Medicine by Alexandros G.Sfakianakis: 12/15/17

Παρασκευή 15 Δεκεμβρίου 2017

Interference of action perception on action production increases across the adult life span

Abstract

Action perception and action production are assumed to be based on an internal simulation process that involves the sensorimotor system. This system undergoes changes across the life span and is assumed to become less precise with age. In the current study, we investigated how increasing age affects the magnitude of interference in action production during simultaneous action perception. In a task adapted from Brass et al. (Brain Cogn 44(2):124–143, 2000), we asked participants (aged 20–80 years) to respond to a visually presented finger movement and/or symbolic cue by executing a previously defined finger movement. Action production was assessed via participants' reaction times. Results show that participants were slower in trials in which they were asked to ignore an incongruent finger movement compared to trials in which they had to ignore an incongruent symbolic cue. Moreover, advancing age was shown to accentuate this effect. We suggest that the internal simulation of the action becomes less precise with age making the sensorimotor system more susceptible to perturbations such as the interference of a concurrent action perception.

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Human c-SRC kinase (CSK) overexpression makes T cells dummy

Abstract

Adoptive cell therapy with T-cell receptor (TCR)-engineered T cells represents a powerful method to redirect the immune system against tumours. However, although TCR recognition is restricted to a specific peptide–MHC (pMHC) complex, increasing numbers of reports have shown cross-reactivity and off-target effects with severe consequences for the patients. This demands further development of strategies to validate TCR safety prior to clinical use. We reasoned that the desired TCR signalling depends on correct pMHC recognition on the outside and a restricted clustering on the inside of the cell. Since the majority of the adverse events are due to TCR recognition of the wrong target, we tested if blocking the signalling would affect the binding. By over-expressing the c-SRC kinase (CSK), a negative regulator of LCK, in redirected T cells, we showed that peripheral blood T cells inhibited anti-CD3/anti-CD28-induced phosphorylation of ERK, whereas TCR proximal signalling was not affected. Similarly, overexpression of CSK together with a therapeutic TCR prevented pMHC-induced ERK phosphorylation. Downstream effector functions were also almost completely blocked, including pMHC-induced IL-2 release, degranulation and, most importantly, target cell killing. The lack of effector functions contrasted with the unaffected TCR expression, pMHC recognition, and membrane exchange activity (trogocytosis). Therefore, co-expression of CSK with a therapeutic TCR did not compromise target recognition and binding, but rendered T cells incapable of executing their effector functions. Consequently, we named these redirected T cells "dummy T cells" and propose to use them for safety validation of new TCRs prior to therapy.

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'Mutiny on the crown: two cases of rare cephalic malformations

The presentation and management of two bizarre congenital cephalic curiosities at the two extremes of the clinical spectrum are discussed herewith. Case 1: presented to us as a neonate with a scalp swelling mirror-imaging her head and face. The journey from clinics to wards and to the operation theatre and to her home is introspected. Case 2: presented to us as dicephalous dibrachius dipus parapagus conjoined twins. The detailed work-up of individual organ systems, the multidisciplinary approach to management and the final outcome are discussed. This is an unsolved mystery for the anatomists, paediatric surgeons, radiologists and the medical fraternity at large.

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Constrictive bronchiolitis presenting with a mixed obstructive and restrictive pattern, associated with acid reflux

A previously healthy 55-year-old woman presented with worsening dyspnoea on exertion. The patient lived at altitude, did not smoke and had no exposure to occupational or environmental toxins. Her physical examination, including pulmonary, was unremarkable. Pulmonary function tests showed forced expiratory volume in 1 s/forced vital capacity ratio 74% predicted, diffusing capacity for carbon monoxide (DLCO) 92% predicted and residual volume 213% predicted. Rheumatological workup was negative. Chest radiograph showed hyperinflation without consolidation, and high-resolution chest CT showed mosaic attenuation with air trapping on expiratory imaging. A decreasing DLCO lead to transbronchial biopsies that were inconclusive. A video-assisted thoracic surgery lung biopsy showed small airway disease suggestive of constrictive bronchiolitis. Oesophagram and a barium swallow showed a hiatal hernia with large volume gastro-oesophageal reflux to the level of the clavicles. The development of constrictive bronchiolitis in this patient was possibly secondary to hiatal hernia and silent gastroesophageal reflux disease (GERD). In the face of presumably idiopathic lung disease, clinicians should perform a GERD workup even in the absence of GERD symptoms.

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Three-vessel coronary artery aneurysmal disease complicated by multivessel thrombosis and cardiogenic shock: the saving role of intracoronary thrombolysis

The benefit of intracoronary thrombolytics in ST-elevation myocardial infarction (STEMI) is not well established. Mainstays of STEMI management include intravenous thrombolytics, percutaneous coronary interventions and surgical revascularisation. However, in cases of STEMI secondary to coronary artery aneurysmal disease (CAAD), standard treatment options may not be suitable due to high thrombus burden, perioperative risk and factors unique to each patient. Thus, STEMI management in CAAD can represent a therapeutically challenging clinical scenario. Here, we describe a patient with severe three-vessel CAAD complicated by multivessel thrombosis and cardiogenic shock for whom traditional management options including placement of haemodynamic support devices were not feasible. As an alternative measure, the patient was treated with intracoronary thrombolysis with remarkable clinical stabilisation and angiographic resolution of thrombosis. He remains clinically stable several years later without recurrent events. This case serves to demonstrate the potential lifesaving benefit of intracoronary thrombolysis in complicated multivessel CAAD.

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Necrotising soft tissue infection without systemic toxicity in a patient with rheumatoid arthritis treated with tocilizumab

A Japanese woman aged 76 years with rheumatoid arthritis treated with prednisolone and tocilizumab presented with a 2-day history of redness and pain in her right thigh. She was hospitalised with a primary diagnosis of cellulitis and antimicrobial therapy was initiated. She had been stable until the fourth day of admission, when the swelling of her right thigh rapidly worsened and demonstrated purpura; she was subsequently unable to walk because of the pain. A diagnosis of necrotising soft tissue infection (NSTI) was made and extensive debridement was performed. Over the next 4 months, additional debridement was performed four times. Her condition improved significantly and she was able to walk later. Physicians should recognise that tocilizumab can mask systemic toxicities and inflammatory findings even in severe infections. To avoid delays in diagnosis and surgical intervention, clinicians should consider NSTIs when they encounter patients treated with tocilizumab, even if it mimics cellulitis.

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Enlarging hypermetabolic nodule: benign non-functional adrenocortical adenoma

Description

A 70-year-old woman with controlled type 2 diabetes mellitus and hypertension presented for evaluation of chronic abdominal discomfort. An incidental 3.2x3.5x3 cm left adrenal mass was identified on CT. Physical examination revealed obesity stage 2 without a Cushingoid appearance and controlled hypertension with a regular heart rate. Biochemical evaluations for Cushing syndrome, primary aldosteronism and pheochromocytoma were negative. A 1-year follow-up CT of the adrenal glands with washout showed a larger left-sided adrenal mass, measuring 4.3x3.4x3 cm (figure 1A). The attenuation values of the mass were indeterminate: non-contrast, 15 Hounsfield unit (HU); portal venous, 70 HU; delayed, 42 HU; absolute washout, 51%. MRI of the abdomen confirmed the left adrenal mass (figure 1B,C). Given the rapidly increasing size, malignancy was suspected and a whole-body positron emission tomography/CT scan using 18F-fluorodeoxyglucose (18F-FDG) was performed, which demonstrated (figure 1D,E) an 18F-FDG avid adrenal mass (standardized uptake...

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Impact of birth characteristics, breast feeding and vital statistics on the eruption of primary teeth among healthy infants in Saudi Arabia: an observational study

Objectives

This study aimed to explore the impact of gender, birth weight, maternal age, type of delivery, gestational age and feeding practices on the eruption of teeth in children with no underlying medical conditions or developmental defects in their first year of life.

Design

A cross-sectional observational study design was used.

Setting

A primary healthcare setting in Riyadh, Saudi Arabia.

Participants

All children in their first year of life attending a vaccination clinic (n=422) were included in the study. Infants with chronic childhood illnesses, those who were below the 5th percentile in height or weight, infants with congenital birth defects and chronic illnesses, infants who were born preterm and low birth weight infants were excluded from the study.

Outcome measures

The type of delivery, birth weight, age of mother, height and weight percentile for age (as plotted on the WHO growth chart for infants) and feeding practices were recorded by the examiner, and this was followed by a clinical examination to determine the presence or absence of each tooth. Regression models were developed to determine the effect of the different variables on the presence of primary teeth.

Results

There was a significant association between the weight percentile of the child (adjusted for age) and the number of erupted primary teeth, suggesting that heavier children have an earlier eruption of teeth. No association was observed between birth weight, height percentile for age or maternal age at the time of birth and the number of erupted primary teeth. Children who were exclusively breast fed were significantly more likely to have an erupted first primary tooth earlier than non-breastfed group.

Conclusions

Breast feeding and the weight of the child may have an influence on the eruption of primary teeth in the first year of life.

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Occupational radiation exposure and its health effects on interventional medical workers: study protocol for a prospective cohort study

Introduction

Although fluoroscopically guided procedures involve a considerably high dose of radiation, few studies have investigated the effects of radiation on medical workers involved in interventional fluoroscopy procedures. Previous research remains in the early stages and has not reached a level comparable with other occupational studies thus far. Furthermore, the study of radiation workers provides an opportunity to estimate health risks at low doses and dose rates of ionising radiation. Therefore, the objectives of this study are (1) to initiate a prospective cohort study by conducting a baseline survey among medical radiation workers who involve interventional fluoroscopy procedures and (2) to assess the effect of occupational radiation exposure and on the overall health status through an in-depth cross-sectional study.

Methods and analysis

Intervention medical workers in Korea will be enrolled by using a self-administered questionnaire survey, and the survey data will be linked with radiation dosimetry data, National Health Insurance claims data, cancer registry and mortality data. After merging these data, the radiation organ dose, lifetime attributable risk due to cancer and the risk per unit dose will be estimated. For the cross-sectional study, approximately 100 intervention radiology department workers will be investigated for blood tests, clinical examinations such as ultrasonography (thyroid and carotid artery scan) and lens opacity, the validation of badge dose and biodosimetry.

