Epilepsy with auditory features: Long-term outcome and predictors of terminal remission

Summary

Objective

To assess the long-term outcome of epilepsy with auditory features (EAF) and to identify the clinical predictors for prognosis.

Methods

The study involved consecutive EAF patients with a follow-up of ≥5 years. Terminal remission (TR) was defined as a period of ≥5 consecutive years of seizure freedom at the last follow-up. We used Kaplan-Meier estimate to calculate the cumulative time-dependent probability of conversion to TR. Log-rank test and multivariate Cox regression analyses were performed to study the association between time to TR and prognostic determinants.

Results

We included 123 EAF patients (male/female = 58/65) with a median follow-up of 11 years (1626.9 person-years). Most were sporadic cases (68.3%), whereas 31.7% reported a family history of epilepsy. At last assessment, 42 patients had achieved TR (34.1%). Of the remaining 81 cases with no TR (65.9%), 37% had been in remission for 1-4 years and 62.9% still had seizures within the past year. The cumulative rates of TR were 26.6%, 35.7%, and 51.6% at 10, 20, and 30 years from inclusion. On multivariate analysis, age at onset > 10 years (hazard ratio [HR] = 3.2, P = .028), auditory aura characterized by distortions only versus simple/complex hallucinations (HR = 2.9, P = .041), and unremarkable scalp electroencephalogram (EEG) versus EEG with focal epileptiform activity (HR = 3.5, P = .041) were associated with TR.

Significance

Our data show a wide prognostic spectrum of EAF, ranging from mild forms with spontaneous remission, to severely refractory epilepsy addressed to surgery. The outcome, less favorable than expected from previous studies, appears to be primarily a function of 3 prognostic negative risk factors: age at onset < 10 years, auditory aura characterized by complex auditory hallucinations, and focal epileptiform abnormalities on scalp EEG. These predictors, easy to collect even at the first visit, may inform both clinicians and patients about the long-term prognosis and aid patient management.

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Basal Cell Carcinoma Induced by Therapeutic Radiation for Tinea Capitis – Clinical Pathological Study

Abstract

Aims

An increased prevalence of aggressive histological subtypes, such as the micronodular and morpheaform, has been seen, irrespective of the clinical course, in basal cell carcinoma (BCC) following irradiation for tinea capitis. The aim of this study was to assess the histopathological features of BCCs among patients irradiated for tinea capitis and correlate them with the clinical course.

Methods and Results

The medical records and BCC biopsy specimens of individuals who were previously irradiated for tinea capitis were revised. Demographic data and clinical characteristics were retrieved. Biopsy specimens were evaluated for histological subtype classification and additional histopathological features. A telephone survey was conducted to assess the clinical behaviour of the tumours. Thirty-one patients (17 male, 14 female) were included. The average age at time of first biopsy was 56 years. The total number of lesions was 185, with 80% of subjects showing multiple lesions. Nodular subtype was the most prevalent, followed by superficial, micronodular, and mixed tumours. Third of the BCC could be classified as aggressive histologically. Stromal fibroplasia and melanin deposits were common. There was no mortality related to BCC. None of the 17 patients who completed the survey had evidence of local invasiveness or metastases.

Conclusions

BCCs following radiation therapy for tinea capitis show unique histological characteristics related to aggressive behaviour. These aggressive features did not reflect the clinical behaviour in the current cohort.

This article is protected by copyright. All rights reserved.

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Hepatic elastin content is predictive of adverse outcome in advanced fibrotic liver disease

Abstract

Aims

Needle biopsy remains essential for diagnosis in assessment of liver disease, although there remains associated risk. Examination is largely limited to subjective evaluation and biopsies are not exploited to provide personalised prognostic information. Elastin is a durable component of fibrotic matrix in chronic disease, conferring resistance to remodelling and potentially influencing tissue biomechanics linked to portal hypertension. We hypothesised that elastin content was predictive of clinical outcome and so could be quantified to increase the beneficial information yield from a liver biopsy.

Methods and results

Elastin content in liver biopsies was determined by image analysis, technically validated in an independent centre, and correlated with outcome in patients with advanced (Ishak stage ≥ 5) chronic hepatitis C virus-related chronic liver disease. Elastin was robustly quantified in an operator- and laboratory-independent manner, with very strong correlation of elastin staining measured by two methods of image classification (r_s = 0.873, p < 0.00001). Elastin content (but not absolute scar content or Ishak stage) was predictive for future clinical outcomes. In a cohort of patients without sustained virologic response, median hepatic elastin content was 3.4%, and 17 patients (57%) progressed to a liver-related clinical outcome; 11 of the 15 patients (73%) with hepatic elastin >3.4% progressed to a clinical outcome, compared to only 6 out of 15 (40%) with elastin <3.4%. The difference in time to outcome was significant.

Conclusions

We describe a simple and reproducible method for elastin quantification in liver biopsies that provides potentially valuable prognostic information to inform clinical management.

This article is protected by copyright. All rights reserved.

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Grade 4 asbestosis does not extend directly from the respiratory bronchiole to the peripheral lung

Abstract

Aim

To confirm whether or not grade 4 asbestosis progresses from the respiratory bronchiole to the peripheral lung.

Methods and results

We retrospectively examined the autopsy or lobectomy specimens from 31 cases (29 males; mean age 64 years) satisfying the pathological criteria of grade 4 asbestosis. Asbestos bodies (ABs) were quantified in samples of dissolved lung and in tissue preparations on glass slides. Respiratory bronchiolar lesions were graded as 0, 1, and ≥ grade 2. Grade 4 asbestosis was subdivided into an atelectatic induration (AI); and usual interstitial pneumonia pattern (UIP pattern). Five, 10, and 16 cases had grade 0, 1, or ≥2 lesions respectively, with mean respective numbers of ABs in dissolved lung of 117,000/g dry lung, 468,000/g, and 968,000/g; and in specimens on glass slides of 7 ABs/cm² of tissue slice, 34 ABs /cm², and 195 ABs /cm². The differences were significant. Fifteen and 16 cases showed AI and UIP patterns, respectively; with mean respective numbers of ABs in dissolved lung of 1,006,000/g dry lung and 354,000/g, and 186 and 56 ABs/cm² on glass slides. The differences were significant. AI patterns originated in subpleural lobules or subpleural zonal areas, and UIP patterns originated in subpleural, peripheral lobules.

Conclusions

Grade 4 asbestosis does not start in the respiratory bronchiole. The presence of a grade 1 lesion is not required for the diagnosis of grade 4 asbestosis.

This article is protected by copyright. All rights reserved.

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Primary perianal adenocarcinoma of intestinal type – a new proposed entity

Abstract

Aims

The currently recognised subtypes of anal canal/perianal adenocarcinoma are those arising from low rectal mucosa or columnar cuff, fistula-related tumours and anal gland carcinoma. This following report presents two examples of a hitherto undescribed subtype of perianal adenocarcinoma with an intestinal phenotype.

Methods and Results

A 74 year old man had a perianal tumour locally excised whereas a 73 year old female underwent an abdominoperineal resection for perianal Paget's disease with an underlying carcinoma. Neither patient had a history of perineal fistulae, Crohn's disease or previous gastrointestinal neoplasia, and neither showed clinical, radiological or endoscopic evidence of another abdominal or pelvic tumour. Both resection specimens contained adenocarcinoma which were similar in demonstrating an intestinal morphology and CDX2 immunopositivity. The man has shown a disease-free outcome thus far but the woman has suffered with nodal and pelvic recurrence within a few months of surgery.

Conclusions

The name 'primary perianal adenocarcinoma of intestinal type' is proposed for this previously unrecognised subtype of perineal neoplasia. Awareness of its distinct existence – by recognising its intestinal morphology and immunophenotype while excluding metastasis from the intestinal tract – should help collate data to determine its specific prognosis and to formulate its best management.

This article is protected by copyright. All rights reserved.

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A Genomic and Clinicopathologic Study of Non–Small Cell Lung Cancers with Discordant ROS1 Gene Status by Fluorescent In Situ Hybridization and Immunohistochemical Analysis

Abstract

Background

ROS1 immunohistochemistry (IHC) using D4D6 antibody is a useful tool for screening patients with non–small cell lung cancer (NSCLC) slated for targeted therapy. Many studies and our data have identified cases that express the ROS1 protein strongly but are negative for ROS1 by fluorescent in situ hybridization (FISH). The present study investigated the driver mutation and clinicopathologic characteristics of 26 discordant cases (ROS1 IHC-positive but FISH-negative) to find new clues for distinguishing real ROS1-rearranged cases.

Patients and Methods

Tumors from 26 discordant cases were analyzed for clinicopathologic characteristics, mutations in EGFR, KRAS, ERBB2, BRAF, and PIK3CA; fusions in ALK and RET; and amplifications in MET, ERBB2, and ROS1.

Results

ROS1-rearranged NSCLCs were significantly more likely to be found in younger patients and at an advanced stage; they showed cribriform features, extracellular mucus, and psammoma bodies, whereas ROS1-discordant cases were found in older patients at a relatively early TNM stage and showed a lepidic growth pattern (all P <.001). Most of ROS1-rearranged NSCLCs were no concurrent mutation, whereas 73% of discordant cases harbored genetic aberrations, including EGFR and ERBB2. Compared with general lung adenocarcinomas, ERBB-2 abnormality was disproportionately high in ROS1-discordant cases. Moreover, we optimized the scoring criteria for ROS1 IHC as "H score >150 and no concurrent mutations"; then the specificity was increased to 81.6%.

Conclusions

Compared with ROS1-rearranged cases, ROS1-discordant patients showed distinct clinical and morphologic features and often harbored another oncogenic driver alteration. The use of optimized screening criteria will increase the specificity of ROS1 antibody.

This article is protected by copyright. All rights reserved.

