Sertraline did not affect depressive behaviors, walking speed, accelerometry-derived physical activity or sedentariness, or time observed in total locomotor or sedentary behavior (all p > 0.10). This study provides the first experimental demonstration of relationships between nonhuman primate behavioral depression and walking speed, activity, and sedentariness and provides evidence for a lack of an effect of SSRI treatment on these phenotypes.

http://ift.tt/2yYRmv0

A Randomized Phase 3 Study Evaluating the Efficacy of Single-dose NEPA, a Fixed Antiemetic Combination of Netupitant and Palonosetron, Versus an Aprepitant Regimen for Prevention of Chemotherapy-induced Nausea and Vomiting (CINV) in Patients Receiving Highly Emetogenic Chemotherapy (HEC)

Abstract

Background

Co-administration of multiple antiemetics that inhibit several molecular pathways involved in emesis is required to optimize CINV control in patients receiving highly emetogenic chemotherapy (HEC). NEPA, a fixed combination of a highly selective NK1 receptor antagonist (RA), netupitant (300 mg), and the pharmacologically distinct 5-HT3RA, palonosetron (PALO 0.50 mg), has shown superior CINV prevention compared to PALO in cisplatin and anthracycline/cyclophosphamide-based settings. This study is the first head-to-head comparison of NEPA versus an aprepitant (APR)/granisetron (GRAN) regimen.

Patients and methods

This randomized, double-blind Phase 3 study conducted in Asia was designed with the primary objective to demonstrate non-inferiority of a single oral dose of NEPA compared with a 3-day oral APR/GRAN regimen in chemotherapy-naïve patients receiving cisplatin-based HEC. All patients also received oral dexamethasone (DEX) on days 1-4. The primary efficacy endpoint was complete response (CR: no emesis/no rescue medication) during the overall (0-120 h) phase. Non-inferiority was defined as a lower 95% CI greater than the non-inferiority margin set at -10%. Secondary efficacy endpoints included no emesis, no rescue medication, and no significant nausea (NSN).

Results

Treatment groups were comparable for the 828 patients analyzed: predominantly male (71%); mean age 54.5 years; ECOG 0-1 (98%); lung cancer (58%). NEPA demonstrated non-inferiority to APR/GRAN for overall CR [NEPA 73.8% vs APR/GRAN 72.4%, 95%CI (-4.5%, 7.5%)]. No emesis [NEPA 75.0% vs APR/GRAN 74.0%, 95%CI (-4.8%, 6.9%)] and NSN rates [NEPA 75.7% vs APR/GRAN 70.4%, 95%CI (-0.6%, 11.4%)] were similar between groups, but significantly more NEPA patients did not take rescue medication [NEPA 96.6% vs APR/GRAN 93.5%, 95%CI (0.2%, 6.1%)]. NEPA was well tolerated with a similar safety profile to APR/GRAN.

Conclusions

In this first study comparing NK1RA regimens and DEX, NEPA administered only on day 1 was non-inferior to a 3-day oral APR/GRAN regimen in preventing CINV associated with HEC.

http://ift.tt/2yYg9z3

Safety and efficacy of alternating treatment with EP2006, a filgrastim biosimilar, and reference filgrastim: a phase 3, randomised, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy

Abstract

Background

In 2015, the biosimilar filgrastim EP2006 became the first biosimilar approved by the US Food and Drug Administration (FDA) for commercial use in the United States, marketed as Zarxio®. This phase 3 randomised, double-blind registration study in patients with breast cancer receiving (neo)adjuvant myelosuppressive chemotherapy (TAC; docetaxel+doxorubicin+cyclophosphamide) compares reference filgrastim, Neupogen^®, with two groups receiving alternating treatment with reference and biosimilar every other cycle.

Patients and methods

A total of 218 patients receiving 5 µg/kg/day filgrastim over six chemotherapy cycles were randomised 1:1:1:1 into four arms. Two arms received only one product, biosimilar or reference (unswitched), and two arms (switched) received alternating treatments every other cycle (biosimilar then reference or vice versa over six cycles). Since the switch occurred from Cycle 2 onwards, this analysis compared pooled switched groups to the unswitched reference group for efficacy during Cycles 2─6. Safety was also assessed. Non-inferiority in febrile neutropenia (FN) rates between groups for Cycles 2─6 was shown if 95% confidence intervals (CIs) were within a pre-defined margin of –15%.