Ethics and dissemination

This study was reviewed and approved by the institutional review board of Korea University (KU-IRB-12-12-A-1). All participants will provide written informed consent prior to enrolment. The findings of the study will be disseminated through peer-reviewed scientific journals, conference presentations, and a report will be submitted to the relevant public health authorities in the Korea Centers for Disease Control and Prevention to help with the development of appropriate research and management policies.

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The lived experience of chronic headache: a systematic review and synthesis of the qualitative literature

Objective

To systematically review the qualitative literature of the lived experience of people with a chronic headache disorder.

Background

Chronic headaches affect 3%–4% of the population. The most common chronic headache disorders are chronic migraine, chronic tension-type headache and medication overuse headache. We present a systematic review and meta-ethnographic synthesis of the lived experience of people with chronic headache.

Methods

We searched seven electronic databases, hand-searched nine journals and used a modified Critical Appraisal Skills Programme checklist to appraise study quality. Following thematic analysis we synthesised the data using a meta-ethnographic approach.

Results

We identified 3586 unique citations; full texts were examined for 86 studies and 4 were included in the review. Included studies differed in their foci: exploring, patient-centred outcomes, chronic headache as a socially invisible disease, psychological processes mediating impaired quality of life, and the process of medication overuse. Initial thematic analysis and subsequent synthesis gave three overarching themes: 'headache as a driver of behaviour' (directly and indirectly), 'the spectre of headache' and 'strained relationships'.

Conclusion

This meta-synthesis of published qualitative evidence demonstrates that chronic headaches have a profound effect on people's lives, showing similarities with other pain conditions. There were insufficient data to explore the similarities and differences between different chronic headache disorders.

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Use of general practice before and after mild traumatic brain injury: a nationwide population-based cohort study in Denmark

Objectives

Traumatic brain injury (TBI) is commonly seen in the emergency department (ED). Approximately 85%–90% of TBIs are mild (mTBI). Some cause symptoms such as headache, dizziness, anxiety, blurred vision, insomnia and concentration difficulties, collectively known as postconcussion syndrome (PCS). Some studies suggest that recovery from mTBI is complete. Others find that symptoms persist for months, even years. The aim of this study was to describe the use of general practice, before and after mTBI, as a proxy for symptoms in a large cohort.

Design

Nationwide population-based matched cohort study.

Setting

Danish EDs and general practice.

Participants

All patients (aged ≥18 years), first-time diagnosed with mTBI in a Danish ED between 1 January 1998 and 31 December 2010 (n=93 517). Ten reference persons per patient with mTBI were randomly matched on gender, age and general practice (n=935 170).

Primary outcome

Overall use of general practice; consultations relating to mental and physical health.

Results

We found higher use of general practice during the first year after mTBI for all ages, both genders and all types of contacts. Age 18–40 years: women, incidence rate ratio (IRR) 1.59 (95% CI 1.57 to 1.61); men, IRR 1.82 (95% CI 1.80 to 1.85). Age 41–65 years: women, IRR 1.75 (95% CI 1.72 to 1.78); men, IRR 1.85(95% CI 1.82 to 1.89). Age 66+ years: women, IRR 1.55 (95% CI 1.52 to 1.58); men, IRR 1.55 (95% CI 1.51 to 1.59). After the first year, the use decreased to the level before mTBI. Individuals with mTBI and higher use of general practice before mTBI had lower socioeconomic status and more comorbidities (P<0.001).

Conclusions

The use of general practice was higher in the first year after mTBI, specifically in the first 3 months. Patients with mTBI had different healthcare-seeking behaviour several years before diagnosis than their matched reference persons. Pretraumatic morbidity should be considered in the evaluation of PCS.

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High fat diet exacerbates imiquimod-induced psoriasis-like dermatitis in mice

Abstract

Psoriasis, a chronic inflammatory skin disease, is closely related to systemic metabolism. An elevated body mass index (BMI) is a risk factor for psoriasis; inflammasomes are activated by adipose tissue macrophages in obese subjects. We hypothesized that hyperlipidemia is involved in the pathogenesis of psoriasis and examined the role of a high fat diet (HFD) in the development of psoriasis in imiquimod (IMQ)-treated mice. The body weight and serum level of cholesterol were significantly higher in mice fed an HFD than a regular diet (RD). HFD mice had higher psoriasis skin scores and the number of neutrophils infiltrating into the lesional skin was elevated. IL-17A mRNA expression was significantly increased in the skin of IMQ-treated HFD mice; the expression of IL-22, IL-23, and TNF-α mRNA was not enhanced. Caspase-1 and IL-1β were activated in the skin of IMQ-treated HFD mice and their serum level of IL-17A, TNF-α, and IL-1β was significantly upregulated. Our findings strongly suggest that hyperlipidemia is involved in the development and progression of psoriasis via systemic inflammation and inflammasome activation.

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HCV load as a possible prognostic factor in patients with HCV-related DLBCL

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Immune thrombocytopenia induced by vonoprazan fumarate: a single center retrospective study

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Efficacy of antithymocyte globulin as first-line treatment for aplastic anemia—a single-center experience

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Neuroprotective effects of hyperbaric oxygen (HBO) therapy on neuronal death induced by sciatic nerve transection in rat

Recent studies shows that hyperbaric oxygen (HBO) therapy exerts some protective effects against neural injuries. The purpose of this study was to determine the neuroprotective effects of HBO following sciatic...

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Cortical vein thrombosis in adult patients of cerebral venous sinus thrombosis correlates with poor outcome and brain lesions: a retrospective study

Cortical vein thrombosis (CVT) receives little attention in adult patients with cerebral venous sinus thrombosis (CVST). This study aimed to investigate the clinical and radiological features of adult CVST pat...

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Molecular detection of Brucella spp in goat and sheep milk samples from apparently healthy and infected animals

Abstract

Brucellosis is a worldwide spread zoonotic disease caused by some strains of Brucella spp. which is a bacterium simply transmitted to human among domesticated animals. PCR assay is authentic, inexpensive, sensitive, and highly specific for Brucella DNA detection in milk samples. This study set to assess the PCR assay for the molecular recognition of Brucella DNA in goats and sheep unpasteurized milk samples in the southeast region of Iran and to determine the frequency distribution of seasonal outbreaks. Eight hundred samples of raw milk from 722 apparently healthy animals and 78 infected animals with a history of abortion were collected from January 2015 to June 2016. In our PCR, a specific genome region, the IS711 element, was targeted to amplify Brucella DNA, and the frequency distribution of seasonal outbreaks was determined. PCR assay amplified Brucella DNA in 10.85% goats and 5.45% sheep milk samples (CI = 95). Among samples with abortion history, the disease occurrence rate was 67.94% but among those without abortion history, it was 2.21%. The most frequent rates of brucellosis were seen in the summer (n = 33), and the lowest rate occurred in the winter (n = 3). The results indicated a significantly higher prevalence (p < 0.05) of disease in samples with abortion history, and the results also indicated that the goats had a higher prevalence of brucellosis as in comparison with sheep. There was a significant statistical difference between the seasons.

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Changes of liver hemodynamic and elastography parameters in patients with colorectal liver metastases receiving preoperative chemotherapy: “a note of caution”

Abstract

Background

New systemic chemotherapy agents have improved prognosis in patients with colorectal liver metastases (CLM), but some of them damage the liver parenchyma and ultimately increase postoperative morbidity and mortality after liver resection. The aims of our study were to determine the degree of hemodynamic and pathological liver injury in CLM patients receiving preoperative chemotherapy and to identify an association between these injuries and postoperative complications after liver resection.

Methods

This is a prospective descriptive study of patients with CLM receiving preoperative chemotherapy before curative liver resection from November 2013 to June 2014. All patients had preoperative elastography and hepatic hemodynamic evaluation. We analyzed clinical preoperative data and postoperative outcomes after grouping the patients by chemotherapy type, development of sinusoidal obstructive syndrome (SOS), and development of major complications.

Results

Eleven from the 20 patients included in the study received preoperative oxaliplatin-based chemotherapy (OBC). Nine patients had SOS at pathological analysis and five patients developed major complications. Patients receiving preoperative OBC had higher values of hepatic venous pressure gradient (HVPG) and developed more SOS and major complications. Patients developing SOS had higher values of HVPG and developed more major complications. Patients with major complications had higher values of HVPG, and patients with a HVPG of 5 mmHg or greater had more major complications than those under 5 mmHg (20 vs 80%, p = 0.005).

Conclusions

OBC and SOS impair liver hemodynamics in CLM patients. An increase in major complications after liver resection in these patients develops at subclinical HVPG levels.

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Contemporary management of high-grade gliomas

CNS Oncology, Ahead of Print.

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Ibrutinib and its use in the treatment of chronic lymphocytic leukemia

Future Oncology, Ahead of Print.

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Welcome to the 14th volume of Future Oncology

Future Oncology, Volume 14, Issue 1, Page 1-3, January 2018.

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Camellia euphlebia exerts its antidepressant-like effect via modulation of the hypothalamic-pituitary-adrenal axis and brain monoaminergic systems

Abstract

Camellia euphlebia (family, Theaceae) is a Chinese folk medicine, known for its multiple pharmacological properties. The present study aimed to provide further insights into the therapeutic basis of C. euphlebia using several animal behavioral tests and physiological indexes. Tail suspension test, forced swimming test, open-field test, chronic unpredictable mild stress (CUMS), reversal of reserpine-induced hypothermia and palpebral ptosis, and 5-hydroxytryptophane-induced head-twitch response were used to evaluate the antidepressant effect of aqueous extract of Camellia euphlebia (AEC) on mice. The possible underlying mechanism was explored by investigating the changes associated with several parameters of animal behavior, as well as the changes in monoamine neurotransmitter and stress hormone levels in these animals during the tests. Mice administered AEC at 100 and 200 mg/kg/day doses for 7 days showed significantly reduced immobility duration in forced swimming test and tail suspension test, whilst exhibiting no apparent changes in locomotor activity. Additionally, administration of AEC also effectively antagonized reserpine-induced palpebral ptosis and hypothermia and enhanced 5-hydroxytryptophane-induced head-twitch response. AEC significantly elevated the levels of serotonin, noradrenaline and dopamine in the blood and brain compared to non-treated mice. After 28 days of administration, the maximum AEC dose (100 mg/kg/day) significantly reversed CUMS-induced inhibition of weight gain and sucrose intake, while decreasing the levels of plasma adrenocorticotropic hormone and serum corticosterone. The antidepressant effect of AEC appeared to involve the alteration of hypothalamic-pituitary-adrenal axis and monoaminergic systems.