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Comparison between Corticosteroid and Lidocaine Injection in the Treatment of Tennis Elbow: A Randomized, Double-Blinded, Controlled Trial

No abstract available

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Outcome Trends of Adult Cancer Patients Receiving Inpatient Rehabilitation: A 13-year review

AbstractObjectiveThis study describes characteristics and trends of inpatient rehabilitation among cancer patients within the United States over a 13-year period.DesignThis was a retrospective study of data from the Uniform Data System for Medical Rehabilitation (UDSMR®) from 2002 to 2014. Patients over the age of 17 admitted to inpatient rehabilitation facilities with a diagnosis of malignant cancer were included. Trends of rehabilitation outcomes including length of stay, Functional Independence Measure (FIM®) Instrument scores, and discharge location were examined.ResultsData from 115,570 cancer patients was evaluated. Mean age was 66 ±14 and 49% were female. Mean length of stay decreased over time (2002: 14 days to 2014:13 days, p70%) were discharged to the community.ConclusionCancer patients receiving acute inpatient rehabilitation demonstrated significant improvements in functional outcomes from admission to discharge. Cancer patients became more independent in important activities of daily living, thereby potentially reducing caregiver burden and ensuring safer discharges back to the community. This study suggests potential benefit of inpatient rehabilitation for appropriate cancer patients. Objective This study describes characteristics and trends of inpatient rehabilitation among cancer patients within the United States over a 13-year period. Design This was a retrospective study of data from the Uniform Data System for Medical Rehabilitation (UDSMR®) from 2002 to 2014. Patients over the age of 17 admitted to inpatient rehabilitation facilities with a diagnosis of malignant cancer were included. Trends of rehabilitation outcomes including length of stay, Functional Independence Measure (FIM®) Instrument scores, and discharge location were examined. Results Data from 115,570 cancer patients was evaluated. Mean age was 66 ±14 and 49% were female. Mean length of stay decreased over time (2002: 14 days to 2014:13 days, p70%) were discharged to the community. Conclusion Cancer patients receiving acute inpatient rehabilitation demonstrated significant improvements in functional outcomes from admission to discharge. Cancer patients became more independent in important activities of daily living, thereby potentially reducing caregiver burden and ensuring safer discharges back to the community. This study suggests potential benefit of inpatient rehabilitation for appropriate cancer patients. Corresponding Author: Jeffrey C. Schneider, 300 1st Avenue, Charlestown, MA 02129. jcschneider@partners.org Disclosures: None Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Effects of anodal transcranial direct current stimulation on somatosensory recovery after stroke: a randomized controlled trial

AbstractObjectiveTo evaluate the effect of anodal transcranial direct current stimulation (tDCS) over the primary somatosensory cortex on the recovery of somatosensation, motor function, and the activities of daily living (ADL) in patients with subacute stroke.DesignThis study was a prospective, randomized sham controlled, double-blinded study. Patients with subacute stroke having somatosensory deficits (N = 24) were enrolled and assigned randomly to the anodal and sham stimulation groups. Patients received 10 consecutive anodal or sham tDCSs over the primary somatosensory cortex on the side of the stroke lesion. Before and after each stimulation session, Nottingham sensory assessments, Semmes Weinstein monofilaments examination, and manual function tests were performed, and modified Brunnstrom classification, modified Barthel index, and functional ambulation categories were assessed.ResultsAlthough there was no clear significant difference between the two groups, when the changes from baseline to post-treatment evaluation were compared between the groups, we observed a partially significant improvement in the anodal stimulation group compared to the sham stimulation group. Interestingly, the tactile sensation of the unaffected side also improved. Moreover, the greater improvement in ADL function was observed in the anodal stimulation group too.ConclusionAnodal tDCS over the primary somatosensory cortex may be a useful adjuvant therapy for the recovery of somatosensation and ADL function in patients with sensory deficits after stroke. Objective To evaluate the effect of anodal transcranial direct current stimulation (tDCS) over the primary somatosensory cortex on the recovery of somatosensation, motor function, and the activities of daily living (ADL) in patients with subacute stroke. Design This study was a prospective, randomized sham controlled, double-blinded study. Patients with subacute stroke having somatosensory deficits (N = 24) were enrolled and assigned randomly to the anodal and sham stimulation groups. Patients received 10 consecutive anodal or sham tDCSs over the primary somatosensory cortex on the side of the stroke lesion. Before and after each stimulation session, Nottingham sensory assessments, Semmes Weinstein monofilaments examination, and manual function tests were performed, and modified Brunnstrom classification, modified Barthel index, and functional ambulation categories were assessed. Results Although there was no clear significant difference between the two groups, when the changes from baseline to post-treatment evaluation were compared between the groups, we observed a partially significant improvement in the anodal stimulation group compared to the sham stimulation group. Interestingly, the tactile sensation of the unaffected side also improved. Moreover, the greater improvement in ADL function was observed in the anodal stimulation group too. Conclusion Anodal tDCS over the primary somatosensory cortex may be a useful adjuvant therapy for the recovery of somatosensation and ADL function in patients with sensory deficits after stroke. Corresponding author: Chung Reen Kim M.D., MS, Department of Physical Medicine and Rehabilitation, Ulsan University Hospital, University of Ulsan College of Medicine, 877 Bangeojinsunhwan-doro, Jeonha 1(il)-dong, Dong-gu, Ulsan, Korea. E-mail: crkim@uuh.ulsan.kr, Tel : 82-52-250-8730, Fax : 82-52-250-8071 We certify that no party having a direct interest in the results of the research supporting this article has or will confer a benefit on us or on any organization with which we are associated. No funds were received in support of this manuscript. Additionally, no benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Letter to the editor involving the article ‘’Comparison Between Corticosteroids and Lidocaine Injection in the Treatment of Tennis Elbow: A Randomised, Double-Blinded, Controlled Trial”

No abstract available

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Madelung’s Disease: Lipectomy or Liposuction?

Background. Madelung's disease is a rare lipid metabolic disorder characterized by diffuse, uncapsulated lipomas in the neck, shoulder, and other areas. It mainly affects middle-aged men and is related to alcohol abuse, and the cause is not clear. Surgical treatments include lipectomy and liposuction. Methods. This systematic review analyzed the treatment of Madelung's disease described in 52 articles including complete patient details, published between 2000 and 2015, and retrieved from the Web of Science, PubMed, Medline, and Embase. Results. Lipectomy was performed in most cases and achieved more complete removal and better control of iatrogenic lesions of nearby structures than liposuction. Liposuction achieved good cosmetic results and is simpler and less invasive than lipectomy, but clinical experience is limited. Conclusions. Both lipectomy and liposuction have advantages and drawbacks. Surgeons should base the choice of optimal treatment on patient characteristics. Novel surgical techniques and etiologically targeted treatments hold promise as future therapies.

http://ift.tt/2C8s8MQ

The efficacy of adding targeted agents to neoadjuvant therapy for locally advanced rectal cancer patients: a meta-analysis

Abstract

Patients with locally advanced rectal cancer (LARC) are at tremendous risk of metastatic diseases. To improve the prognoses of LARC patients, the efficacy of adding targeted agents to neoadjuvant therapy has been investigated by many researchers but remains controversial. A literature search of relevant databases was conducted through December 2016, 804 studies were identified and 32 investigations were ultimately included. A total of 1196 patients from 31 cohorts of 29 studies were eligible for quantitative synthesis in this single-arm setting meta-analysis. As pathologic complete response (pCR) shows promise as a prognosis indicator, we focused on pCR rates to evaluate whether adding targeted agents to neoadjuvant therapies improves the outcome of LARC patients. In our study, we revealed pooled estimates of pCR of 27% (95%CI, 21–34%) and 14% (95%CI, 9–21%) for bevacizumab-relevant cohorts and cetuximab-relevant cohorts, respectively. The safety of adding targeted agents to neoadjuvant therapy was also evaluated by pooling the data of Grade 3/4 toxicity. In conclusion, our study revealed that adding bevacizumab to the neoadjuvant therapy regimens provides appreciable pCR for LARC patients. Meanwhile, the efficacy of cetuximab remains inconclusive, RCTs with larger scale and better study design that stress more on mutational status are needed.

Since pathologic complete response (pCR) shows promise as a prognosis indicator, in this meta-analysis we pooled the data of pCR rates extracted from the included studies to evaluate whether adding targeted agents to neoadjuvant therapies improves the outcome of LARC patients. Our study revealed that adding bevacizumab to the neoadjuvant therapy regimens provides an appreciable pCR for LARC patients. Meanwhile, cetuximab fails to benefit LARC patients when the administration is not conducted based on their KRAS status.

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Clinical impact of ulceration width, lymphovascular invasion, microscopic satellitosis, perineural invasion, and mitotic rate in patients undergoing sentinel lymph node biopsy for cutaneous melanoma: a retrospective observational study at a comprehensive cancer center

Abstract

The prognostic significance of the width of the ulceration in primary melanomas remains unclear, and there is a relative paucity of data for lymphovascular invasion (LVI), microscopic satellitosis (MS), perineural invasion (PNI), and mitotic rate when compared with other pathological elements currently required for reporting. To evaluate the prognostic importance of the ulceration width and other important pathologic measurements, a single-institutional retrospective study was conducted using records of cutaneous melanoma patients who underwent sentinel lymph node (SLN) biopsy at The University of Texas, MD Anderson Cancer Center between 2003 and 2008. We identified 1898 eligible patients with median tumor thickness of 1.25 mm and median follow-up of 6.7 years. By multivariable analyses, the strongest risk factor for SLN positivity was high tumor thickness followed by the presence of LVI. The pathologic measures with the strongest influence on recurrence-free survival (RFS) were tumor thickness and positive SLN status. Ulceration width and presence of MS were also significantly associated with RFS while PNI was not. Factors with the strongest influence on melanoma-specific survival (MSS) were positive SLN status and mitotic rate. In conclusion, SLN biopsy should probably be offered if the primary tumor has LVI. MS is an adverse prognostic factor for RFS, but its influence on outcome is modest. Ulceration width predicts RFS but loses its independent prognostic significance for MSS when adjusting for currently used clinicopathological factors. In view of its impact on MSS, mitotic rate should be recorded for cutaneous invasive melanomas across all T categories.

SLN biopsy should be offered if the primary tumor has LVI. MS is an adverse prognostic factor for RFS, but its influence on outcome is modest. Ulceration width predicts RFS but lost its independent prognostic significance for MSS when adjusting for other contemporary clinicopathological factors. In view of its impact on MSS, mitotic rate should be recorded for cutaneous invasive melanomas across all T categories.

http://ift.tt/2EUvOCY

A blood tumor marker combination assay produces high sensitivity and specificity for cancer according to the natural history

Abstract

Diagnosis using a specific tumor marker is difficult because the sensitivity of this detection method is under 20%. Herein, a tumor marker combination assay, combining growth-related tumor marker and associated tumor marker (Cancer, 73(7), 1994), was employed. This double-blind tumor marker combination assay (TMCA) showed 87.5% sensitivity as the results, but a low specificity, ranging from 30 to 76%. To overcome this low specificity, we exploited complex markers, a multivariate analysis and serum fractionation by biochemical biopsy. Thus, in this study, a combination of new techniques was used to re-evaluate these serum samples. Three serum panels, containing 90, 120, and 97 samples were obtained from the Mayo Clinic. The final results showed 80-90% sensitivity, 84-85% specificity, and 83-88% accuracy. We demonstrated a notable tumor marker combination assay with high accuracy. This TMCA should be applicable for primary cancer detection and recurrence prevention.

Utilizing three kind of tumor marker combination assay(TMCA), combining specific tumor marker, associated tumor marker and growth-related tumor marker, we can get high sensitivity of detection, but low specificity. By utilizing TMCA, complex tumor marker, a multivariate analysis formula and protein serum fractionation, we can get high sensitivity and high specificity of detection.

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Skin microbiota and human 3D skin models

Abstract

Although the role of the microbiota in skin homeostasis is still emerging there is growing evidence that an intact microbiota supports the skin barrier. The increasing number of research efforts that are trying to shed more light on the human skin-microbiota interaction require the use of suitable experimental models. Three-dimensional (3D) skin equivalents have been established as a valuable tool in dermatological research because they contain a fully differentiated epidermal barrier that reflects the morphological and molecular characteristics of normal human epidermis. In this review we provide an overview of current 3D skin models and illustrate the potential of 3D skin models to study the human skin-microbiota interplay.

This article is protected by copyright. All rights reserved.