Results

A total of 109 patients switched treatment, and 52 patients received reference in all cycles. Baseline characteristics were similar between groups. The incidence of FN was 0% (reference) versus 3.4% (n=3, switched) across Cycles 2–6, with a difference of –3.4% (95% CI: –9.65–4.96), showing non-inferiority. Infections occurred in 9.3% (switched) versus 9.9% (reference). Hospitalisation due to FN was low (one patient in Cycle 6; switched). Adverse events related to filgrastim were reported in 42.1% (switched) versus 39.2% (reference) (all cycles). Musculoskeletal/connective tissue disorders related to filgrastim occurred in 35.5% (switched) versus 39.2% (reference) (all cycles), including bone pain (30.8% versus 33.3%). No neutralising antibodies were detected.

Conclusions

There were no clinically meaningful results regarding efficacy, safety or immunogenicity when switching from reference to biosimilar filgrastim/EP2006, or vice versa.

http://ift.tt/2yVHUGJ

Characterization of male breast cancer: Results of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program

Abstract

Background

Male breast cancer (BC) is rare, managed by extrapolation from female BC. The International Male BC Program aims to better characterize and manage this disease. We report the results of part 1, a retrospective-joint-analysis of cases diagnosed during a 20-year-period.

Methods

Patients with follow-up and tumor samples, treated between 1990-2010, in 93 centers/nine countries. Samples were centrally analyzed in three labs (UK, NL, US).

Results

Of 1822 patients enrolled, 1483 were analyzed; 63.5% were diagnosed between 2001-2010, 57 (5.1%) had metastatic disease (M1). Median age at diagnosis: 68.4 years. Of 1054 M0 cases, 56.2% were node-negative (N0) and 48.5% had T1 tumors; 4% had breast conserving surgery (BCS), 18% sentinel lymph-node biopsy; half received adjuvant radiotherapy; 29.8% (neo)adjuvant chemotherapy and 76.8% adjuvant endocrine therapy (ET), mostly tamoxifen (88.4%). Per central pathology, for M0 tumors: 84.8% ductal invasive carcinomas, 51.5% grade 2; 99.3% ER-positive; 81.9% PR-positive; 96.9% AR-positive (ER, PgR or AR Allred score ≥3); 61.1% Ki67 expression low (<14% positive cells); using IHC surrogates, 41.9% were Luminal-A-like, 48.6% Luminal-B-like/HER-2-negative, 8.7% HER-2-positive, 0.3% triple negative. Median follow-up: 8.2 years (0·0-23·8) for all, 7.2 years (0·0 -23·2), for M0, 2.6 years (0·0-12·7) for M1 patients. A significant improvement over time was observed in age-corrected-breast-cancer-mortality. Breast-cancer-specific-mortality was higher for men <50 years. Better OS and RFS were observed for highly-ER + (p = 0·001), highly-PR + (p = 0·002), highly-AR+ disease (p = 0·019). There was no association between OS/RFS and HER-2 status, Ki67, IHC subtypes nor grade.

Conclusions

Male BC is usually ER, PR, and AR positive, Luminal B-like/HER2-negative. 56% patients had T1 tumors but only 4% had BCS. ER was highly positive in > 90% of cases but only 77% received adjuvant ET. ER, PR, and AR were associated with OS and RFS, while grade, Ki67, and IHC surrogates were not. Significant improvement in survival over time was observed.

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Virulence genes fliC, toxA and phzS are common among Pseudomonas aeruginosa isolates from diabetic foot infections

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http://ift.tt/2iHhd4m

Degradation of edible oil during deep-frying process by electron spin resonance spectroscopy and physicochemical appreciation