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Synergistic targeting of the regulatory and catalytic subunits of PI3K{delta} in mature B cell malignancies

Purpose: Aberrant activation of the B cell receptor (BCR) is implicated in the pathogenesis of mature B-cell tumors, a concept validated in part by the clinical success of inhibitors of the BCR-related kinases BTK (Bruton's tyrosine kinase) and PI3K (Phosphatidylinositol-4,5-bisphosphate 3-kinase delta). These inhibitors have limitations, including the paucity of complete responses, acquired resistance, and toxicity. Here we examined the mechanism by which the cyclic-AMP/PDE4 signaling axis suppresses PI3K, towards identifying a novel mechanism-based combinatorial strategy to attack BCR-dependency in mature B-cell malignancies. Experimental Design: We used in vitro and in vivo diffuse large B-cell lymphoma (DLBCL) cell lines and primary chronic lymphocytic leukemia (CLL) samples to pre-clinically evaluate the effects of the combination of the FDA-approved phosphodiesterase 4 (PDE4) inhibitor roflumilast and idelalisib on cell survival and tumor growth. Genetic models of gain- and loss-of-function were employed to map multiple signaling intermediaries downstream of the BCR. Results: Roflumilast elevates the intracellular levels of cyclic-AMP and synergizes with idelalisib in suppressing tumor growth and PI3K activity. Mechanistically, we show that roflumilast suppresses PI3K by inhibiting BCR-mediated activation of the P85 regulatory subunit, distinguishing itself from idelalisib, an ATP-competitive inhibitor of the catalytic P110 subunit. Using genetic models, we linked the PDE4-regulated modulation of P85 activation to the oncogenic kinase SYK. Conclusions: These data demonstrate that roflumilast and idelalisib suppress PI3K by distinct mechanisms, explaining the basis for their synergism, and suggest that the repurposing of PDE4 inhibitors to treat BCR-dependent malignancies is warranted.

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Merkel cell carcinoma patients presenting without a primary lesion have elevated markers of immunity, higher tumor mutation burden and improved survival

Purpose: Patients presenting with nodal Merkel cell carcinoma without an identifiable (unknown) primary lesion (MCC-UP) are nearly twice as likely to survive compared to similarly staged patients with known primary lesions (MCC-KP). The basis of this previously reported finding is unclear. Experimental Design: Survival analyses and markers of immunity were evaluated in 123 patients with advanced MCC. Whole exome sequence data was analyzed from 16 tumors. Results: As in prior studies, patients with nodal MCC-UP had strikingly improved MCC-specific survival as compared to MCC-KP patients (HR 0.297, p < 0.001). Surprisingly, patients presenting with distant metastatic MCC-UP also had significantly improved survival (HR 0.296, p = 0.038). None of the 72 patients with MCC-UP were immunosuppressed as compared to 12 of the 51 (24%) patients with MCC-KP (p < 0.001). Merkel polyomavirus oncoprotein antibody median titer was higher in MCC-UP patients (26,229) than MCC-KP patients (3,492; p < 0.001). Additionally, the median number of nonsynonymous exome mutations in MCC-UP tumors (688 mutations) was markedly higher than MCC-KP tumors (10 mutations, p = 0.016). Conclusions: This is the first study to our knowledge to explore potential underlying immune-mediated mechanisms of MCC-UP presentation. In this cohort, MCC-UP patients were never immune suppressed, had higher oncoprotein antibody titers, and higher tumor mutational burdens. Additionally, we show that nodal tumors identified in MCC-UP patients did indeed arise from primary skin lesions as they contained abundant UV-signature mutations. These findings suggest that stronger underlying immunity against MCC contributes to primary lesion elimination and improved survival.

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HSP27-mediated Extracellular and Intracellular Signaling Pathways Synergistically Confer Chemo-Resistance in Squamous Cell Carcinoma of Tongue

Purpose: Squamous cell carcinoma of tongue (SCCT) is the most common type of the oral cavity carcinoma. Chemo-resistance in SCCT is common and the underlying mechanism remains largely unknown. We aim to identify key molecules and signaling pathways mediating chemo-resistance in SCCT. Experimental Design: Using a proteomic approach we identify that the HSP27 was a potential mediator for chemo-resistance in SCCT cells. To further validate this role of HSP27, we performed various mechanistic studies using in vitro and in vivo models as well as serum and tissue samples of SCCT patients. Results: The HSP27 protein level was significantly increased in the multidrug-resistant SCCT cells and cell culture medium. Both HSP27 knockdown and anti-HSP27 antibody treatment reversed chemo-resistance. Inversely, both HSP27 overexpression and recombinant human HSP27 protein treatment enhanced chemo-resistance. Moreover, chemotherapy significantly induced HSP27 protein expression in both SCCT cells and their culture medium, so is that in tumor tissues and serum of SCCT patients. HSP27 overexpression predicts a poor outcome of SCCT patients receiving chemotherapy. Mechanically, extracellular HSP27 binds to TLR5 and then activates NF-B signaling to maintain SCCT cells survival. TLR5 knockdown or restored IBα protein level disrupts extracellular HSP27-induced NF-B transactivation and chemo-resistance. Moreover, Intracellular HSP27 binds to BAX and BIM to repress their translocation to mitochondrion and subsequent cytochrome C release upon chemotherapy, resulting into inhibition of the mitochondrial apoptotic pathway. Conclusions: HSP27 plays pivotal role in chemo-resistance of SCCT cells via a synergistic extracellular and intracellular signaling. HSP27 may represent a potential biomarker and therapeutic target for precision SCCT treatment.

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Ipilimumab plus Lenalidomide after Allogeneic and Autologous Stem Cell Transplantation for Patients with Lymphoid Malignancies

Purpose: Prevention or treatment of relapsed lymphoid malignancies after hematopoietic stem cell transplantation (HSCT) requires novel strategies. We hypothesized that anti-tumor-cell responses could be enhanced by the addition of lenalidomide to the cytotoxic T-lymphocyte-associated protein 4 inhibitor ipilimumab. Experimental Design: We conducted a phase 2 investigator-initiated trial to assess the safety and activity of ipilimumab and lenalidomide in patients with lymphoid malignancies that relapsed after allogeneic HSCT and in high-risk patients after autologous HSCT. Patients received 10 mg of oral lenalidomide daily for 21 days followed by intravenous ipilimumab at 3 mg/kg body weight. The regimen was repeated 4 weeks later for a total of 4 treatments. Results: We enrolled 17 patients (10 allogeneic and 7 autologous transplant recipients). Immune-mediated toxicity was limited to 1 patient with asymptomatic hypothyroidism and 1 with dermatitis in the allogeneic and autologous groups, respectively. One allogeneic transplant recipient had a flare of prior graft-versus-host disease (GVHD) while taking lenalidomide that precluded further treatment. All others finished treatment without GVHD. Four of 10 patients in the allogeneic group had complete responses (three of which were durable at 19+, 21+ and 32+ months), and 3 had partial responses. The disease in 6 of 7 patients in the autologous group remains in remission. The groups had similar immune responses; including a 2- to 3 -fold increases in inducible ICOS+CD4+FoxP3- T cells number. Conclusions:Our early-phase data suggested that ipilimumab plus lenalidomide is well tolerated after HSCT. Adverse events did not differ significantly between the allogeneic and autologous groups.

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Genome-wide association study identifies a new locus at 7q21.13 associated with hepatitis B virus-related hepatocellular carcinoma

Purpose: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. In China, chronic hepatitis B virus (HBV) infection remains the major risk factor for HCC. In the present study, we performed a genome-wide association study (GWAS) among Chinese populations to identify novel genetic loci contributing to susceptibility to HBV-related HCC. Experimental Design: GWAS scan is performed in a collection of 205 HBV-related HCC trios (each trio includes an affected proband and his/her both parents), and 355 chronic HBV carriers with HCC (cases) and 360 chronic HBV carriers without HCC (controls), followed by two rounds of replication studies totally consisting of 3,796 cases and 2,544 controls. Results: We identified a novel association signal within the CDK14 gene at 7q21.13 (index rs10272859, odds ratio = 1.28, P = 9.46 x 10-10). Furthermore, we observed that the at-risk rs10272859[G] allele was significantly associated with higher mRNA expression levels of CDK14 in liver tissues. Chromosome conformation capture assays in liver cells confirmed that a physical interaction exists between the promoter region of CDK14 and the risk-associated SNPs in strong linkage disequilibrium with the index rs10273859 at 7q21.13. This index rs10272859 also showed significant association with the survival of HCC patients. Conclusions: Our findings highlight a novel locus at 7q21.13 conferring both susceptibility and prognosis to HBV-related HCC, and suggest the CDK14 gene to be the functional target of the 7q21.13 locus.