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Cancers, Vol. 10, Pages 57: Recommendations and Choices for BRCA Mutation Carriers at Risk for Ovarian Cancer: A Complicated Decision

Cancers, Vol. 10, Pages 57: Recommendations and Choices for BRCA Mutation Carriers at Risk for Ovarian Cancer: A Complicated Decision

Cancers doi: 10.3390/cancers10020057

Authors: Kelsey Lewis Karen Lu Amber Klimczak Samuel C. Mok

Current ovarian cancer screening guidelines in high-risk women vary according to different organizations. Risk reducing surgery remains the gold standard for definitive treatment in BRCA mutation carriers, but research advancements have created more short-term options for patients to consider. The decisions involved in how a woman manages her BRCA mutation status can cause a great deal of stress and worry due to the imperfect therapy options. The goal of this review was to critically analyze the screening recommendations and alternative options for high-risk ovarian cancer patients and evaluate how these discrepancies and choices affect a woman's management decisions.

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Fine needle aspiration of pilomatrixoma: Cytologic features on thinprep and diagnostic pitfalls

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Issue Information - Masthead

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Issue Information - Copyright

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Annals of Neurology: Volume 83, Number 2, February 2018

A raster display of repeated motor cortical evoked potentials with single pulses of deep brain stimulation in the globus pallidus, pars interna in a patient with cervical dystonia. Each line represents a single trial, with stimulation beginning at the left margin, and the length of each line equivalent to 50 msec of recording. Dark blue = 0 mV, lighter blue-green colors = negative voltage, purple-red colors = positive voltage. Note that the evoked potential is negative at about 10 msec, positive at about 25 msec, and then near zero again at 50 msec. See Ni et al., pp 352–362, this issue. Ann Neurol 2018;83:1–1

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Issue Information - TOC

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Evaluation of visual function in preschool-age children using a vision screening protocol

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The 24-hour intraocular pressure control by tafluprost/timolol fixed combination after switching from the concomitant use of tafluprost and timolol gel-forming solution, in patients with primary open-angle glaucoma

http://ift.tt/2Hz4RTZ

Palliative Care for Movement Disorders

Abstract

Purpose of review

While care for patients with movement disorders has traditionally focused on motor symptoms, there is increasing evidence that optimal care for these disorders is more complex both in terms of the spectrum of symptoms experienced by patients (e.g., pain, depression) and the multidimensional needs of patients and their families. Palliative care is an approach to the care of patients and families affected by serious illnesses that seeks to relieve suffering by addressing complex medical symptoms, psychosocial issues, spiritual well-being, and goals of care. While traditionally associated with cancer and hospice, more recent work in palliative care has focused on integrating a palliative care approach from the time of diagnosis for patients with chronic illnesses, including movement disorders.

Recent findings

Studies of patients with movement disorders and their family caregivers suggest that these patients have significant unmet needs under current models of care, including underrecognition and treatment of non-motor symptoms, inadequate psychosocial support, and suboptimal end-of-life care. We describe how a palliative care approach can empower clinicians, patients, and families to reduce common sources of suffering and optimize quality of life. This field recognizes the importance of primary palliative care (palliative skills useful for any clinician caring for persons caring for serious illness) as a foundation of the palliative care approach and complementary to specialist palliative care. In this article, we will focus on primary palliative care skills for movement disorder specialists including providing a diagnosis and prognosis with compassion, discussing goals of care, complex symptom management, caregiver support, spiritual and emotional well-being, and referral to hospice and specialist palliative care.

Summary

A palliative care approach complements other efforts in movement disorder care. Research is needed to evaluate and develop therapeutic interventions and models of care applying a palliative care approach.

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Was 4β-hydroxycholesterol ever going to be a useful marker of CYP3A4 activity?

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Lack of correlation of desiccation and radiation tolerance in microorganisms from diverse extreme environments tested under anoxic conditions

Abstract

Four facultative anaerobic and two obligate anaerobic bacteria were isolated from extreme environments (deep subsurface halite mine, sulfidic anoxic spring, mineral-rich river) in the frame MASE (Mars Analogues for Space Exploration) project. The isolates were investigated under anoxic conditions for their survivability after desiccation up to six months and their tolerance to ionizing radiation up to 3000 Gy. The results indicated that tolerances to both stresses are strain-specific features. Yersinia intermedia MASE-LG-1 showed a high desiccation tolerance but its radiation tolerance was very low. The most radiation tolerant strains were Buttiauxella sp. MASE-IM-9 and Halanaerobium sp. MASE-BB-1. In both cases, cultivable cells were detectable after an exposure to 3 kGy of ionizing radiation, but cells only survived desiccation for 90 and 30 days, respectively.Although a correlation between desiccation and ionizing radiation resistance has been hypothesized for some aerobic microorganisms, our data showed that there was no correlation between tolerance to desiccation and ionizing radiation, suggesting that the physiological basis of both forms of tolerances is not necessarily linked. In addition, these results indicated that facultative and obligate anaerobic organisms living in extreme environments possess varied species-specific tolerances to extremes.

http://ift.tt/2Hz2QXY

Intermittent energy restriction for weight loss: Spontaneous reduction of energy intake on unrestricted days

Abstract

There is increasing interest for the use of intermittent energy restriction (IER) in weight management. However, there are concerns that IER could result in 'rebound' overconsumption of energy on unrestricted days. We studied self-reported food records from participants in two trials of IER versus continuous energy restriction (Study 1; 44 women on IER for 6 months and Study 2; 72 women on two types of IER for 4 months). Energy intake was assessed on restricted and unrestricted days immediately before and after restricted days and on other unrestricted days. We assessed consistency of days of the week chosen as restricted days, and whether this was associated with greater weight loss. Reported energy intake was reduced on unrestricted days in Study 1 and 2 and was 19% lower compared with the allocated isoenergetic diet, and respectively 21% and 29% lower than their baseline reported daily intakes. Energy intake appeared to be similarly reduced the day immediately before and after restricted days and on other unrestricted days. Seventy percent of women in Study 1 and 79% in Study 2 undertook consistent days of restriction each week (>50% of restricted days on the same 2 days each week). When studies were combined percentage weight loss at 3 months was −5.8 (−6.7 to −4.7) % in the consistent group and −7.4 (−8.7 to −6.2) % in the non-consistent group (p = .09). Food records from patients undertaking IER suggest a spontaneous reduction in energy intake below their baseline reported intakes and the prescribed isoenergetic diet during all unrestricted days including the days immediately before and after restricted days which contributes to the weight loss success with these diets. Consistency of restricted days was not associated with weight loss success. These findings need to be confirmed in larger groups of patients ideally using objective measures of energy balance.

There is increasing interest in the potential for intermittent energy restriction (IER) to be used in weight management. However, there are concerns that IER could result in 'rebound' overconsumption of energy on unrestricted days. We studied self -reported food records from participants in two trials of IER versus continuous energy restriction. IER is associated with a spontaneous reduction in energy intake during all unrestricted days including the days immediately before and after the two day period of energy restriction. Consistency of restricted days was not associated with weight loss success.

http://ift.tt/2EH8bui

Expression of miR-634 in gastric carcinoma and its effects on proliferation, migration, and invasion of gastric cancer cells

Abstract

This study aims to observe the expression of microRNA (miR)-634 in different gastric cancer cell lines and tissues, and to study the effects of miR-634 on the proliferation, migration, and invasion of the gastric cancer cells. The miR-634 mimics and miR-634 inhibitors were transfected by lentivirus into human gastric cancer SGC-7901 and MGC-803 cells, and the miR-634 cells without transfection were used as the control group (NC group). The expression of miR-634 in the transfected cells was detected by qRT-PCR. Cell viability was measured by the CCK8 assay. The migration and invasion ability of the cells were detected by scratch assays and Transwell^® chamber assays, respectively, and the luciferase assay verified the binding of miR-634 to the target gene JAG1. The expression level of miR-634 in gastric cancer tissues and cell lines was significantly lower than that in normal adjacent tissues and control cells. The survival of cells was significantly decreased, and number of cells migrating and invading was decreased in the miR-634 mimics group. However, in the miR-634 inhibitor group, the opposite results were observed. Over-expression of miR-634 inhibited the proliferation, migration, and invasion of gastric cancer cell lines, and the miR-634 target gene was JAG1.

Over-expression of miR-634 inhibited the proliferation, migration, and invasion of gastric cancer cell lines, and the miR-634 target gene was JAG1.

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Pharmacokinetics of second-line anti-tuberculosis drugs in children with multidrug-resistant tuberculosis in India [PublishAheadOfPrint]

We studied the pharmacokinetics of levofloxacin (LFX), pyrazinamide (PZA), ethionamide (ETH) and cycloserine (CS) in children with multidrug-resistant tuberculosis (MDR TB) being treated according to the Revised National TB Control Programme (RNTCP) guidelines in India. This observational, pharmacokinetic study was conducted in 25 children with MDR TB at the Sarojini Naidu Medical College, Agra, India who were being treated with a 24-month daily regimen. Serial blood samples were collected after directly observed administration of drugs. Estimation of plasma LFX, PZA, ETH and CS were undertaken according to validated methods by HPLC. Adverse events were noted at six months of treatment. The peak concentration (C_max) of LFX was significantly higher in female than male children (11.5μg/ml vs 7.3μg/ml; p = 0.017). Children below 12 years had significantly higher exposure (AUC_0-8) of ETH than those above 12 years of age (17.5μg/ml.h vs 9.4μg/ml; p = 0.030). Multiple linear regression analysis showed significant influence of gender on C_{max of} ETH and age on C_max and AUC_0-8 of CS. This is the first and only study from India reporting on the pharmacokinetics of LFX, ETH, PZA and CS in children with MDR TB treated in the Government of India programme. More studies on the safety and pharmacokinetics of second-line anti-TB drugs in children with MDR TB from different settings are required.

http://ift.tt/2EGQrTU

A complex interplay between sphingolipid and sterol metabolism revealed by perturbations to the Leishmania metabolome caused by miltefosine [PublishAheadOfPrint]

With the World Health Organization reporting over 30,000 deaths and 200-400,000 new cases annually, visceral Leishmaniasis is a serious disease affecting some of the world's poorest people. As drug resistance continues to rise, there is a huge unmet need to improve treatment. Miltefosine remains one of the main treatments for Leishmaniasis, yet its mode of action (MoA) is still unknown. Understanding the MoA of this drug and parasite response to treatment could help pave the way for new, more successful treatments for Leishmaniasis. A novel method has been devised to study the metabolome and lipidome of Leishmania donovani axenic amastigotes treated with miltefosine. Miltefosine caused a dramatic decrease in many membrane phospholipids (PLs), in addition to amino acid pools, while sphingolipids (SLs) and sterols increased. Leishmania major promastigotes devoid of SL biosynthesis through loss of the serine palmitoyl transferase gene (LCB2) were 3-fold less sensitive to miltefosine than WT parasites. Changes in the metabolome and lipidome of miltefosine treated L. major mirrored those of L. donovani. A lack of SLs in the LCB2 was matched by substantial alterations in sterol content. Together these data indicate that SLs and ergosterol are important for miltefosine sensitivity and perhaps, MoA.