Abstract

During frying process of edible oil, lipid oxidation occurs, which is a complex process and involves free radical chain reactions. The impacts of oil with different fatty acid composition on free radicals were evaluated. An ESR study was performed to identify and quantify the formed radicals, along with the assessment of physicochemical parameters including peroxide value, oxidative stability, fatty acid composition and volatile profile. Results showed an increase of formed free radicals in frying oils over frying time. Besides, frying oils with higher content of unsaturated fatty acids were more prone to be oxidized, as well as physicochemical parameters evidencing this phenomenon. Volatile compounds produced by β-scission homolytic cleavage of peroxide group during thermal oxidation in frying oils were detected by GC-MS/MS. Results implied major aldehyde volatile compounds were derived from hydroperoxide and oil with higher proportions of unsaturated fatty acids are more likely to produce volatile oxidation products.

http://ift.tt/2yRIIvX

Using short-wave infrared radiation to improve aqueous enzymatic extraction of peanut oil: Evaluation of peanut cotyledon microstructure and oil quality

Abstract

In this study, the effects of short-wave infrared radiation (SIR) on enzyme-assisted aqueous extraction process (EAEP) of peanut oil (PO) were investigated, including peanuts cotyledon cells mircrostructure and yield as well as quality of extracted PO. GC-flash electronic nose (EN) combined with principal components analysis (PCA) was applied to select conditions for SIR process. The appropriate roasting condition based on the overall flavor was determined as 150 °C for 55 min. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to investigate the effects of SIR on cotyledon microstructure. The results demonstrated that SIR damaged the cell microstructure and oil body membrane, and the extraction of oil was facilitated. Accordingly, the oil yield increased significantly by 8.74% compared to that of the control (p < 0.05). Further analysis on the quality properties of PO revealed that the content of polyphenols of oil extracted from SIR roasted peanuts (2.79 ± 0.05 mg GAE/kg) was 62.21% higher than that from the control. It was in consistent with the significantly enhanced oxidation stability of oil in the present study (p < 0.05). Furthermore, the variety and relative content of volatile compounds which contributed to a better overall flavor were greatly increased.

Practical applications: SIR as a mild and efficient roasting method could enhance the oil extraction yield in EAEP and improve the oxidation stability of the extracted oil. With the appropriate pre-roasting of peanuts by SIR, the overall flavor of EAEP extracted peanut oil was improved. Its volatiles pattern was close to that of the commercial hot-pressed PO. It was confirmed that SIR is a novel choice for roasting processing, as well as a potential and available pre-roasting method of peanuts to improve the EAEP technology.

http://ift.tt/2z0CI6t

The expression of APE1 in triple-negative breast cancer and its effect on drug sensitivity of olaparib.

Related Articles

The expression of APE1 in triple-negative breast cancer and its effect on drug sensitivity of olaparib.

Tumour Biol. 2017 Oct;39(10):1010428317713390

Authors: Chen T, Liu C, Lu H, Yin M, Shao C, Hu X, Wu J, Wang Y

Abstract
Triple-negative breast cancer is a kind of breast cancer with poor prognosis and special biological behavior, which lacked endocrine therapy and targeted therapy. We investigate the effect of human APE1 (apurinic/apyrimidyl endonuclease 1), a rate-limiting enzyme of base excision repair, on the prognosis in triple-negative breast cancer and drug sensitivity of olaparib. The expression of APE1 was detected by immunohistochemistry in the triple-negative breast cancer tissues and its effect on survival of triple-negative breast cancer patients was followed. To find whether APE1 effect the drug sensitivity in triple-negative breast cancer cells, the APE1-knockout HCC1937 cell line (triple-negative breast cancer cell line) was established by CRISPR/Cas9 system. Then, we use the wild-type and knockout one to test the drug sensitivity of olaparib. The expression of APE1 in triple-negative breast cancer tissues was significantly higher than that in the adjacent tissues (85.6% vs 14.4%) and its expression was related to tumor size (p < 0.05). We also found that it is an independent prognostic factor in patients with triple-negative breast cancer (overall survival, p = 0.01). In vitro assay, the half maximal inhibitory concentration of olaparib in HCC1937-APE1-KO was significantly increased (17.22 vs 91.85 μM) compared to the wild type. The growth curve showed that olaparib had a stronger lethality on HCC1937 compared to HCC1937- APE1-KO (p < 0.05 on day 3). HCC1937 resulted in more mitotic G2/M arrest and increased apoptosis rate after treatment with 40 μM of olaparib, while HCC1937-APE1-KO did not change significantly. When HCC1937 was treated with different concentrations of olaparib, it was found that APE1 expression decreased more significantly at 15 μM of olaparib was. In HCC1937-APE1-KO, the expression of endogenous poly (ADP-ribose) polymerase 1 was also less than that of HCC1937. These results suggested that the expression of APE1 was an important basis for the maintenance of poly (ADP-ribose) polymerase 1, and the deletion of APE1 may be related to the resistance of olaparib.