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Mitochondrial inhibition augments the efficacy of imatinib by resetting the metabolic phenotype of gastrointestinal stromal tumor

Purpose: Imatinib dramatically reduces GIST 18 F-FDG uptake, providing an early indicator of treatment response. Despite decreased glucose internalization, many GIST cells persist, suggesting that alternative metabolic pathways are used for survival. The role of mitochondria in imatinib-treated GIST is largely unknown. Experimental Design: We quantified the metabolic activity of several human GIST cell lines. We treated human GIST xenografts and genetically engineered Kit V558del/+ mice with the mitochondrial oxidative phosphorylation inhibitor VLX600 in combination with imatinib and analyzed tumor volume, weight, histology, molecular signaling, and cell cycle activity. In vitro assays on human GIST cell lines were also performed. Results: Imatinib therapy decreased glucose uptake and downstream glycolytic activity in GIST-T1 and HG129 cells by approximately half and upregulated mitochondrial enzymes and improved mitochondrial respiratory capacity. Mitochondrial inhibition with VLX600 had a direct antitumor effect in vitro while appearing to promote glycolysis through increased AKT signaling and glucose transporter expression. When combined with imatinib, VLX600 prevented imatinib-induced cell cycle escape and reduced p27 expression, leading to increased apoptosis when compared to imatinib alone. In Kit V558del/+ mice, VLX600 alone did not induce tumor cell death, but had a profound antitumor effect when combined with imatinib. Conclusions: Our findings show that imatinib alters the metabolic phenotype of GIST and this may contribute to imatinib resistance. Our work offers preclinical proof of concept of metabolic targeting as an effective strategy for the treatment of GIST.

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Neuronal oscillations: Unavoidable and useful?

Abstract

Neuronal systems have a high propensity to engage in oscillatory activity because both the properties of individual neurons as well as canonical circuit motifs favour rhythmic activity. In addition, coupled oscillators can engage in a large variety of dynamical regimes, ranging from synchronization with different phase offsets to chaotic behaviour. Which regime prevails depends on differences between preferred oscillation frequencies, coupling strength and coupling delays. The ability of delay coupled oscillator networks to generate a rich repertoire of temporally structured activation sequences is exploited by central pattern generator networks for the control of movements. However, it less clear whether temporal patterning of neuronal discharges also plays a role in cognitive processes. Here it will be argued that the temporal patterning of neuronal discharges emerging from delay coupled oscillator networks plays a pivotal role in all instances in which selective relations have to be established between the responses of distributed assemblies of neurons. Examples are the dynamic formation of functional networks, the selective routing of activity in densely interconnected networks, the attention dependent selection of sensory signals, the fast and context dependent binding of responses for further joint processing in pattern recognition and the formation of associations by learning. Special consideration is given to arguments that challenge a functional role of oscillations and synchrony in cognition because of the volatile nature of these phenomena and recent evidence will be reviewed suggesting that this volatility is functionally advantageous.

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Cross-modal refinement of visual performance after brief somatosensory deprivation in adult mice

Abstract

It is well established that the congenital lack of one sensory modality enhances functionality in the spared senses. However, whether a late onset deprivation of one sense leads to such alterations is largely unknown. Here, we investigated whether a somatosensory deprivation induced by bilateral whisker removal affects visual acuity and contrast sensitivity in fully adult mice. Using the visual cortex dependent visual water task, we found that a brief somatosensory deprivation markedly improved behavioral visual acuity and contrast sensitivity by about 40%. Determining these attributes of vision using periodic optical imaging of intrinsic signals in the same mice revealed that visual cortex responses elicited by weak visual stimuli were massively increased after somatosensory deprivation. Strikingly, comparison of visual acuity and contrast sensitivity values determined by the visual water task and intrinsic signal imaging revealed that these measurements were almost identical, even at the level of individual animals. In summary, our results suggest that a brief manipulation of somatosensory experience profoundly boosts visual cortex dependent vision in adults.

http://ift.tt/2BgzRFi

The roles of TRPV1, TRPA1 and TRPM8 channels in chemical and thermal sensitivity of the mouse oral mucosa

Abstract

Spices in food and beverages and compounds in tobacco smoke interact with sensory irritant receptors of the transient receptor potential (TRP) cation channel family. TRPV1 (vanilloid type 1), TRPA1 (ankyrin 1) and TRPM8 (melastatin 8) not only elicit action potential signaling through trigeminal nerves, eventually evoking pungent or cooling sensations, but by their calcium conductance they also stimulate the release of calcitonin gene-related peptide (CGRP). This is measured as an index of neuronal activation to elucidate the chemo- and thermosensory transduction in the isolated mouse buccal mucosa of wildtypes and pertinent knockouts. We found that the lipophilic capsaicin, mustard oil and menthol effectively get access to the nerve endings below the multi-layered squamous epithelium, while cigarette smoke and its gaseous phase were weakly effective releasing CGRP. The hydrophilic nicotine was ineffective unless applied unprotonated in alkaline (pH9) solution, activating TRPA1 and TRPV1. Also mustard oil activated both these irritant receptors in millimolar but only TRPA1 in micromolar concentrations; in combination (1mM) with heat (45°C) it showed supraadditive, i.e. heat sensitizing, effects in TRPV1 and TRPA1 knockouts, suggesting action on an unknown heat-activated channel and mustard oil receptor. Menthol caused little CGRP release by itself, but in subliminal concentration (2mM) it enabled a robust cold response that was absent in TRPM8^-/- but retained in TRPA1^-/- and strongly reduced by TRPM8 inhibitors. In conclusion, all three relevant irritant receptors are functionally expressed in the oral mucosa and play their specific roles in inducing neurogenic inflammation and sensitization to heat and cold.

http://ift.tt/2CjGCWb

An EEG Index of Sensorimotor Interhemispheric Coupling after unilateral stroke: clinical and neurophysiological study

Abstract

Brain connectivity has been employed to investigate on post-stroke recovery mechanisms and assess the effect of specific rehabilitation interventions. Changes in interhemispheric coupling after stroke have been related to the extent of damage in the corticospinal tract (CST) and thus, to motor impairment. In this study we aim at defining an index of interhemispheric connectivity derived from electroencephalography (EEG), correlated with CST integrity and clinical impairment.

Thirty sub-acute stroke patients underwent clinical and neurophysiological evaluation: CST integrity was assessed by Transcranial Magnetic Stimulation and high-density EEG was recorded at rest. Connectivity was assessed by means of Partial Directed Coherence and the normalized Inter-Hemispheric Strength (nIHS) was calculated for each patient and frequency band on the whole network and in three sub-networks relative to the frontal, central (sensorimotor) and occipital areas.

Interhemipheric coupling as expressed by nIHS on the whole network was significantly higher in patients with preserved CST integrity in beta and gamma bands. The same index estimated for the 3 sub-networks showed significant differences only in the sensorimotor area in lower beta, with higher values in patients with preserved CST integrity. The sensorimotor lower beta nIHS showed a significant positive correlation with clinical impairment.

We propose an EEG-based connectivity index which is a measure of the interhemispheric cross-talking and correlates with functional motor impairment in subacute stroke patients. Such index could be employed to evaluate the effects of training aimed at re-establishing interhemispheric balance and eventually drive the design of future connectivity-driven rehabilitation interventions.

http://ift.tt/2BgzHOc

The locus coeruleus - norepinephrine system as pacemaker of attention –A developmental mechanism of derailed attentional function in autism spectrum disorder

Abstract

Children with autism spectrum disorder (ASD) exhibit diminished visual engagement to environmental stimuli. Aberrant attentional function provides an explanation by reduced phasic alerting and orienting to exogenous stimuli. We review aberrant attentional function (alerting, orienting, and attentional control) in children with ASD as studied by neurocognitive and neurophysiological tasks as well as magnetic resonance imaging studies. The locus coeruleus – norepinephrine (LC-NE) system is outlined as a pacemaker of attentional function. The LC-NE system regulates adaptive gain in synaptic signal transmission, which moderates phasic alerting ('promoting') and the activation of the ventral frontoparietal attention network within orienting ('permitting'). In children with ASD, atypical LC-NE activity is proposed as underlying mechanism of aberrant attentional function. It may manifest as a) increased tonic activity with reduced phasic reactivity to exogenous stimuli, b) attenuated bottom-up signaling mitigating salience and predictive reward attribution during phasic alerting, and c) reduced activation of the ventral frontoparietal attention system attenuating orienting to exogenous stimuli. Increased tonic pupil dilation and aberrant pupil reactivity are discussed as indicators of atypical LC-NE activity. Pupillometry is outlined as feasible method to assess alerting, orienting, and attentional control that can be dissected from the pupil dilation time course. In children with ASD, aberrant attentional function through atypical LC-NE activity is proposed as developmental mechanism leading to reduced social attention as well as social interaction and communication impairments.

http://ift.tt/2CjQsHI

Release from informational masking by auditory stream segregation: Perception and its neural correlate

Abstract

In the analysis of acoustic scenes we easily miss sounds or are insensitive to sound features that are salient if presented in isolation. This insensitivity that is not due to interference in the inner ear is termed informational masking (IM). So far, the cellular mechanisms underlying IM remained elusive. Here, we apply a sequential IM paradigm to humans and gerbils using a sound-level-increment-detection task determining the sensitivity to target tones in a background of standard (same frequency) and distracting tones (varying in level and frequency). The amount of IM that was indicated by the level-increment thresholds depended on the frequency separation between the distracting and the standard and target tones. In humans and gerbils we observed similar perceptual thresholds. A release from IM of more than 20 dB was observed in both species if the distracting tones were well segregated in frequency from the other tones. Neuronal rate responses elicited by similar sequences in gerbil inferior colliculus and auditory cortex were recorded. At both levels of the auditory pathway the neuronal thresholds obtained with a signal-detection theoretic approach deducing the sensitivity from the analysis of the neurons' receiver operating characteristics matched the psychophysical thresholds revealing that IM already emerges at midbrain level. By applying objective response measures in physiology and psychophysics we demonstrated that the population of neurons has a sufficient sensitivity for explaining the perceptual level-increment thresholds indicating IM. There was a good correspondence between the neuronal and perceptual release from IM being related to auditory stream segregation.

http://ift.tt/2BgzDhq

YY1 Facilitates Enhancer-Promoter Contacts to Promote Gene Expression [Research Watch]

YY1 preferentially occupies active enhancers and promoters and forms dimers to promote DNA looping.

http://ift.tt/2yHzJMm

Value in Using CAR T Cells for DLBCL [News in Brief]

Tisagenlecleucel therapy produces durable responses in adults with relapsed or refractory disease.

http://ift.tt/2ATI712

KAT2A Is a {alpha}-KGDH-Dependent Histone Succinyltransferase [Research Watch]