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Alginate Oligosaccharide-Induced Modification of the lasI-lasR and rhlI-rhlR Quorum Sensing Systems in Pseudomonas aeruginosa [PublishAheadOfPrint]

Pseudomonas aeruginosa plays a major role in many chronic infections. Its ability to readily form biofilms contributes to its success as an opportunistic pathogen and its resistance/tolerance to antimicrobial/antibiotic therapy. A low molecular weight alginate oligomer (OligoG CF-5/20), derived from marine algae, has previously been shown to impair motility in P. aeruginosa biofilms and disrupt pseudomonal biofilm assembly. As these bacterial phenotypes are regulated by quorum sensing (QS), we hypothesized that OligoG CF-5/20 may induce alterations in QS signalling in P. aeruginosa. QS regulation was studied using Chromobacterium violaceum CV026 biosensor assays that showed a significant reduction in acyl homoserine lactone (AHL) production following OligoG CF-5/20 treatment (≥2%; P<0.05). This effect was confirmed by liquid chromatography/mass spectrometry (LC/MS) analysis of C4-AHL and 3-oxo-C12-AHL production (≥2%; P<0.05). Moreover, quantitative PCR (qPCR) showed that reduced expression of both the las and rhl systems was induced following 24 h treatment with OligoG CF-5/20 (≥0.2%; P<0.05). Circular dichroism (CD) spectroscopy indicated that these alterations were not due to steric interaction between the AHL and OligoG CF-5/20. Confocal laser scanning microscopy and COMSTAT image analysis demonstrated that OligoG CF-5/20 treated biofilms had a dose-dependent decrease in biomass which was associated with inhibition of eDNA synthesis (≥0.5%; P<0.05). These changes correlated with alterations in extracellular production of the pseudomonal virulence factors pyocyanin, rhamnolipids, elastase and total protease (P<0.05). The ability of OligoG CF-5/20 to modify QS signalling in P. aeruginosa PAO1 which may influence critical downstream functions, such as virulence factor production and biofilm formation.

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GRL-079, a novel P2-Tp-THF-C5-alkylamine- and P2 -Abt-containing HIV-1 protease inhibitor, is extremely potent against multi-drug-resistant HIV-1 variants including HIVDRVRp51 and has a high genetic barrier against the emergence of resistant variants [PublishAheadOfPrint]

We identified four novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs), GRL-078, -079, -077, and -058, containing an alkylamine at the C5 position of P2-tetrahydropyrano-tetrahydrofuran (Tp-THF) and a P2' -cyclopropyl (Cp)(or isopropyl)-aminobenzothiazole (Abt). Their 50% effective concentrations (EC₅₀s) were 2.5-30 nM against wild-type HIV-1_NL4-3, 0.3-6.7 nM against HIV-2_EHO, and 0.9-90 nM against laboratory-selected-PI-resistant HIV-1 and clinical HIV-1 variants resistant to multiple FDA-approved PIs (HIV_MDR). GRL-078, -079, -077, and -058 also effectively blocked the replication of HIV-1 variants highly resistant to darunavir (DRV:HIV_DRV^R_p51), with EC₅₀ values of 38, 62, 61, and 90 nM, respectively, while four FDA-approved PIs examined [amprenavir, atazanavir, lopinavir (LPV), and DRV] virtually had no activity (EC₅₀>1,000 nM) against HIV_DRV^R_p51. Structurally, GRL-078, -079, and -058 form strong hydrogen bond interactions between the C5-modified-Tp-THF and Asp29/Asp30/Gly48 of wild-type protease while P2' -Cp-Abt forms strong hydrogen bonds with Asp30' . The Tp-THF and Cp-Abt moieties also have good nonpolar interactions with protease residues located in the flap region. When selected with LPV and DRV using a mixture of 11 HIV_MDR strains (HIV_11MIX), HIV_11MIX became highly resistant to LPV and DRV over 13-32 and 32-41 weeks, respectively. However, when selected with GRL-079 and GRL-058, HIV_11MIX failed to replicate at >0.08 μM and >0.2 μM, respectively. Thermal stability results supported the highly favorable anti-HIV-1 potency of GRL-079 as well as other PIs. The present data strongly suggest that the C5-modified P2-Tp-THF and P2' -Abt moiety contribute to the potent anti-HIV-1 profiles of the four PIs against HIV-1_NL4-3 and a wide spectrum of HIV_MDRs.

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Pharmacokinetics of penicillin G in preterm and term neonates [PublishAheadOfPrint]

Group B streptococci are common causative agents of early-onset neonatal sepsis (EOS). Pharmacokinetic (PK) data for penicillin G have been described for extremely preterm neonates but poorly for late-preterm and term neonates. Thus, evidence-based dosing recommendations are lacking. We described PK of penicillin G in neonates with gestational age (GA) ≥32 weeks and postnatal age <72 h. Penicillin G was administered intravenously at a dose of 25,000 or 50,000 IU/kg/q12h. At steady state, PK blood samples were collected prior to and at 5 min, 1 h, 3 h, 8 h, 12 h after injection. Non-compartmental PK analysis was performed with WinNonlin. In combination with data from neonates with GA ≤28 weeks we developed a population PK model using NONMEM software and performed probability of target attainment (PTA) simulations. In total, 16 neonates with GA ≥32 weeks were included in non-compartmental analysis. The median (interquartile range) volume of distribution (VD) was 0.50 (0.42-0.57) L/kg, clearance (CL) 0.21 (0.16-0.29) L/h and half-life 3.6 (3.2-4.3) h. In population PK analysis that included 35 neonates, a two-compartment model best described the data. The final parameter estimates were 10.3 L/70kg and 29.8 L/70kg for VD of the central and peripheral compartment, respectively, and 13.2 L/h/70kg for CL. Considering fraction of unbound penicillin G of 40%, PTA of time when the unbound drug exceeds MIC of 40% was >90% for MICs ≤2 mg/L with doses of 25,000 IU/kg/q12h. In neonates, regardless of GA, PK parameters of penicillin G are similar. The dose of 25,000 IU/kg/q12h is suggested for treatment of group B streptococcal EOS diagnosed within the first 72 hours of life.

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Verapamil targets membrane energetics in Mycobacterium tuberculosis [PublishAheadOfPrint]

Mycobacterium tuberculosis (Mtb) kills more people than any other bacterial pathogen and is becoming increasingly untreatable due to the emergence of resistance. Verapamil, an FDA-approved calcium channel blocker, potentiates the effect of several anti-tuberculosis (TB) drugs in vitro and in vivo. This potentiation is widely attributed to inhibition of Mtb's efflux pumps, resulting in intrabacterial drug accumulation. Here, we confirm and quantify verapamil's synergy with several anti-TB drugs, including bedaquiline and clofazimine, but find that this effect is not due to increased intrabacterial drug accumulation. Consistent with its in vitro potentiating effects on TB drugs that target or require oxidative phosphorylation, we show that the cationic amphiphile verapamil disrupts membrane function and induces a membrane stress response, similar to other membrane-active agents. We recapitulate these activities in vitro using inverted mycobacterial membrane vesicles, indicating a direct effect of verapamil on membrane energetics. Consistent with such mechanism of action, we observe bactericidal activity against non-replicating 'persister' Mtb. In addition, we demonstrate a pharmacokinetic interaction whereby human-equivalent doses of verapamil cause a boost of rifampicin exposure in mice, providing a potential explanation for the observed treatment shortening effect of verapamil in mice receiving first line drugs. Our findings thus elucidate the mechanistic basis for verapamil's potentiation of TB drugs in vitro and in vivo, and highlight a previously unrecognized role for Mtb's membrane as pharmacologic target.

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Impact of oral fidaxomicin administration on the intestinal microbiota and susceptibility to Clostridium difficile colonization in mice [PublishAheadOfPrint]

Clostridium difficile infection (CDI), a common cause of hospital-acquired infections, typically occurs after disruption of the normal gut microbiome by broad-spectrum antibiotics. Fidaxomicin is a narrow-spectrum antibiotic that demonstrates reduced impact on the normal gut microbiota and is approved for the treatment of CDI. To further explore the benefits of this property, we used a murine model to examine the effects of fidaxomicin versus vancomycin on gut microbiota and susceptibility to C. difficile colonization while tracking microbiota recovery over time.

Mice were exposed to fidaxomicin or vancomycin by oral gavage for 3 days, and subsequently challenged with C. difficile spores at predetermined time points up to 21 days post-antibiotic exposure. Fecal samples were subsequently collected for analysis. Twenty-four hours post-challenge, mice were euthanized and colon contents harvested. The microbiota was characterized using 16S rDNA gene sequencing.

All fidaxomicin exposed mice (except for one at Day 8) were resistant to C. difficile colonization. However, 9 of 15 vancomycin exposed mice were susceptible to C. difficile colonization until Day 12. All vancomycin exposed mice recovered colonization resistance by Day 16. Bacterial diversity was similar prior to antibiotic exposure in both arms and decreased substantially after exposure. A shift in taxonomic structure and composition occurred after both exposures; however, the shift was greater in vancomycin- than in fidaxomicin-exposed mice.

In summary, compared with vancomycin, fidaxomicin exposure had less impact on microbiota composition, promoted faster microbial recovery and had less impact on loss of C. difficile colonization resistance.

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Mesoscopic Energy Minimization Drives Pseudomonas aeruginosa Biofilm Morphologies and Consequent Stratification of Antibiotic Activity Based on Cell Metabolism [PublishAheadOfPrint]

Segregation of bacteria based on their metabolic activity in biofilms plays an important role in the development of antibiotic drug resistance. Mushroom-shaped biofilm structures, which are reported for many bacteria, exhibit topographically varying levels of multiple drug resistance from the cap of the mushroom to its stalk. Understanding the dynamics behind the formation of such structures can aid in design of drug delivery systems, antibiotics, or physical systems for removal of biofilms. We explore the development of metabolically heterogenous Pseudomonas aeruginosa biofilms using numerical models and laboratory knock-out experiments on wild-type and chemotaxis deficient mutants. We show that chemotactic processes dominate the transformation of slender and hemispherical structures into mushroom structures with a signature cap. Cellular Potts model simulation and experimental data provide evidence that accelerated movement of bacteria along the periphery of the biofilm, due to nutrient cues, results in the formation of mushroom structures and bacterial segregation. Multi-drug resistance of bacteria is one of the most threatening dangers to public health. Understanding the mechanisms of the development of mushroom shaped biofilms helps to identify the multidrug resistant regions. We decoded the dynamics of the structural evolution of bacterial biofilms and the physics behind the formation of biofilm structures as well as the biological triggers that produce them. Combining in-vitro gene knock-out experiments with in-silico models shows that chemotactic motility is one of the main driving forces for the formation of stalks and caps. Our result provides physicists and biologists with a new perspective on biofilm removal and eradication strategies.

http://ift.tt/2CClWZy

Promoter variation and gene expression of mcr-1-harboring plasmids in clinical isolates of Escherichia coli and Klebsiella pneumoniae from a Chinese hospital [PublishAheadOfPrint]