PMID: 29064327 [PubMed - indexed for MEDLINE]

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Looking for the best immune-checkpoint inhibitor in pre-treated NSCLC patients: An indirect comparison between nivolumab, pembrolizumab, and atezolizumab

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Safety, Tolerability and Pharmacokinetics of L-Ornithine Phenylacetate in Patients with Acute Liver Injury/Failure and Hyperammonemia

Abstract

Cerebral edema remains a significant cause of morbidity and mortality in patients with acute liver failure (ALF) and has been linked to elevated blood ammonia levels. L-ornithine phenylacetate (OPA) may decrease ammonia by promoting its renal excretion as phenylacetylglutamine (PAGN), decreasing the risk of cerebral edema. We evaluated the safety, tolerability, and pharmacokinetics of OPA in patients with ALF and acute liver injury (ALI), including those with renal failure. Forty-seven patients with ALI/ALF and ammonia ≥60µM were enrolled. Patients received OPA in a dose escalation scheme from 3.3g/24h to 10g/24h; 15 patients received 20g/24h throughout the infusion for up to 120h. Plasma phenylacetate concentrations [PA] were uniformly below-target (<75µg/ml) in those receiving 3.3g/24h (median[IQR] 5.0[5.0]µg/ml), and increased to target levels in all but one who received 20g/24h (150[100]µg/ml). Plasma [PAGN] increased, and conversion of PA to PAGN became saturated, with increasing OPA dose. Urinary PAGN clearance and creatinine clearance were linearly related (r=0.831, P<0.0001). Mean ammonia concentrations based on the area-under-the-curve decreased to a greater extent in patients who received 20g/24h OPA compared to those who received the 3.3 or 6.7g/24h maximal dose (P=0.046 and 0.022, respectively). Of the reported serious adverse events (AEs) including 11 deaths, none were attributable to study medication. The only non-serious AEs possibly related to study drug were headache and nausea/vomiting. Conclusions. OPA was well-tolerated in patients with ALI/ALF, and no safety signals were identified. Target [PA] was achieved at infusion rates of 20g/24h, leading to ammonia excretion in urine as PAGN in proportion to renal function. Randomized, controlled studies of high-dose OPA are needed to determine its utility as an ammonia-scavenging agent in patients with ALF. This article is protected by copyright. All rights reserved.

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Hepatitis B reactivation in chronic hepatitis C patients treated with interferon or pan-oral direct-acting antivirals

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Intracameral ketorolac concentration at the beginning and end of cataract surgery following preoperative topical ketorolac administration

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Transcription factor YY1 can control AID-mediated Mutagenesis in mice

Abstract

Activation-induced cytidine deminase (AID) is crucial for controlling the immunoglobulin (Ig) diversification processes of somatic hypermutation (SHM) and class switch recombination (CSR). AID initiates these processes by deamination of cytosine, ultimately resulting in mutations or double strand DNA breaks needed for SHM and CSR. Levels of AID control mutation rates, and off-target non-Ig gene mutations can contribute to lymphomagenesis. Therefore, factors that control AID levels in the nucleus can regulate SHM and CSR, and may contribute to disease. We previously showed that transcription factor YY1 can regulate the level of AID in the nucleus and Ig CSR. Therefore, we hypothesized that conditional knock-out of YY1 would lead to reduction in AID localization at the Ig locus, and reduced AID-mediated mutations. Using mice that overexpress AID (IgκAID yy1^f/f) or that express normal AID levels (yy1^f/f), we found that conditional knock-out of YY1 results in reduced AID nuclear levels, reduced localization of AID to the Sμ switch region, and reduced AID-mediated mutations. We find that the mechanism of YY1 control of AID nuclear accumulation is likely due to YY1-AID physical interaction which blocks AID ubiquitination.

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