Succinylation of histone H3K27 induces changes in gene expression that promote glioblastoma growth.

http://ift.tt/2yGPDqf

CAR T-cell Therapy Impresses in Multiple Myeloma [News in Brief]

Phase I trial detects responses in 81% of patients with relapsed or refractory disease.

http://ift.tt/2AS38sV

The Alcohol-Abuse Drug Disulfiram Targets NPL4 to Exert Antitumor Effects [Research Watch]

Disulfiram reduced cancer mortality in patients who continued disulfiram for alcohol dependency.

http://ift.tt/2yGvQHp

Response to Immune Checkpoint Blockade is Influenced by HLA-I Genotype [Research Watch]

Maximal HLA-I loci heterozygosity is linked to improved survival after immune checkpoint blockade.

http://ift.tt/2ATCKPH

First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study [Research Articles]

Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF- and RAS-mutant cell lines. In this multicenter phase I trial (NCT01781429), 135 patients were enrolled to an accelerated 3 + 3 dose-escalation cohort and six distinct dose-expansion cohorts. Dose escalation included 27 patients, dosed from 10 to 900 mg twice daily and established the recommended phase II dose (RP2D) of 600 mg twice daily. Ulixertinib exposure was dose proportional to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108-patient expansion cohort, 32% of patients required dose reduction. The most common treatment-related adverse events were diarrhea (48%), fatigue (42%), nausea (41%), and dermatitis acneiform (31%). Partial responses were seen in 3 of 18 (17%) patients dosed at or above maximum tolerated dose and in 11 of 81 (14%) evaluable patients in dose expansion. Responses occurred in patients with NRAS-, BRAF V600–, and non–V600 BRAF-mutant solid tumors.

SIGNIFICANCE: Here, we describe the first-in-human dose-escalation study of an ERK1/2 inhibitor for the treatment of patients with advanced solid tumors. Ulixertinib has an acceptable safety profile with favorable pharmacokinetics and has shown early evidence of clinical activity in NRAS- and BRAF V600- and non-V600–mutant solid-tumor malignancies. Cancer Discov; 8(2); 1–12. ©2017 AACR.

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Commonalities in epileptogenic processes from different acute brain insults: Do they translate?

Summary

The most common forms of acquired epilepsies arise following acute brain insults such as traumatic brain injury, stroke, or central nervous system infections. Treatment is effective for only 60%-70% of patients and remains symptomatic despite decades of effort to develop epilepsy prevention therapies. Recent preclinical efforts are focused on likely primary drivers of epileptogenesis, namely inflammation, neuron loss, plasticity, and circuit reorganization. This review suggests a path to identify neuronal and molecular targets for clinical testing of specific hypotheses about epileptogenesis and its prevention or modification. Acquired human epilepsies with different etiologies share some features with animal models. We identify these commonalities and discuss their relevance to the development of successful epilepsy prevention or disease modification strategies. Risk factors for developing epilepsy that appear common to multiple acute injury etiologies include intracranial bleeding, disruption of the blood-brain barrier, more severe injury, and early seizures within 1 week of injury. In diverse human epilepsies and animal models, seizures appear to propagate within a limbic or thalamocortical/corticocortical network. Common histopathologic features of epilepsy of diverse and mostly focal origin are microglial activation and astrogliosis, heterotopic neurons in the white matter, loss of neurons, and the presence of inflammatory cellular infiltrates. Astrocytes exhibit smaller K⁺ conductances and lose gap junction coupling in many animal models as well as in sclerotic hippocampi from temporal lobe epilepsy patients. There is increasing evidence that epilepsy can be prevented or aborted in preclinical animal models of acquired epilepsy by interfering with processes that appear common to multiple acute injury etiologies, for example, in post–status epilepticus models of focal epilepsy by transient treatment with a trkB/PLCγ1 inhibitor, isoflurane, or HMGB1 antibodies and by topical administration of adenosine, in the cortical fluid percussion injury model by focal cooling, and in the albumin posttraumatic epilepsy model by losartan. Preclinical studies further highlight the roles of mTOR1 pathways, JAK-STAT3, IL-1R/TLR4 signaling, and other inflammatory pathways in the genesis or modulation of epilepsy after brain injury. The wealth of commonalities, diversity of molecular targets identified preclinically, and likely multidimensional nature of epileptogenesis argue for a combinatorial strategy in prevention therapy. Going forward, the identification of impending epilepsy biomarkers to allow better patient selection, together with better alignment with multisite preclinical trials in animal models, should guide the clinical testing of new hypotheses for epileptogenesis and its prevention.

http://ift.tt/2Bgrwli

Background

Physician recommendations for colorectal cancer (CRC) screening have consistently been shown to be a strong predictor of screening. The aim of this study was to investigate perceptions of CRC screening modalities and recommendation behaviors among physicians in Korea.

Methods

A cross-sectional, nationally representative survey conducted between November 2013 and February 2014. In total, 379 physicians (241 primary care physicians and 138 physicians affiliated with the Korean Association for the Study of Intestinal Diseases responded to this survey (overall response rate of 31.4%).

Results

About 29% of all respondents "always" recommended and about 67% "sometimes" recommended CRC screening. Colonoscopy was perceived as an effective primary screening tool for CRC, and 80% of the physicians recommended colonoscopy for CRC screening. Only 7% recommended FOBT. In multivariate analysis, recommending FOBT was associated with stronger belief in the screening efficacy of FOBT (aOR 3.70, 95% CI 2.09, 6.57), weaker belief in the screening efficacy of colonoscopy (aOR 0.29, 95% CI 0.12, 0.69), and negative decisional balance for colonoscopy screening (aOR 0.82, 95% CI 0.71, 0.95).

Conclusions

Although FOBT is provided free-of-charge through a nationwide CRC screening program, colonoscopy was more commonly recommended and preferred by physicians.

http://ift.tt/2CCp74k

A Promising Forcep Strip Method for Gastrointestinal Subepithelial Tumors Originating from the Muscularis Propria

Subepithelial tumors (SETs) originating from the muscularis propria layer are unlikely to be resected completely and safely. We developed the Forcep Strip Method (FSM) for the resection of SETs in the stomach.

http://ift.tt/2BhhCQ2

Emerging Therapies

At present, the only definitive cure for β-thalassemia is a bone marrow transplant (BMT); however, HLA–blood-matched donors are scarcely available. Current therapies undergoing clinical investigation with most potential for therapeutic benefit are the β-globin gene transfer of patient-specific hematopoietic stem cells followed by autologous BMT. Other emerging therapies deliver exogenous regulators of several key modulators of erythropoiesis or iron homeostasis. This review focuses on current approaches for the treatment of hemoglobinopathies caused by disruptions of β-globin.

http://ift.tt/2BryPcn

Opioids in the treatment of pain. Beliefs, knowledge, and attitudes of the general Spanish population. Identification of subgroups through cluster analysis

A lack of information has been found related to patients' perception towards pain management.

http://ift.tt/2CjgpXY

Hot off the Press: SGEM#196: Gastroparesis – I Feel Like Throwing Up

Abstract

This randomized controlled trial compared haloperidol along with conventional therapy to placebo along with conventional therapy for gastroparesis in the emergency department. The primary outcomes of pain and nausea scores at 1 hour were significantly improved in the haloperidol group, but not in the placebo group. In this summary, we discuss a quality assessment of the article and summarized the social media commentary from the blog post/podcast.

http://ift.tt/2k1TUAf

An efficient parallel simulation of unsteady blood flows in patient-specific pulmonary artery

Summary

Simulation of blood flows in the pulmonary artery provides some insight into certain diseases by examining the relationship between some continuum metrics, e.g. the wall shear stress acting on the vascular endothelium, which responds to flow-induced mechanical forces by releasing vasodilators/constrictors. In [?kheyfets2015patient], V. Kheyfets studies numerically a patient-specific pulmonary circulation to show that decreasing wall shear stress is correlated with increasing pulmonary vascular impedance. In this paper, we develop a scalable parallel algorithm based on domain decomposition methods to investigate an unsteady model with patient specific pulsatile waveforms as the inlet boundary condition. The unsteady model offers tremendously more information about the dynamic behavior of the flow field, but computationally speaking, the simulation is a lot more expensive since a problem which is similar to the steady state problem has to be solved many times, and therefore, the traditional sequential approach is not suitable anymore. We show computationally that simulations using the proposed parallel approach with up to 10,000 processor cores can be obtained with much reduced compute time. This makes the technology potentially usable for the routine study of the dynamic behavior of blood flows in the pulmonary artery, in particular, the changes of the blood flows and the wall shear stress in the spatial and temporal dimensions. This article is protected by copyright. All rights reserved.

http://ift.tt/2BwgtGS

Machine Learning in Detection of Undiagnosed Celiac Disease

http://ift.tt/2AzspEj

Letter: The clinical relevance of differentiating non-alcoholic steatohepatitis from simple steatosis, reply

http://ift.tt/2Bvpe47

Does Administration of Hypertonic Solutions Improve Mortality in Hemorrhagic Shock Compared With Isotonic Solutions?

Of the 570 identified studies, 12 met inclusion criteria (2,932 patients). Study locations included the United States (8), Brazil (2), the United Kingdom (1), and Australia (1). Settings were out-of-hospital (8), ED (3), and ICU (1). For hypertonic solutions, all 12 studies used 7.5% sodium chloride with or without dextran (4.2% or 6%); 1 study examined hypertonic solutions only, 6 studies examined hypertonic saline with dextran only, and the remaining studies examined both solutions. Control groups used normal saline solution or lactated Ringer's solution.

http://ift.tt/2AznXp5

Is Adenosine or an Intravenous Calcium Channel Blocker More Effective for Treating Supraventricular Tachycardia?