Next generation sequencing of six mcr-1-harboring Escherichia coli and Klebsiella pneumoniae isolates collected from a tertiary care hospital in China revealed significant sequence variations in the regions flanking the mcr-1 gene. While sequence variations significantly affect the expression and promoter activity of mcr-1, the mcr-1 gene expressions do not correlate with the in vitro colistin resistance levels, which warrants further in-depth investigations.

http://ift.tt/2EKFYqk

Population Pharmacokinetic properties of Sulfadoxine and Pyrimethamine: A pooled analysis to Inform Optimal Dosing in African Children with Uncomplicated Malaria. [PublishAheadOfPrint]

Sulfadoxine/pyrimethamine with amodiaquine is recommended by the World Health Organization as seasonal malaria chemoprevention for children between 3 to 59 months in the sub-Sahel regions of Africa. Sub-optimal dosing in children may lead to treatment failure and increased resistance. Pooled individual patient data from four previously published trials on the pharmacokinetics of sulfadoxine and pyrimethamine in 415 paediatric and 386 adult patients were analysed using nonlinear mixed effects modelling to evaluate the current dosing regimen and, if needed, propose an optimised dosing regimen in children under five years old. The population pharmacokinetics of sulfadoxine and pyrimethamine were both best described by a one-compartment disposition model, with first-order absorption and elimination. Body weight, age and nutrition status (measured as weight-for-age z-scores) were found to be significant covariates. Allometric scaling with total body weight and maturation of clearance in children using post-gestational age improved the model fit. Underweight-for-age children were found to have 15.3% and 26.7% lower bioavailability of sulfadoxine and pyrimethamine, respectively, for each z-score unit below minus 2. Under current dosing recommendations, simulation predicted that the median day 7 concentration was below the 25^th percentile of a typical adult patient (50 kg) for sulfadoxine for patients in 8-9, 19-24, 46-49 and 74-79 kg weight bands, and for pyrimethamine for the weight-bands 8-9, 14-24 and 42-49 kg. An evidence-based dosing regimen was constructed that would achieve sulfadoxine and pyrimethamine exposure in young children and underweight-for-age young children that was similar to that currently seen in a typical adult.

http://ift.tt/2CClFWw

Treatment with atorvastatin provides additional benefits to imipenem in a model of Gram-negative pneumonia induced by Klebsiella pneumoniae in mice [PublishAheadOfPrint]

The clinical pathogen Klebsiella pneumoniae is a relevant cause of nosocomial infections and resistance to current treatment with carbapenem antibiotics is becoming a significant problem. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) used for controlling plasma cholesterol levels. There is clinical evidence showing other effects of statins, including decrease of lung inflammation. In the current study, we show that pretreatment with atorvastatin markedly attenuated lung injury, which was correlated with a reduction in the cellular influx into the alveolar space and lungs and down-modulation of the production of pro-inflammatory mediators in the initial phase of infection in C57BL/6 mice with K. pneumoniae. However, atorvastatin did not alter the number of bacteria in the lungs and blood of infected mice, despite decreasing local inflammatory response. Interestingly, mice that received combined treatment with atorvastatin and imipenem displayed better survival rate than mice treated with vehicle, atorvastatin or imipenem alone. These findings suggest that atorvastatin could be an adjuvant in host-directed therapies for multidrug-resistant K. pneumoniae, based on its powerful pleiotropic immunomodulatory effects. Together with antimicrobial approaches, combination therapy with anti-inflammatory compounds could improve the efficiency of therapy during acute lung infections.

http://ift.tt/2EGJ92l

Optimization and evaluation of piperacillin plus tobramycin combination dosage regimens against Pseudomonas aeruginosa for patients with altered pharmacokinetics via the hollow-fiber infection model and mechanism-based modeling [PublishAheadOfPrint]

Augmented renal clearance (ARC) in critically-ill patients can result in suboptimal drug exposures and treatment failure. Combination dosage regimens accounting for ARC have never been optimized and evaluated against Pseudomonas aeruginosa using the hollow-fiber infection model (HFIM). Using a P. aeruginosa isolate from a critically-ill patient and static concentration time-kill experiments (SCTK), we studied clinically relevant piperacillin and tobramycin concentrations, alone and in combinations, at two inocula (10^5.8 and 10^7.6 CFU/mL) over 72h. We subsequently evaluated the effect of optimized piperacillin (4 g q4h, 0.5h infusion) plus tobramycin (5 mg/kg q24h, 7 mg/kg q24h and 10 mg/kg q48h as 0.5h infusions) regimens on killing and regrowth in the HFIM, simulating a creatinine clearance of 250 mL/min. Mechanism-based modeling was performed in S-ADAPT. In SCTKs, piperacillin plus tobramycin (except combinations with 8 mg/liter tobramycin at low inoculum) achieved synergistic killing (≥2 log₁₀vs. the most active monotherapy at 48h and 72h) and prevented regrowth. Piperacillin monotherapy (4 g q4h) in the HFIM provided 2.4 log₁₀ initial killing followed by regrowth at 24h with resistance emergence. Tobramycin monotherapies displayed rapid initial killing (≥5 log₁₀ at 13h) followed by extensive regrowth. As predicted by mechanism-based modeling, the piperacillin plus tobramycin dosage regimens were synergistic and provided ≥5 log₁₀ killing with resistance suppression over 8 days in the HFIM. Optimized piperacillin plus tobramycin regimens provided significant bacterial killing and suppressed resistance emergence. These regimens appear highly promising for effective and early treatment, even in the near-worst case scenario of ARC.

http://ift.tt/2HuyLZo

Complete genome sequencing of Acinetobacter baumannii str. K50 disclosed the large conjugative plasmid pK50a encoding the carbapenemase OXA-23 and the extended-spectrum {beta}-lactamase GES-11 [PublishAheadOfPrint]

Multidrug-resistant (MDR) Acinetobacter baumannii strains appeared as serious emerging nosocomial pathogens in clinical environments and especially in intensive care units (ICUs). A. baumannii strain K50 recovered from a hospitalized patient in Kuwait exhibited resistance to carbapenems, and additionally to ciprofloxacin, chloramphenicol, sulfonamides, amikacin and gentamicin. Genome sequencing revealed that the strain possesses two plasmids, pK50a (79.6 kb) and pK50b (9.5 kb) and a 3.75 Mb chromosome. A. baumannii K50 exhibits an Average Nucleotide Identity (ANI) value of 99.98% to the previously reported Iraqi clinical isolate AA-014, even though that the latter strain lacked plasmid pK50a. Strain K50 belongs to the Sequence Type ST158 (Pasteur scheme) and ST499 according to the Oxford scheme. Plasmid pK50a is a member of the Aci6 (RG6) group of Acinetobacter plasmids, and encodes a conjugative transfer module and two antibiotic resistance gene regions comprising the transposon Tn2008. The transposon carries the carbapenemase gene bla_OXA-23 and a class 1 integron harboring the resistance genes bla_GES-11, aacA4, dfrA7, qacE1 and sul1 conferring resistance to all β-lactams and reduced susceptibility to carbapenems, resistance to aminoglycosides, trimethoprim, quaternary ammonium compounds and sulfamethoxazole, respectively. The class 1 integron is flanked by MITEs (Miniature Inverted repeat Transposable Element) delimiting the element at its insertion site.

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A new marker of echinocandins activity in an in vitro PK/PD model correlates with an animal model of Aspergillus fumigatus infection [PublishAheadOfPrint]

The lack of a quantifiable marker for echinocandins activity hinders in vitro PK/PD studies for Aspergillus spp. We developed an in vitro PK/PD model simulating anidulafungin pharmacokinetics and assessing its pharmacodynamics against A. fumigatus with a new easily quantifiable, sensitive and reproducible marker. Two clinical A. fumigatus isolates previously used in animals (AZN8196,V52-35) with identical anidulafungin EUCAST (0.03 μg/ml) and CLSI (0.015 μg/ml) MEC and one (AFU79728) with MEC>16 μg/ml were tested in a two-compartment PK/PD dialysis/diffusion closed model containing a dialysis membrane tube (DM) inoculated with 10³ cfu/mL. During anidulafungin exposure, two types of fungal forms were observed inside the DM, floating conidia that were quantified by cultures and attached aberrant mycelia that were quantified by the vertical height of the mycelia covering the DM. No aberrant mycelia were found for the resistant isolate and in the drug-free controls. In vitro exposure-effect relationship was similar with that found in animals using survival as an endpoint with fAUC_0-24 (range) associated with 50% of maximal activity of 2.21 (1.81-2.71) vs 2.62 (1.88-3.65) (p=0.41), respectively. The Hillslopes were also similar, 1.96 vs 1.34 (p=0.29). Analysis of each isolate separately showed increased antifungal susceptibility between AZN8196 and V52-35 (p<0.001) despite the same CLSI and EUCAST MECs but 2 two-fold lower MICs using Etest and XTT method. Dose fractionation studies with all three echinocandins showed that their activity is best described by fAUC rather than fC_max. The new marker correlated with in vivo outcome and can be used for in vitro PK/PD studies exploring pharmacodynamics of echinocandins against Aspergillus spp.

http://ift.tt/2Czcbv7

PGI2, a novel SGI1-relative multidrug-resistant genomic island characterized in Proteus mirabilis [PublishAheadOfPrint]

A novel 61,578 bp genomic island named Proteus genomic island 2 (PGI2) was characterized in P. mirabilis of swine origin in China. The 23.85-kb backbone of PGI2 is related to that of Salmonella genomic island 1 and Acinetobacter genomic island 1. The MDR region of PGI2 is a complex class 1 integron containing fourteen different resistance genes. PGI2 was conjugally mobilized in trans to Escherichia coli in the presence of a conjugative IncC helper plasmid.

http://ift.tt/2EGJ5Q9

Elevated Plasma Moxifloxacin Concentrations and SLCO1B1 g.-11187G>A Polymorphism in Adults with Pulmonary Tuberculosis [PublishAheadOfPrint]

Moxifloxacin exhibits concentration-dependent prolongation of human QTc intervals and bactericidal activity against Mycobacterium tuberculosis. However, moxifloxacin plasma concentrations are variable between patients. We evaluated whether human gene polymorphisms affect moxifloxacin plasma concentrations in tuberculosis patients from two geographic regions. We enrolled a convenience sample of 49 adults with drug-sensitive pulmonary tuberculosis from Africa and the United State s enrolled in two treatment trials of moxifloxacin as part of multidrug therapy. Pharmacokinetic parameters were evaluated by noncompartmental techniques. Human single-nucleotide polymorphisms of transporter genes were evaluated with analysis of covariance on moxifloxacin exposure and peak concentration (C_max). Moxifloxacin area under the concentration-time curve from 0 to 24 h (AUC_0-24) and C_max were significantly increased by drug mg/kg dosage and genotype of variant g.-11187G>A in the SLCO1B1 gene (rs4149015), but not by geographic region. Median moxifloxacin AUC_0-24 was 46% higher and C_max 30% higher in 4 (8% of) participants who had the SLCO1B1 g.-11187 AG genotype compared with 45 participants who had the wild type GG genotype (median from model, AUC_0-24 34.4 vs. 23.6 μg*h/mL, P =.005; C_max 3.5 vs. 2.7 μg/mL, P =.009, ANCOVA). Because moxifloxacin exhibits concentration-dependent prolongation of human QTc intervals, and prolonged QTc intervals are associated with cardiac arrhythmia, further study is needed to evaluate risk associated with the SLCO1B1 g.-11187G>A variant.