The search strategy identified 237 new references since the 2006 review,1 of which 2 new studies were identified that met the inclusion criteria. These were added to 5 studies from the existing review, resulting in 7 total studies comprising 622 participants. Six studies were conducted with adults and one study was conducted with pediatric patients. Verapamil was used in all studies, although one study had both a verapamil and a diltiazem treatment arm.

http://ift.tt/2BrpGk3

Differentiating the Preterm Phenotype: Distinct Profiles of Cognitive and Behavioral Development Following Late and Moderately Preterm Birth

To explore patterns of comorbidity in cognitive and behavioral outcomes at 2 years' corrected age among children born late or moderately preterm (LMPT) and to identify predictors of different patterns of comorbidity.

http://ift.tt/2j7JTAB

Barth Syndrome: Different Approaches to Diagnosis

The diagnosis of Barth syndrome is challenging owing to the wide phenotypic spectrum with allelic heterogeneity. Here we report 3 cases of Barth syndrome with phenotypic and allelic heterogeneity that were diagnosed by different approaches, including whole exome sequencing and final confirmation by reverse-transcription polymease chain reaction.

http://ift.tt/2zf5GPy

A phase II study of 2-weeks of adjuvant whole breast/chest wall and/or regional nodal radiotherapy in patients with breast cancer

To report results in terms of feasibility and early toxicity of hypofractionated adjuvant whole breast/chest wall and/or regional nodal radiotherapy in patients with breast cancer.Materials & methods: Between June 2013 and October 2014, 50 patients with breast cancer, post mastectomy or after breast conservation surgery (BCS) were prospectively included. The trial was approved by institutional ethics committee and registered with ClinicalTrials.gov, number XXXX. Patients were planned on simulator with two tangential fields to breast/chest wall and incident field to supraclavicular fossa.

http://ift.tt/2ARLrtx

Deviations from Standard Chemoradiation among Early Stage Anal Cancer Patients

The optimal chemoradiation regimen for early stage (T1-T2N0M0) anal cancer patients is not well established. We sought to evaluate treatment practice patterns for early stage anal cancer patients using the National Cancer Database. Over 10% of patients with early stage anal cancer received high dose external beam radiation with concurrent chemotherapy (including 20.7% of T1 and 6.9% of T2 primary tumors), suggesting possible overtreatment of these early stage cancers.

http://ift.tt/2yEQEPr

NCI: Taking Risks to Advance Science

Norman Sharpless, M.D., offers his thoughts on his experience thus far as NCI director and areas, like big data, where NCI can play an important role in advancing science.

http://ift.tt/2BuW3Oy

A Simple Fluorescence-based Reporter Assay to Identify Cellular Components Required for Ricin Toxin A Chain (RTA) Trafficking in Yeast

In the manuscript, we describe the use of a yeast-based fluorescence reporter assay to identify cellular components involved in the trafficking and killing processes of the cytotoxic A subunit of the plant toxin ricin (RTA).

http://ift.tt/2BfxToX

Cognitive clinico-radiological paradox in early stages of multiple sclerosis

Abstract

Objective

To investigate whether the strength of the association between magnetic resonance imaging (MRI) metrics and cognitive outcomes differs between various multiple sclerosis subpopulations.

Methods

A total of 1052 patients were included in this large cross-sectional study. Brain MRI (T1 and T2 lesion volume and brain parenchymal fraction) and neuropsychological assessment (Brief International Cognitive Assessment for Multiple Sclerosis and Paced Auditory Serial Addition Test) were performed.

Results

Weak correlations between cognitive domains and MRI measures were observed in younger patients (age≤30 years; absolute Spearman's rho = 0.05–0.21), with short disease duration (<2 years; rho = 0.01–0.21), low Expanded Disability Status Scale [EDSS] (≤1.5; rho = 0.08–0.18), low T2 lesion volume (lowest quartile; <0.59 mL; rho = 0.01–0.20), and high brain parenchymal fraction (highest quartile; >86.66; rho = 0.01–0.16). Stronger correlations between cognitive domains and MRI measures were observed in older patients (age>50 years; rho = 0.24–0.50), with longer disease duration (>15 years; rho = 0.26–0.53), higher EDSS (≥5.0; rho = 0.23–0.39), greater T2 lesion volume (highest quartile; >5.33 mL; rho = 0.16–0.32), and lower brain parenchymal fraction (lowest quartile; <83.71; rho = 0.13–0.46). The majority of these observed results were confirmed by significant interactions (P ≤ 0.01) using continuous variables.

Interpretation

The association between structural brain damage and functional cognitive impairment is substantially weaker in multiple sclerosis patients with a low disease burden. Therefore, disease stage should be taken into consideration when interpreting associations between structural and cognitive measures in clinical trials, research studies, and clinical practice.

http://ift.tt/2BfaW5a

Serum and Plasma Copy Number Detection Using Real-time PCR

This manuscript describes the copy number variation analysis performed in serum or plasma DNA using real-time PCR approach. This method is suitable for the prediction of drug resistance in castration resistant prostate cancer patients, but it could be informative also for other diseases.

http://ift.tt/2BdKUiy

Effects of Propofol on Cellular Bioenergetics in Human Skeletal Muscle Cells.

Objectives: Propofol may adversely affect the function of mitochondria and the clinical features of propofol infusion syndrome suggest that this may be linked to propofol-related bioenergetic failure. We aimed to assess the effect of therapeutic propofol concentrations on energy metabolism in human skeletal muscle cells. Design: In vitro study on human skeletal muscle cells. Settings: University research laboratories. Subjects: Patients undergoing hip surgery and healthy volunteers. Interventions: Vastus lateralis biopsies were processed to obtain cultured myotubes, which were exposed to a range of 1-10 [mu]g/mL propofol for 96 hours. Measurements and Main Results: Extracellular flux analysis was used to measure global mitochondrial functional indices, glycolysis, fatty acid oxidation, and the functional capacities of individual complexes of electron transfer chain. In addition, we used [1-14C]palmitate to measure fatty acid oxidation and spectrophotometry to assess activities of individual electron transfer chain complexes II-IV. Although cell survival and basal oxygen consumption rate were only affected by 10 [mu]g/mL of propofol, concentrations as low as 1 [mu]g/mL reduced spare electron transfer chain capacity. Uncoupling effects of propofol were mild, and not dependent on concentration. There was no inhibition of any respiratory complexes with low dose propofol, but we found a profound inhibition of fatty acid oxidation. Addition of extra fatty acids into the media counteracted the propofol effects on electron transfer chain, suggesting inhibition of fatty acid oxidation as the causative mechanism of reduced spare electron transfer chain capacity. Whether these metabolic in vitro changes are observable in other organs and at the whole-body level remains to be investigated. Conclusions: Concentrations of propofol seen in plasma of sedated patients in ICU cause a significant inhibition of fatty acid oxidation in human skeletal muscle cells and reduce spare capacity of electron transfer chain in mitochondria. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

http://ift.tt/2BteVNP

Generic Protocol for Optimization of Heterologous Protein Production Using Automated Microbioreactor Technology

This manuscript describes a generic approach for tailor-made design of microbial cultivation media. This is enabled by an iterative workflow combining Kriging-based experimental design and microbioreactor technology for sufficient cultivation throughput, which is supported by lab robotics to increase reliability and speed in liquid handling media preparation.

http://ift.tt/2kuL9xQ

Fluorescence-mediated Tomography for the Detection and Quantification of Macrophage-related Murine Intestinal Inflammation

Target-specific probes represent an innovative tool for analyzing molecular mechanisms, such as protein expression in various types of disease (e.g., inflammation, infection, and tumorigenesis). In this study, we describe a quantitative three-dimensional tomographic assessment of intestinal macrophage infiltration in a murine model of colitis using F4/80-specific fluorescence-mediated tomography.

http://ift.tt/2kxWXPM

Severity of button batteries ingestions: data from French Poison Control Centres between 1999 and 2015.

Background: Although the ingestion of button batteries is an infrequent situation, it leads to a significant risk of causing serious damage. Objective: This study was carried out to describe all the cases of button battery ingestion recorded by the French Poison Control Centers over 16 years. Patients and methods: All the cases of button battery ingestion were recorded from 1 January 1999 to the end of June 2015, analysed (age, sex, number of ingested button batteries, clinical signs and treatments) and graded for severity according to the poisoning severity score. Results: The incidence of button batteries ingestions was constant over the 16-year period, with an average of 266+/-98.5 cases per year and a total of 4030 cases. Nevertheless, 21 cases were severe and two deaths occurred. Interestingly, for the two patients who died, the battery was stuck in the oesophagus and they presented anorexia and/or dysphagia, abdominal pain and fever and in one case, a melena 3 weeks after ingestion. Importantly, these symptoms were observed even if the battery was expelled in one fatal case. Conclusion: Ingestions of button batteries still occur and may cause serious damage, especially in children, and if the button battery is stuck in the oesophagus as it might cause severe symptoms. Patients who have ingested a button battery must be directed to the emergency department for medical evaluation, even if the button battery has been expelled from the body and even more if gastrointestinal symptoms are present. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2AxnZh1

Paediatric procedural sedation and analgesia by emergency physicians in a country with a recent establishment of emergency medicine.

Objectives: Paediatric patients receive less procedural sedation and analgesia (PSA) in the emergency department compared with adults, especially in countries where emergency medicine is at an early stage of development. The objectives of this study were to evaluate the adverse events and efficacy of paediatric PSA in a country with a recent establishment of emergency medicine and to describe which factors aided implementation. Methods: This is a prospective, multicentre, observational study of paediatric patients undergoing PSA by the first trained emergency physicians (EPs) in The Netherlands. A standardized data collection form was used at all participating hospitals to collect data on adverse events, amnesia, pain scores, and procedure completion. A survey was used to interpret which factors had aided PSA implementation. Results: We recorded 351 paediatric PSA. The mean age was 9.5 years (95% confidence interval: 9.1-10.0). Esketamine was most frequently used (42.4%), followed by propofol (34.7%). The adverse event rate was low (3.0%). Amnesia was present in 86.8%. The median pain score was 2 (out of 10) for patients without amnesia. Procedures were successfully completed in 93.9% of the cases. Conclusion: Paediatric PSA provided by the first EPs in The Netherlands showed appropriate levels of sedation and analgesia with a high rate of procedure completion and a low rate of adverse events. Our paper suggests that EPs provided with a proper infrastructure of mentorship, training and guidelines can implement effective paediatric PSA. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2BqAJtN

Sebaceous tumours: more than skin deep

Clinical presentation

A 77-year-old man presented to our skin cancer centre with various cutaneous tumours occurring in 2006–2017. Histopathology showed a 'hidradenocarcinoma' on the left upper back (2006) and a sebaceous adenoma (figure 1) on the left shoulder (2011). In 2017, he developed a sebaceous carcinoma on the middle upper back, which manifested as a slowly enlarging, asymptomatic nodule. Medical history was significant for curative resection of colorectal cancer in 1988.