http://ift.tt/2CAop6G

A novel mechanism for activation of GLI1 by nuclear SMO that escapes anti-SMO inhibitors

Small molecule inhibitors of the Hedgehog (HH) pathway receptor Smoothened (SMO) have been effective in treating some patients with basal cell carcinoma (BCC), where the HH pathway is often activated, but many patients are poorly responsive. In this study, we report the results of investigations on PTCH1 signalling in the HH pathway that suggest why most BCC patients respond poorly to SMO inhibitors. In immortalised human keratinocytes, PTCH1 silencing led to the generation of a compact, holoclone-like morphology with increased expression of SMO and the downstream HH pathway transcription factor GLI1. Notably, while siRNA silencing of SMO in PTCH1-silenced cells was sufficient to suppress GLI1 activity, this effect was not phenocopied by pharmacological inhibition of SMO, suggesting the presence of a second undefined pathway through which SMO can induce GLI1. Consistent with this possibility, we observed increased nuclear localisation of SMO in PTCH1-silenced cells as mediated by a putative SMO nuclear/nucleolar localisation signal (N(o)LS). Mutational inactivation of the N(o)LS ablated this increase and suppressed GLI1 induction. Immunohistological analysis of human and mouse BCC confirmed evidence of nuclear SMO, although the pattern was heterogeneous between tumours. In PTCH1-silenced cells, >80% of the genes found to be differentially expressed were unaffected by SMO inhibitors, including the putative BCC driver gene CXCL11. Our results demonstrate how PTCH1 loss results in aberrant regulation of SMO-independent mechanisms important for BCC biology, and highlights a novel nuclear mechanism of SMO-GLI1 signalling that is unresponsive to SMO inhibitors.

http://ift.tt/2sEq4s2

BMI Can Underestimate Breast Cancer Risk [News in Brief]

Postmenopausal women with high body fat levels are at higher risk, even with normal BMI.

http://ift.tt/2BH2KwT

Disruption of Wnt/{beta}-catenin exerts anti-leukemia activity and synergizes with FLT3 inhibition in FLT3-mutant acute myeloid leukemia

Purpose: Wnt/β-catenin signaling is required for leukemic stem cell function. FLT3 mutations are frequently observed in acute myeloid leukemia (AML). Anomalous FLT3 signaling increases β-catenin nuclear localization and transcriptional activity. FLT3 tyrosine kinase inhibitors (TKIs) are used clinically to treat FLT3-mutated AML patients, but with limited efficacy. We investigated the anti-leukemia activity of combined Wnt/β-catenin and FLT3 inhibition in FLT3-mutant AML. Experimental Design: Wnt/β-catenin signaling was inhibited by the b-catenin/CBP antagonist C-82/PRI-724 or siRNAs, and FLT3 signaling by sorafenib or quizartinib. Treatments on apoptosis, cell growth, and cell signaling were assessed in cell lines, patient samples, and in vivo in immunodeficient mice by flow cytometry, western blot, RT-PCR, and CyTOF.  Results: We found significantly higher β-catenin expression in cytogenetically unfavorable and relapsed AML patient samples and in the bone-marrow-resident leukemic cells compared to circulating blasts. Disrupting Wnt/b-catenin signaling suppressed AML cell growth, induced apoptosis, abrogated stromal protection, and synergized with TKIs in FLT3-mutated AML cells and stem/progenitor cells in vitro. The aforementioned combinatorial treatment improved survival of AML-xenografted mice in two in vivo models and impaired leukemia cell engraftment. Mechanistically, the combined inhibition of Wnt/β-catenin and FLT3 cooperatively decreased nuclear β-catenin and the levels of c-Myc and other Wnt/β-catenin and FLT3 signaling proteins. Importantly, β-catenin inhibition abrogated the microenvironmental protection afforded the leukemic stem/progenitor cells.  Conclusions: Disrupting Wnt/β-catenin signaling exerts potent activities against AML stem/progenitor cells and synergizes with FLT3 inhibition in FLT3-mutant AML. These findings provide a rationale for clinical development of this strategy for treating FLT3-mutated AML patients.

http://ift.tt/2Hxvo47

Capecitabine efficacy is correlated with TYMP and RB expression in PDX established from triple-negative breast cancers

Purpose: triple-negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy have a poor outcome. We developed patient-derived xenografts (PDX) from residual tumors to identify efficient chemotherapies and predictive biomarkers in a context of resistance to anthracyclines and taxanes-based treatments. Experimental Design: PDX were established from residual tumors of primary breast cancer patients treated in neoadjuvant setting. TNBC PDX were treated by anthracyclines, taxanes, platins and capecitabine. Predictive biomarkers were identified by transcriptomic and immunohistological analysis. Downregulation of RB1 was performed by siRNA in a cell line established from a PDX. Results: residual TNBC PDX were characterized by a high tumor take, a short latency and a poor prognosis of the corresponding patients. With the exception of BRCA1/2 mutated models, residual PDX were resistant to anthracyclines, taxanes, and platins. Capecitabine, the oral prodrug of 5-FU, was highly efficient in 60% of PDX with two models showing complete responses. Prior treatment of a responder PDX with 5-FU increased expression of thymidylate synthase and decreased efficacy of capecitabine. Transcriptomic and IHC analyses of 32 TNBC PDX, including both residual tumors and treatment-naïve derived tumors, identified RB and TYMP proteins as predictive biomarkers for capecitabine response. Finally, RB1 knockdown in a cell line established from a capecitabine-responder PDX decreased sensitivity to 5-FU treatment. Conclusions: we identified capecitabine as efficient chemotherapy in TNBC PDX models established from residual disease and resistant to anthracyclines, taxanes and platins. RB positivity and high expression of TYMP were significantly associated with capecitabine response.

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Molecular lymph node status for prognostic stratification of prostate cancer patients undergoing radical prostatectomy with extended pelvic lymph node dissection

Purpose: Molecular lymph node (LN) analysis using quantitative polymerase chain reaction (qPCR) detects LN metastases with higher sensitivity than histopathology. However, the prognostic role of molecular LN status in prostate cancer (PCa) patients treated with radical prostatectomy (RP) and extended pelvic LN dissection (ePLND) is unclear. To investigate the association of molecular compared to histopathologic LN status with biochemical recurrence. Experimental Design: Patients with intermediate and high risk PCa were prospectively enrolled and underwent RP with ePLND including obturator, internal, external and common iliac region. LNs ≥3mm were bisected and examined by standard histopathology and qPCR for Kallikrein3 (KLK3) expression. Biochemical recurrence was defined by confirmed postoperative PSA>0.2ng/ml. Results: In 111 patients, 2411 of 3173 removed LNs were examined by both methods. Histopathology detected 68 LN metastases in 28 (25%) patients. Molecular analysis confirmed elevated KLK3 expression in 65 histopathologic LN metastases of all 28 pN1-patients (pN1/molN1) and additionally reclassified 224 histopathologic negative LNs and 32 (29%) pN0-patients as LN-positive (pN0/molN1). At a median follow-up of 48 months 52 (47%) patients developed biochemical recurrence. Median biochemical recurrence-free survival (bRFS) was 9 months [95%CI0.0-20.1] in pN1/molN1-patients, 24 months [95%CI1.7-46.3] in pN0/molN1 patients and was not reached in pN0/molN0 patients (p<0.001). On multivariable Cox regression analysis, molecular LN status (HR 4.1 [95%CI1.9-8.8],p<0.001) but not histopathologic LN status (HR 1.5 [95%CI0.8-3.0],p=0.198) was confirmed as independent predictor of biochemical recurrence. Conclusion: Molecular LN analysis identified pN0-patients with a high risk of biochemical recurrence and provided superior prognostic information in comparison with histopathology alone.

http://ift.tt/2HyFkKo

The Airway Transcriptome as a Biomarker for Early Lung Cancer Detection

Lung cancer remains the leading cause of cancer-related death due to its advanced stage at diagnosis. Early detection of lung cancer can be improved by better defining who should be screened radiographically, and determining which imaging-detected pulmonary nodules are malignant. Gene expression biomarkers measured in normal-appearing airway epithelium provide an opportunity to use lung cancer associated molecular changes in this tissue for early detection of lung cancer. Molecular changes in the airway may result from an etiologic field of injury and/or field cancerization. The etiologic field of injury reflects the aberrant physiological response to carcinogen exposure that creates a susceptible microenvironment for cancer initiation. In contrast, field cancerization reflects effects of "first-hit" mutations in a clone of cells from which the tumor ultimately arises or the effects of the tumor on the surrounding tissue.  These fields might have value both for assessing lung cancer risk and diagnosis. Cancer-associated gene expression changes in the bronchial airway have recently been used to develop and validate a 23-gene classifier that improves the diagnostic yield of bronchoscopy for lung cancer among intermediate-risk patients. Recent studies have demonstrated that these lung cancer-related gene expression changes extend to nasal epithelial cells that can be sampled non-invasively. While the bronchial gene expression biomarker is being adopted clinically, further work is necessary to explore the potential clinical utility of gene-expression profiling in the nasal epithelium for lung cancer diagnosis, risk assessment, and precision medicine for lung cancer treatment and chemoprevention.

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Concurrent Inhibition of Neurosphere and Monolayer Cells of Pediatric Glioblastoma by Aurora A Inhibitor MLN8237 Predicted Survival Extension in PDOX models

Purpose: Pediatric glioblastoma (pGBM) is highly aggressive tumor in need of novel therapies. Our objective was to demonstrate the therapeutic efficacy of MLN8237 (Alisertib), an orally available selective inhibitor of Aurora A kinase (AURKA), and to evaluate which in vitro model system (monolayer or neurosphere) can predict therapeutic efficacy in vivo. Experimental Design: AURKA mRNA expressions were screened with qRT-PCR. In vitro anti-tumor effects were examined in 3 matching pairs of monolayer and neurosphere lines established from patient derived orthotopic xenograft (PDOX) models of the untreated (IC-4687GBM), recurrent (IC-372GBM) and terminal (IC-R0315GBM) tumors; and in vivo therapeutic efficacy through log rank analysis of survival times in 2 models (IC-4687GBM and IC-R0315GBM) following MLN8237 treatment (30 mg/kg/day, p.o., 12 days). Drug concentrations in vivo, mechanism of action and resistance were also investigated. Results: AURKA mRNA over-expression was detected in 14 pGBM tumors, 10 PDOX models and 6 cultured pGBM lines as compared with 11 low grade gliomas and normal brains. MLN8237 penetrated into pGBM xenografts in mouse brains. Significant extension of survival times were achieved in IC-4687GBM of which both neurosphere and monolayer were inhibited in vitro, but not in IC-R0315GBM of which only neurosphere cells responded (similar to IC-3752GBM cells). Apoptosis mediated MLN8237 induced cell death, and the presence of AURKA-negative and CD133+ cells appears to have contributed to in vivo therapy resistance. Conclusions: MLN8237 successfully targeted AURKA in a subset of pGBMs. Our data suggest that combination therapy should aim at AURKA-negative and/or CD133+ pGBM cells to prevent tumor recurrence.

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Androgen Deprivation Therapy Potentiates the Efficacy of Vascular Targeted Photodynamic Therapy of Prostate Cancer Xenografts

Purpose: WST11 vascular targeted photodynamic therapy (VTP) is a local ablation approach relying upon rapid, free radical-mediated destruction of tumor vasculature. A phase III trial showed that VTP significantly reduced disease progression when compared to active surveillance in patients with low-risk prostate cancer (PCa). The aim of this study was to identify a druggable pathway that could be combined with VTP to improve its efficacy and applicability to higher risk PCa tumors. Experimental Design: Transcriptome analysis of VTP treated tumors (LNCaP-AR xenografts) was used to identify a candidate pathway for combination therapy. The efficacy of the combination therapy was assessed in mice bearing LNCaP-AR or VCaP tumors. Results: Gene Set Enrichment Analysis (GSEA) identifies the enrichment of androgen responsive gene sets within hours post-VTP treatment, suggesting that the androgen receptor (AR) may be a viable target in combination with VTP. We tested this hypothesis in mice bearing LNCaP-AR xenograft tumors by using androgen deprivation therapy (ADT), degarelix, in combination with VTP. Compared to either ADT or VTP alone, a single dose of degarelix in concert with VTP significantly inhibited tumor growth. A sharp decline in serum PSA confirmed AR inhibition in this group. Tumors treated by VTP and degarelix displayed intense TUNEL staining 7 days post-treatment, supporting an increased apoptotic frequency underlying the effect on tumor inhibition. Conclusions: Improvement of local tumor control following androgen deprivation combined with VTP provides the rationale and preliminary protocol parameters for clinical trials in patients presented with locally advanced PCa.

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Combination approach for detecting different types of alterations in circulating tumor DNA in leiomyosarcoma

Purpose: The clinical utility of circulating tumor DNA (ctDNA) monitoring has been shown in tumors that harbor highly recurrent mutations. Leiomyosarcoma (LMS) represents a type of tumor with a wide spectrum of heterogeneous genomic abnormalities; thus, targeting hotspot mutations or a narrow genomic region for ctDNA detection may not be practical. Here we demonstrate a combinatorial approach that integrates different sequencing protocols for the orthogonal detection of single nucleotide variants (SNVs), small indels and copy number alterations (CNAs) in ctDNA. Experimental design: We employed Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) for the analysis of SNVs and indels, together with a genome-wide interrogation of CNAs by Genome Representation Profiling (GRP). We profiled 28 longitudinal plasma samples and 25 tumor specimens from 7 patients with LMS. Results: We detected ctDNA in 6 of 7 of these patients with >98% specificity for mutant allele fractions down to a level of 0.01%. We show that results from CAPP-Seq and GRP are highly concordant, and the combination of these methods allows for more comprehensive monitoring of ctDNA by profiling a wide spectrum of tumor-specific markers. By analyzing multiple tumor specimens in individual patients obtained from different sites and at different times during treatment, we observed clonal evolution of these tumors that was reflected by ctDNA profiles. Conclusions: Our strategy allows for a comprehensive monitoring of a broad spectrum of tumor-specific markers in plasma. Our approach may be clinically useful not only in LMS but also in other tumor types that lack recurrent genomic alterations.

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Integrated Pharmacokinetic/Pharmacodynamic Model of a Bispecific CD3xCD123 DART(R) Molecule in Nonhuman Primates: Evaluation of Activity and Impact of Immunogenicity

Purpose: Flotetuzumab (MGD006 or S80880) is a bispecific molecule that recognizes CD3 and CD123 membrane proteins, redirecting T-cells to kill CD123-expressing cells for the treatment of acute myeloid leukemia. In this study, we developed a mathematical model to characterize MGD006 exposure-response relationships and to assess the impact of its immunogenicity in cynomolgus monkeys. Experimental Design: 32 animals received multiple escalating doses (100-300-600-1000 ng/kg/day) via intravenous infusion continuously 4-days a week. The model reflects sequential binding of MGD006 to CD3 and CD123 receptors. Formation of the MGD006/CD3 complex was connected to total T-cells undergoing trafficking, whereas the formation of the tri-molecular complex results in T-cell activation and clonal expansion. Activated T-cells were used to drive the peripheral depletion of CD123-positive cells. Anti-drug antibody development was linked to MGD006 disposition as an elimination pathway. Model validation was tested by predicting the activity of MGD006 in 8 monkeys receiving continuous 7-day infusions. Results: MGD006 disposition and total T-cell and CD123-positive cell profiles were well characterized. Anti-drug antibody development led to the suppression of T-cell trafficking but did not systematically abolish CD123-positive cell depletion. Target cell depletion could persist after drug elimination owing to the self-proliferation of activated T-cells generated during the first cycles. The model was externally validated with the 7-day infusion dosing schedule. Conclusions:A translational model was developed for MGD006 that features T-cell activation and expansion as a key driver of pharmacological activity and provides a mechanistic quantitative platform to inform dosing strategies in ongoing clinical studies.

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TGF-{beta}1 genetic variants predict clinical outcomes of HPV-positive oropharyngeal cancer patients after definitive radiotherapy

Purpose. Transforming growth factor-β1 (TGF-β1) plays a critical role in inflammation and immune responses and treatment response and survival. TGF-β1 variants may affect its expression level or functional efficiency, thus modifying tumor status and survival in HPV-positive squamous cell carcinoma of the oropharynx (SCCOP). Experimental design. We determined tumor HPV16 status and genotyped three TGF-β1 polymorphisms in 564 incident SCCOP patients treated with radiotherapy or chemoradiation. Univariate and multivariable Cox models were used to evaluate the associations between the three polymorphisms and survival. Results. Overall, 85% of patients (482 of 564) had HPV16-positive SCCOP. We found that TGF-β1 rs1982073 had statistically significant associations with survival, while TGF-β1rs1800469 and TGF-β1rs1800471 did not. Patients with TGF-β1 rs1982073 CT/CC variant genotypes had significantly better overall, disease-specific, and disease-free survival compared with those with the corresponding common homozygous TT genotype (all log-rank: P <0.001). Furthermore, these genotypes were significantly associated with an approximately 5 times reduced risk of overall death, death owing to disease, and recurrence after multivariable adjustment. Moreover, the stratified analyses by tumor HPV status indicated that the significant effects of TGF-β1 rs1982073 polymorphism on survival were found among HPV16-positive SCCOP patients only. Finally, the functional relevance of these variants was further characterized. Conclusions. Our findings support that the TGF-β1 rs1982073 polymorphism plays a significant role in the prognosis of SCCOP, especially in HPV16-positive SCCOP patients treated with chemoradiation. Prospective studies with larger sample sizes are needed to confirm these findings.

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Prediction of the optimal dosing regimen using a mathematical model of tumour uptake for immunocytokine-based cancer immunotherapy

PURPOSE: Optimal dosing is critical for immunocytokine-based cancer immunotherapy to maximize efficacy and minimize toxicity. Cergutuzumab amunaleukin (CEA-IL2v) is a novel CEA-targeted immunocytokine. We set out to develop a mathematical model to predict intratumoral CEA-IL2v concentrations following various systemic dosing intensities. EXPERIMENTAL DESIGN: Sequential measurements of CEA-IL2v plasma concentrations in 74 patients with solid tumors were applied in a series of differential equations to devise a model that also incorporates the peripheral concentrations of IL-2 receptor-positive cell populations (i.e. CD8+, CD4+, NK and B cells) which affect tumor bioavailability of CEA-IL2v. Imaging data from a subset of 14 patients were subsequently utilized to additionally predict antibody uptake in tumor tissues. RESULTS: We created a PKPD mathematical model that incorporates the expansion of IL-2R-positive target cells at multiple doses levels and different schedules of CEA-IL2v. Model-based prediction of drug levels correlated with the concentration of IL-2R-positive cells in the peripheral blood of patients. The pharmacokinetic model was further refined and extended by adding a model of antibody uptake, which is based on drug dose and the biological properties of the tumor. In silico predictions of our model correlated with imaging data and demonstrated that a dose-dense schedule comprising escalating doses and shortened intervals of drug administration can improve intratumoral drug uptake and overcome consumption of CEA-IL2v by the expanding population of IL-2R-positive cells. CONCLUSIONS: The model presented here allows simulation of individualized treatment plans for optimal dosing and scheduling of immunocytokines for anti-cancer immunotherapy.

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Phase Ib Study of Glasdegib, A Hedgehog Pathway Inhibitor, in Combination With Standard Chemotherapy in Patients With AML or High-Risk MDS

Purpose: This open-label, multicenter, dose-finding, phase Ib study (NCT01546038) evaluated the safety, pharmacokinetics, pharmacodynamics, and clinical activity of the novel Hedgehog pathway Smoothened inhibitor glasdegib (PF-04449913) in patients (N = 52) with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). Experimental Design: Glasdegib 100 or 200 mg was administered orally, once daily in 28-day cycles, in combination with low-dose cytarabine (arm A) or decitabine (arm B) to newly diagnosed patients considered not suitable for standard induction chemotherapy, and in combination with cytarabine/daunorubicin (arm C) to fit patients. The study followed a standard 3+3 dose-escalation design. The primary endpoint was dose-limiting toxicity (DLT). Ten additional patients were enrolled in expansion cohorts of arms A (n = 23) and C (n = 22) to confirm the recommended phase II dose (RP2D). Results: No DLTs were observed in arms A and B; 1 DLT (grade 4 neuropathy) occurred in arm C. The most common treatment-related non-hematologic adverse events were mostly grades 1-2 in all arms. Muscle spasms, dysgeusia, and alopecia  were generally mild. Overall, sixteen (31%) patients achieved a complete remission (CR)/CR with incomplete blood count recovery. 100 mg daily was selected as the RP2D for glasdegib in combination with standard chemotherapies in the absence of an estimated maximum tolerated dose in this setting. Conclusions: Treatment with glasdegib in combination with standard chemotherapy was generally well-tolerated and consistent with prior findings, warranting further evaluation of glasdegib-based combinations in patients with AML or high-risk MDS.