The most recent lesion was subjected to extensive immunohistochemical assessment. The neoplastic cells were positive for cytokeratin 5/6, cytokeratin 7, cluster of differentiation antigen 10, adipophilin, androgen receptor, epithelial membrane antigen, KI67 antigen, MLH1 and PMS2, but stained negative for gross cystic disease fluid protein 15, prostate-specific antigen, carbohydrate antigen 19/9, CDX2 protein, hepatocyte-specific antigen, carcinoembryonic antigen, cluster of differentiation antigen 117 and cytokeratin 19. Given the variety of histological manifestations of the patient's skin neoplasms, further studies were...

http://ift.tt/2AycuG5

Chronic cough in Swiss bagpipe player

Introduction

A 34-year-old man presented to our GI clinic with chronic cough. Coughing episodes exacerbated on days of bagpipe playing and the morning after. Methacholine testing revealed airway hyperreactivity. Allergic bronchopulmonary aspergillosis could be excluded; CT scan of the chest was without pathological findings. Also bronchoscopy with bronchoalveolar lavage (BAL) and mucosal biopsy failed to reveal a pulmonary aetiology of the cough. Minor findings in BAL were an elevated number of macrophages and bacteria representative of the oral flora. A trial with inhalative budesonide and formoterol and consecutively 8 weeks of proton pump inhibitor treatment were started, but only led to inadequate reduction of symptoms. The patient was then referred to us, where we performed high-resolution oesophageal manometry (HRM) and 24-hour multichannel intraluminal impedance-pH (24h-MII-pH) testing after unremarkable upper endoscopy.

Questions

What do you expect to see on HRM and 24h-MII-pH? Which additional diagnostic testing could be useful? What is this patient's...

http://ift.tt/2BqAJdh

Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohns disease (ANDANTE I and II)

Objective

Neutralising pro-inflammatory interleukin-6 (IL-6) may effectively treat Crohn's disease (CD). Effects of PF-04236921, an anti-IL-6 antibody, in adults with CD are reported.

Design

Parallel-group, dose-ranging, double-blind trial with 4-week screening and 12-week treatment periods. After induction, patients entered 28-week follow-up or 48-week open-label extension (OLE) with 28-week follow-up. Adults with confirmed CD and inadequate response to anti-tumour necrosis factor (TNF) therapy were included. Induction study: 249 patients randomised 1:1:1:1 to placebo, PF-04236921 10, 50 or 200 mg by subcutaneous injection on days 1 and 28. OLE study: PF-04236921 50 mg every 8 weeks up to six doses followed by 28-week follow-up.

Results

247 patients were randomised and received treatment in the induction study. The 200 mg dose was discontinued due to safety findings in another study (NCT01405196) and was not included in the primary efficacy analysis. Crohn's Disease Activity Index (CDAI)-70 response rates with PF-04236921 50 mg were significantly greater than placebo at weeks 8 (49.3% vs 30.6%, P<0.05) and 12 (47.4% vs 28.6%, P<0.05) and met the primary end point. Week 12 CDAI remission rates with PF-04236921 50 mg and placebo were 27.4% and 10.9%, respectively (16.5% difference; P<0.05). 191 subjects received treatment in the OLE. Common treatment-emergent and serious adverse events in both studies included worsening CD, abdominal pain and nasopharyngitis.

Conclusions

PF-04236921 50 mg induced clinical response and remission in refractory patients with moderate-to-severe CD following failure of anti-TNF therapy. GI abscess and perforation were observed, a specific focus of attention during future clinical development.

Trial registration number

NCT01287897 and NCT01345318.

http://ift.tt/2Ayv411

Helicobacter pylori eradication failure may have confounded the recent large-scale health database study that showed proton pump inhibitors increase gastric cancer risk

The current guidelines recommend that when patients require long-term use of proton pump inhibitors (PPIs), Helicobacter pylori (H. pylori) should be eradicated beforehand because it improves atrophic gastritis, a precancerous lesion.1 2 The recent analysis by Cheung et al3 of the data of more than 60 000 adults registered in a territory-wide health database in Hong Kong who underwent H. pylori eradication showed that the long-term use of PPIs increased the risk of gastric cancer by 2.4-fold. Moreover, the risk of gastric cancer increased with the dose and duration of PPI use. The fact that long-term PPI administration increases the risk of gastric cancer even after H. pylori eradication is unexpected.

However, the study has some limitations. First, although it is based on a large sample, it is an observational study rather than a prospective randomised interventional study. As a result, the clinical backgrounds of the PPI user...

http://ift.tt/2BqNl43

Exosomal adrenomedullin derived from cancer-associated fibroblasts promotes lipolysis in adipose tissue

We read with great interest the recent publication by Sagar et al, which reported activated lipolysis in adipose tissues induced by exosome-transmitted adrenomedullin (AM) from pancreatic cancer (PC) cells.1 Researchers detected AM expressed in PC-derived exosomes and observed elevated AM expression in both tissue and plasma specimens from patients with PC. Biofunctional analysis showed that both AM and PC-derived exosomes promoted lipolysis and this effect could be abolished by blocking the AM receptor, suggesting PC-induced lipolysis is dependent on exosomal AM. A further mechanistic experiment illustrated that the lipolysis induced by AM is mediated through mitogen-activated protein kinases p38 and ERK1/2. Taken together, the results published by Sagar et al reveal a novel molecular mechanism of adipose tissue loss, providing novel insight into early-onset paraneoplastic effects of PC.

Exosomal AM derived from cancer-associated fibroblasts (CAF) promotes lipolysis in adipose tissue. Intriguingly, we noticed that in addition to PC cells, stromal cells also...

http://ift.tt/2AAUQBD

Near-infrared fluorescence molecular endoscopy detects dysplastic oesophageal lesions using topical and systemic tracer of vascular endothelial growth factor A

Message

The incidence of oesophageal adenocarcinoma (EAC) is steeply rising. Early lesion detection is a critical factor for improving disease prognosis. We developed and investigated wide-field near-infrared fluorescence molecular endoscopy (NIR-FME), using systemic and topical administration of a fluorescence-labelled antibody against vascular endothelial growth factor (VEGFA). Fourteen patients with Barrett's oesophagus (BE) underwent endoscopic mucosal resection (EMR) combined with NIR-MFE. From a total of 20 confirmed aberrant lesions identified with NIR-FME, 4 lesions were missed by high-definition (HD) narrowband imaging (NBI) and white-light endoscopy (WLE). This overall 25% detection enhancement advocates NIR-FME as a promising 'red-flag' technique for improving early oesophageal lesion detection. ClinicalTrials.gov ID NCT02129933.

In more detail

Worldwide, >450 000 people are diagnosed with oesophageal cancer each year. In the western world, at least 80% of these cancers concern EAC.1–4 Late-stage disease detection challenges the efficacy of therapies, resulting in 400 000 deaths each year. Therefore, there...

http://ift.tt/2BsaSkT

Rheological and structural properties of enzyme-induced gelation of milk proteins by ficin and Polyporus badius

Abstract

The rheological and microstructural characteristics of ewes' milk curd obtained by coagulating with milk-clotting enzymes, including ficin extract and Polyporus badius were evaluated. The gelation of milk was examined by small amplitude oscillatory shear measurements (SAOS). Different concentrations of ficin and P. badius extracts (1, 3, and 5%) were utilized to coagulate milk proteins. The ewes' samples containing ficin and mushroom enzymes were heated from 25 to 45°C at a heating rate 1°C/min and kept for 30 min. Then, the curds were cooled down to 25°C with the same heating rate. The ficin extract could induce stronger gels at 45°C and 5% ficin. Similar results were also found for 5% P. badius extract and incubation at 45°C. However, P.badius gels achieved a network with more viscous characteristics and had a softer texture than ficin gels. Therefore, it may be concluded the induced gels with mushroom had higher moisture and lower protein contents, which related to the high proteolytic activity of P. badius. The microstructure survey showed that the mushroom-induced gel had a more compact structure. By increasing enzyme concentration, both gels showed a coarser and more compact protein network. Whereas, the P. badius gels had more fusions and folds which indicate the greater proteolysis occurred during gelation and there was greater breakdown of protein. Our findings suggest the application of ficin and P. badius enzymes to develop a novel procedure to coagulate milk proteins and providing new structures in food systems.

Effect of milk-clotting enzymes including ficin extract and Polyporus badius on the rheological and structural properties of coagulant milk from ewes' samples were investigated. Results showed that the ficin-induced gels can develop stronger gels at 45°C and 5% ficin. Similar results were also found for 5% P. badius extract and incubation at 45°C. It may conclude the induced gels with mushroom have higher moisture and lower protein contents, which may be related to the high proteolytic activity of P. badius. Both gels showed a coarser and more compact protein network by increasing the enzyme concentration. Whereas, the P. badius gels had more fusions and folds which indicate the higher proteolysis occurred during gelation and more breakdown of protein can clarify its softer texture. Our findings suggest the application of ficin and P. badius enzymes to develop a novel procedure to coagulate milk proteins and providing new structures in food systems.

http://ift.tt/2oe3ww9

Influence of steeping duration, drying temperature, and duration on the chemical composition of sorghum starch

Abstract

The quest for high-quality starch that would meet the needs of manufacturers is ever increasing. This study investigated the effect of steeping duration, drying temperature, and duration on the chemical properties of sorghum starch, to possibly alter the characteristics of sorghum starch for food applications. Steeping duration, drying temperature, and drying time of starch isolation were optimized using a central composite design and nine parameters including pH, amylose content, moisture, protein, ash, crude fiber, fat, carbohydrate, and total energy determined. Results obtained showed that most of the parameters were majorly influenced by steeping and drying duration. Steeping duration significantly (p < .05) increased the moisture, protein, and ash content of the sorghum with a corresponding decrease in pH values. The obtained experimental and predicted values of the investigated parameters were similar, with statistical indices indicating the relative validity of the generated models [absolute average deviation (AAD between 0 and 0.20), bias factor (B_f, 1–1.02), and accuracy factor (A_f, 1–1.21)]. The varying values of the parameters obtained indicates the potential use of the sorghum starches as thickeners, starch substitutes, and for other desired roles in food processing.