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Foretinib overcomes entrectinib resistance associated with the NTRK1 G667C mutation in NTRK1 fusion-positive tumor cells in a brain metastasis model

Background: Rearrangement of the neurotrophic tropomyosin receptor kinase 1 (NTRK1) gene, which encodes tyrosine receptor kinase A (TRK-A), occurs in various cancers, including colon cancer. Although entrectinib is effective in the treatment of central nervous system (CNS) metastases that express NTRK1 fusion proteins, acquired resistance inevitably results in recurrence. CNS is a sanctuary for targeted drugs; however, the mechanism by which CNS metastases become entrectinib-resistant remains elusive and must be clarified to develop better therapeutics. Experimental design: The entrectinib-resistant cell line KM12SM-ER was developed by continuous treatment with entrectinib in the brain metastasis-mimicking model inoculated with the entrectinib-sensitive human colon cancer cell line KM12SM, which harbors the TPM3-NTRK1 gene fusion. The mechanism of entrectinib resistance in KM12SM-ER cells was examined by next-generation sequencing. Compounds that overcame entrectinib resistance were screened from a library of 122 kinase inhibitors. Results: KM12SM-ER cells, which showed moderate resistance to entrectinib in vitro, had acquired the G667C mutation in NTRK1. The kinase inhibitor foretinib inhibited TRK-A phosphorylation and the viability of KM12SM-ER cells bearing the NTRK1-G667C mutation in vitro. Moreover, foretinib markedly inhibited the progression of entrectinib-refractory KM12SM-ER-derived liver metastases and brain tumors in animal models, predominantly through inhibition of TRK-A phosphorylation. Conclusion: These results suggest that foretinib may be effective in overcoming entrectinib resistance associated with the NTRK1-G667C mutation in NTRK1 fusion-positive tumors in various organs, including the brain, and provide a rationale for clinical trials of foretinib in cancer patients with entrectinib-resistant tumors harboring the NTRK1-G667C mutation, including patients with brain metastases.

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Natural Disasters and the Importance of Minimizing Subsequent Radiation Therapy Interruptions for Locally Advanced Lung Cancer

Disasters can jeopardize access to not just safe shelter and sanitary provisions but also potentially life-saving cancer therapies. Radiation therapy is particularly problematic in a disaster, owing to the reliance on dependable electrical power, the requirement of specialized teams for quality delivery, and the daily regularity with which it is given. Because radiation is the primary treatment for locally advanced lung cancer, here we will briefly summarize the magnitude and gravity of lung cancer treatment interruptions from a disaster and propose potential solutions.

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Radiation Biology and Circulating Tumor Cells

The metastatic process is multifactorial, and the biological mechanisms and microenvironmental factors that drive tumor cells to leave the primary site and colonize distant secondary sites are areas of active research. An excellent 2017 review, "Emerging biological principles of metastasis," describes the known biological programs that promote the metastatic dissemination of cancer cells (1). Metastatic cells acquire genetic and epigenetic alterations and phenotypic changes that promote invasion into circulatory systems, a process described as epithelial-mesenchymal transition (2).

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Radiation Therapy in a Time of Disaster

What constitutes a disaster? The United Nations defines it as "a serious disruption of the functioning of a community or a society [exceeding its ability] to cope" and requiring assistance from external sources, perhaps national or international (1). These bleak features—precipitous social disruption and conditions of extreme dependency and need—separate the vastness and isolation of "disaster" from other relief aid terminologies, such as "hazard," "risk," "emergency," or "epidemic," which are more anticipatory, classificatory, or managerial in nature.

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Role of Overall Treatment Time in the Management of Prostate Cancer Patients: How to Manage Unscheduled Treatment Interruptions

Prostate cancer patients are commonly treated with external beam radiation therapy (RT) and, thanks to modern treatment techniques such as intensity modulated RT and image guided RT that limit dose outside of the prostate, the acute traditional 7- to 9-week course of external beam treatment is generally uneventful with modest morbidity. However, occasionally, there are patients in whom substantial acute symptoms develop, often urinary, who might require a treatment interruption, thus increasing their overall treatment time (OTT).

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Establishment and Characterization of a High and Stable Porcine CD163-Expressing MARC-145 Cell Line

Isolation and identification of diverse porcine reproductive and respiratory syndrome viruses (PRRSVs) play a fundamental role in PRRSV research and disease management. However, PRRSV has a restricted cell tropism for infection. MARC-145 cells are routinely used for North American genotype PRRSV isolation and vaccine production. But MARC-145 cells have some limitations such as low virus yield. CD163 is a cellular receptor that mediates productive infection of PRRSV in various nonpermissive cell lines. In this study, we established a high and stable porcine CD163- (pCD163-) expressing MARC-145 cell line toward increasing its susceptibility to PRRSV infection. Indirect immunofluorescence assay (IFA) and Western blotting assays showed that pCD163 was expressed higher in pCD163-MARC cell line than MARC-145 cells. Furthermore, the ability of pCD163-MARC cell line to propagate PRRSV was significantly increased as compared with MARC-145 cells. Finally, we found that pCD163-MARC cell line had a higher isolation rate of clinical PRRSV samples and propagated live attenuated PRRS vaccine strains more efficiently than MARC-145 cells. This pCD163-MARC cell line will be a valuable tool for propagation and research of PRRSV.

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Retracted: Analysis of the Influence of Complexity and Entropy of Odorant on Fractal Dynamics and Entropy of EEG Signal

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Erratum to “Unilateral Aplasia versus Bilateral Aplasia of the Vertebral Artery: A Review of Associated Abnormalities”

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Erratum to “Health Brokers: How Can They Help Deal with the Wickedness of Public Health Problems?”

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Induction of ER and mitochondrial stress by the alkylphosphocholine erufosine in oral squamous cell carcinoma cells

Induction of ER and mitochondrial stress by the alkylphosphocholine erufosine in oral squamous cell carcinoma cells

Induction of ER and mitochondrial stress by the alkylphosphocholine erufosine in oral squamous cell carcinoma cells, Published online: 20 February 2018; doi:10.1038/s41419-018-0342-2

Induction of ER and mitochondrial stress by the alkylphosphocholine erufosine in oral squamous cell carcinoma cells

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Adapting an Early Palliative Care Intervention to Family Caregivers of Persons with Advanced Cancer in the Rural Deep South: A Qualitative Formative Evaluation

There is a scarcity of early palliative care interventions to support family caregivers of persons with advanced cancer living in the rural Southern U.S..

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Information Framing Reduces Initial Negative Attitudes in Cancer Patients’ Decisions about Hospice Care

Negative attitudes toward hospice care might prevent patients with cancer from discussing and choosing hospice as they approach end of life. When making a decision, people often naturally focus on either expected benefits or avoidance of harm. Behavioral research demonstrated that framing information in an incongruent manner with patients' underlying motivational focus reduces their negative attitudes toward a disliked option.

http://ift.tt/2GtBdhC

Glutamate-induced and NMDA receptor-mediated neurodegeneration entails P2Y1 receptor activation

Glutamate-induced and NMDA receptor-mediated neurodegeneration entails P2Y1 receptor activation

Glutamate-induced and NMDA receptor-mediated neurodegeneration entails P2Y1 receptor activation, Published online: 20 February 2018; doi:10.1038/s41419-018-0351-1

Glutamate-induced and NMDA receptor-mediated neurodegeneration entails P2Y1 receptor activation

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The interactome and spatial redistribution feature of Ca2+ receptor protein calmodulin reveals a novel role in invadopodia-mediated invasion

The interactome and spatial redistribution feature of Ca²⁺ receptor protein calmodulin reveals a novel role in invadopodia-mediated invasion

The interactome and spatial redistribution feature of Ca²⁺ receptor protein calmodulin reveals a novel role in invadopodia-mediated invasion, Published online: 20 February 2018; doi:10.1038/s41419-017-0253-7

The interactome and spatial redistribution feature of Ca²⁺ receptor protein calmodulin reveals a novel role in invadopodia-mediated invasion

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Ceramide-induced BOK promotes mitochondrial fission in preeclampsia

Ceramide-induced BOK promotes mitochondrial fission in preeclampsia

Ceramide-induced BOK promotes mitochondrial fission in preeclampsia, Published online: 20 February 2018; doi:10.1038/s41419-018-0360-0

Ceramide-induced BOK promotes mitochondrial fission in preeclampsia

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Contribution of TMEM16F to pyroptotic cell death

Contribution of TMEM16F to pyroptotic cell death

Contribution of TMEM16F to pyroptotic cell death, Published online: 20 February 2018; doi:10.1038/s41419-018-0373-8

Contribution of TMEM16F to pyroptotic cell death

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UT Physicians Otolaryngology at Texas Medical Center Clinic Redesign Improves the Patient Experience

With a 50 percent increase in faculty in the Department of Otorhinolaryngology-Head & Neck Surgery at McGovern Medical School at... Read the full article...

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Ex vivo metabolic fingerprinting identifies biomarkers predictive of prostate cancer recurrence following radical prostatectomy

Ex vivo metabolic fingerprinting identifies biomarkers predictive of prostate cancer recurrence following radical prostatectomy

<i>Ex vivo</i> metabolic fingerprinting identifies biomarkers predictive of prostate cancer recurrence following radical prostatectomy, Published online: 20 February 2018; doi:10.1038/bjc.2017.470

Ex vivo metabolic fingerprinting identifies biomarkers predictive of prostate cancer recurrence following radical prostatectomy

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Plasticity and intratumoural heterogeneity of cell surface antigen expression in breast cancer

Plasticity and intratumoural heterogeneity of cell surface antigen expression in breast cancer

Plasticity and intratumoural heterogeneity of cell surface antigen expression in breast cancer, Published online: 20 February 2018; doi:10.1038/bjc.2017.497

Plasticity and intratumoural heterogeneity of cell surface antigen expression in breast cancer

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Risk of cancer in patients with epistaxis and haemoptysis

Risk of cancer in patients with epistaxis and haemoptysis

Risk of cancer in patients with epistaxis and haemoptysis, Published online: 20 February 2018; doi:10.1038/bjc.2017.494

Risk of cancer in patients with epistaxis and haemoptysis

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Pathological complete response and prognosis after neoadjuvant chemotherapy for HER2-positive breast cancers before and after trastuzumab era: results from a real-life cohort

Pathological complete response and prognosis after neoadjuvant chemotherapy for HER2-positive breast cancers before and after trastuzumab era: results from a real-life cohort

Pathological complete response and prognosis after neoadjuvant chemotherapy for <i>HER2</i>-positive breast cancers before and after trastuzumab era: results from a real-life cohort, Published online: 20 February 2018; doi:10.1038/bjc.2018.4

Pathological complete response and prognosis after neoadjuvant chemotherapy for HER2-positive breast cancers before and after trastuzumab era: results from a real-life cohort

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miR-146a-5p mediates epithelial–mesenchymal transition of oesophageal squamous cell carcinoma via targeting Notch2

miR-146a-5p mediates epithelial–mesenchymal transition of oesophageal squamous cell carcinoma via targeting Notch2

<i>miR-146a-5p</i> mediates epithelial–mesenchymal transition of oesophageal squamous cell carcinoma via targeting <i>Notch2</i>, Published online: 20 February 2018; doi:10.1038/bjc.2017.471

miR-146a-5p mediates epithelial–mesenchymal transition of oesophageal squamous cell carcinoma via targeting Notch2

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Development of a prognostic scoring system for patients with advanced cancer enrolled in immune checkpoint inhibitor phase 1 clinical trials

Development of a prognostic scoring system for patients with advanced cancer enrolled in immune checkpoint inhibitor phase 1 clinical trials

Development of a prognostic scoring system for patients with advanced cancer enrolled in immune checkpoint inhibitor phase 1 clinical trials, Published online: 20 February 2018; doi:10.1038/bjc.2017.480

Development of a prognostic scoring system for patients with advanced cancer enrolled in immune checkpoint inhibitor phase 1 clinical trials

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