This study optimized steeping duration, drying temperature, and drying duration of sorghum starch and investigated its effects thereof.

http://ift.tt/2CBAOsn

Delmopinol hydrochloride reduces Salmonella on cantaloupe surfaces

Abstract

Since the surfaces of cantaloupes are highly rough or irregular, bacteria can easily attach and become difficult to remove. Appropriate postharvest washing and sanitizing procedures can help control Salmonella and other pathogens on cantaloupe or other melons during postharvest operations. Delmopinol hydrochloride (delmopinol) is a cationic surfactant that is effective for treating and preventing gingivitis and periodontitis. The application of delmopinol to two cantaloupe cultivars was evaluated for reducing the level of inoculated Salmonella. Athena and Hale's Best Jumbo (HBJ) cantaloupe rind plugs (2.5 cm. dia.) were inoculated with nalidixic acid-resistant Salmonella Michigan (approx. 1.0 × 109 CFU/ml). After 15 min, rind plugs were sprayed with 10 ml of a delmopinol spray solution (0% or 1.0% vol/vol) and held at 35°C for 1 hr or 24 hr. Rind plugs were diluted with Butterfield's phosphate buffer, shaken and sonicated, and solutions were enumerated on 50 ppm nalidixic acid-tryptic soy agar. The texture quality and color of additional cantaloupes were evaluated, after 1% delmopinol spray treatment, over 14-day storage at 4°C. A 1.0% application of delmopinol after 1 hr reduced Salmonella concentration by ~3.1 log CFU/ml for both "HBJ" skin rind plugs and "Athena" stem scar rind plugs in comparison to the control (p < .05). No differences were observed in the texture and color (L*, a*, b* values) of 1% delmopinol-treated cantaloupes as compared to control. Storage of cantaloupes treated with 1.0% delmopinol solution for 1 hr had a greater effect on reducing concentration of Salmonella compared to 24-hr treatment. A surface spray application of 1% delmopinol on cantaloupes could be an alternative antimicrobial postharvest treatment that could make surface bacteria more susceptible to sanitizers or physical removal.

Delmopinol hydrochloride (delmopinol) is a cationic surfactant that is effective for treating and preventing gingivitis and periodontitis. The application of delmopinol to two cantaloupe cultivars was evaluated for reducing the level of inoculated Salmonella. A 1.0% spray application of delmopinol, 1 hr after inoculation, reduced Salmonella concentration by ~3.1 log CFU/ml for "Hale's Best Jumbo" skin rind plugs and for "Athena" stem scar rind plugs in comparison to the control.

http://ift.tt/2ogEM6f

The inhibitory potential of Zataria multiflora and Syzygium aromaticum essential oil on growth and aflatoxin production by Aspergillus flavus in culture media and Iranian white cheese

Abstract

Antifungal activity of essential oils (EOs) of Zataria multiflora (thyme) and Syzygium aromaticum (clove) against Aspergillus flavus growth and aflatoxin B₁ production was studied in potato dextrose agar (PDA) and potato dextrose broth (PDB), as well as in Iranian white cheese as a food model. The results showed that the inhibitory potential of EOs in the PDB medium is more than PDA medium. Clove EO on PDB medium prevented fungal growth and aflatoxin B₁ production at 300 and 100 ppm, respectively. However, the thyme EO was not able to inhibit fungal growth completely and showed the strongest inhibition effect at 400 ppm. EOs also had more inhibitory activity in laboratory culture media than the food environments. EOs in all concentrations reduced aflatoxin B₁ production and fungal growth in cheese, but only the clove EO at 150 ppm was able to prevent the fungal growth and aflatoxin B₁ production completely. Thyme EO reduced aflatoxin B₁ value to below detection threshold (2 ppb) at 10 μl. Our findings propose EOs as a natural inhibitor to control fungal contamination of foodstuffs such as Iranian white cheese.

Since Zataria multiflora and Syzygium aromaticum essential oils have very high inhibitory potential against growth of Aspergillus flavus, therefore their use in culture media and food samples like Iranian white cheese can inhibit aflatoxin production.

http://ift.tt/2CB4hSS

Surveillance for Hepatobiliary Cancers in Patients with Primary Sclerosing Cholangitis

ABSTRACT

Background and Aims: Primary sclerosing cholangitis (PSC) is a risk factor for cholangiocarcinoma (CCA) and gallbladder carcinoma (GBCa). Surveillance for GBCa is recommended, but the clinical utility of surveillance for other hepatobiliary cancers (HBCa) in PSC, namely CCA and hepatocellular carcinoma (HCC), is unclear. We aimed to determine whether surveillance is associated with better survival after diagnosis of HBCa in patients with PSC. Methods: Medical records of PSC patients seen at Mayo Clinic Rochester from 1995-2015 were reviewed. Patients were included if they had ≥1 year of follow-up and developed HBCa. Patients were categorized according to their surveillance status (abdominal imaging and carbohydrate antigen 19-9 and alpha-fetoprotein). The primary endpoints were HBCa recurrence, HBCa-related death, and all-cause mortality. Overall survival was assessed by the Kaplan-Meier survival method. HBCa-related survival was assessed using the competing risks regression model. Tests of significance were 2-tailed, and a p-value < 0.05 was considered statistically significant. Results: From 1995-2015, a total of 79 of 830 PSC patients were diagnosed with HBCa. Cumulative follow-up was 712 and 283 person-years pre- and post-HBCa diagnosis, respectively. Seventy-eight percent (54/79) developed CCA, 21% (17/79) HCC, 6% (5/79) GBCa, 3% (2/79) both CCA and HCC, and 1% (1/79) both HCC and GBCa. Fifty-one percent (40/79) were under surveillance and 49% (39/79) were not. Patients in the surveillance group had significantly higher 5-year overall survival (68% vs. 20%, respectively; p<0.001) and significantly lower 5-year probability of experiencing an HBCa-related adverse event (32% versus 75%, respectively; p<0.001), compared with the no-surveillance group. Conclusion: This study demonstrates that surveillance for HBCa significantly improves outcomes, including survival, in patients with PSC. This article is protected by copyright. All rights reserved.

http://ift.tt/2BukxaG

Inhibition of EGR1 inhibits glioma proliferation by targeting CCND1 promoter

Abstract

Background

Gliomas are the most common primary tumors in central nervous system. The prognosis of the patients with glioma is poor regardless of the development of therapeutic strategies. Its aggressive behavior mainly depends on the potent ability of proliferation. The transcription factor EGR1 (early growth response 1) is a member of a zinc finger transcription factor family which plays an essential role in cell growth and proliferation.

Methods

EGR1 expression levels in 39 glioma tissues and 10 normal brain tissues were tested by RT-qPCR and Western-blotting. The effects of EGR1 on U251 cells, U251 stem-like cells (GSCs), and U87 cells proliferation were assessed using in vitro and in vivo cell proliferation assays. The specific binding between EGR1 and CCND1 promoter was confirmed by CHIP assay. EGF was used to improve EGR1 expression in this assay.

Results

EGR1 expression levels in human gliomas are decreased compared with normal brain tissues, however, the patients with low EGR1 expression level showed significantly enhanced patient survival in all glioma patients. EGR1 silencing inhibited proliferation and induced G1 phase arrest in glioma cells. EGR1 contributed to proliferation by directly raising CCND1. Meanwhile, EGR1 overexpression induced by EGF was able to promote the proliferation of glioma cells.

Conclusions

Our results show that stable knockdown EGR1 would inhibit glioma proliferation. The results suggest EGR1 showing lower expression in cancer tissues compared with normal tissues maybe still play an important role in tumor proliferation.

http://ift.tt/2ACy7VX

Efficacy and Safety of Ethanol Ablation for Branchial Cleft Cysts [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Branchial cleft cyst is a common congenital lesion of the neck. This study evaluated the efficacy and safety of ethanol ablation as an alternative treatment to surgery for branchial cleft cyst.

MATERIALS AND METHODS:

Between September 2006 and October 2016, ethanol ablation was performed in 22 patients who refused an operation for a second branchial cleft cyst. After the exclusion of 2 patients who were lost to follow-up, the data of 20 patients were retrospectively evaluated. All index masses were confirmed as benign before treatment. Sonography-guided aspiration of the cystic fluid was followed by injection of absolute ethanol (99%) into the lesion. The injected volume of ethanol was 50%–80% of the volume of fluid aspirated. Therapeutic outcome, including the volume reduction ratio, therapeutic success rate (volume reduction ratio of >50% and/or no palpable mass), and complications, was evaluated.

RESULTS:

The mean index volume of the cysts was 26.4 ± 15.7 mL (range, 3.8–49.9 mL). After ablation, the mean volume of the cysts decreased to 1.2 ± 1.1 mL (range, 0.0–3.5 mL). The mean volume reduction ratio at last follow-up was 93.9% ± 7.9% (range, 75.5%–100.0%; P < .001). Therapeutic success was achieved in all nodules (20/20, 100%), and the symptomatic (P < .001) and cosmetic (P < .001) scores had improved significantly by the last follow-up. In 1 patient, intracystic hemorrhage developed during the aspiration; however, no major complications occurred in any patient.

CONCLUSIONS:

Ethanol ablation is an effective and safe treatment for patients with branchial cleft cysts who refuse, or are ineligible for, an operation.

http://ift.tt/2kw1Mcq

Αρχειοθήκη ιστολογίου

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Παρασκευή 15 Δεκεμβρίου 2017

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