Allosteric effects of the proton donor on the microbial proton pump, proteorhodopsin

Proteorhodopsin (PR) is a microbial proton pump that is ubiquitous in marine environments and may play an important role in the oceanic carbon cycle. Photoisomerization of the retinal chromophore in PR leads to a series of proton transfers between specific acidic amino acid residues and the Schiff base of retinal, culminating in a proton motive force to facilitate ATP synthesis. The proton donor in a similar retinal protein, bacteriorhodopsin, acts as a latch to allow influx of bulk water. However, it is unclear if the proton donor in PR, E108, utilizes the same latch mechanism to become internally hydrated.

https://ift.tt/2PNKl5V

Solid State NMR Identification of Intermolecular Interactions in Amelogenin Bound to Hydroxyapatite

Biomineralization processes govern the formation of hierarchical hard tissues such as bone and teeth in living organisms, and mimicking these processes could lead to the design of new materials with specialized properties. However, such advances require structural characterization of the proteins guiding biomineral formation to understand and mimic their impact. In their "active" form, biomineralization proteins are bound to a solid surface, severely limiting our ability to use many conventional structure characterization techniques.

https://ift.tt/2wsbB17

Actin dynamics couples extracellular signals to the mobility and molecular stability of telomeres

Genome regulatory programs such as telomere function require extracellular signals to be transmitted from the microenvironment to the nucleus and chromatin. Although the cytoskeleton has been shown to directly transmit stresses, we show that the intrinsically dynamic nature of the actin cytoskeleton is important in relaying extracellular signals to telomeres. Interestingly, this mechanical pathway not only transmits physical stimuli but also chemical stimuli. The cytoskeletal network continuously reorganizes and applies dynamic forces on the nucleus and feeds into the regulation of telomere dynamics.

https://ift.tt/2wsoMiH

Correction to: A suggestion to introduce the diagnosis of “diffuse midline glioma of the pons, H3 K27 wildtype (WHO grade IV)”

The citation of the original publication in PubMed contains an error. The seventh author name is wrongly cited.

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Prognostic value of CpG island methylator phenotype in gastric cancer

Cancer Science, Volume 109, Issue 8, Page 2623-2625, August 2018.


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In this Issue

Cancer Science, Volume 109, Issue 8, Page 2340-2341, August 2018.


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Issue Information

Cancer Science, Volume 109, Issue 8, Page 2337-2339, August 2018.


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Altitude and Variable Effects on Infant Mortality in the United States

High Altitude Medicine &Biology, Ahead of Print.


https://ift.tt/2MX0OpX

Re: "Increased Cytokines at High Altitude: Lack of Effect of Ibuprofen on Acute Mountain Sickness, Physiological Variables, or Cytokine Levels" by Lundeberg, et al. (High Alt Med Biol 2018 [Epub ahead of print]; DOI: 10.1089/ham.2017.0144)

High Altitude Medicine &Biology, Ahead of Print.


https://ift.tt/2NtjuL7

Molecular investigations of viral meningitis among HIV-infected adults in Accra, Ghana

Meningitis is one of the leading causes of death among patients living with the human immunodeficiency virus (HIV) in sub-Saharan Africa. Based on clinical presentations alone, the different types of meningiti...

https://ift.tt/2ojCBvW

Understanding experiences of the Swedish health care system from the perspective of newly arrived refugees

Refugees seek medical advice for a variety of reasons. Previous research suggests that understanding the refugees' experiences of and access to healthcare are important factors for improving their health as ac...

https://ift.tt/2NthHWp

Significance of re-biopsy of histological tumor samples in advanced non-small-cell lung cancer in clinical practice

Abstract

The significance of evaluating oncogenes, including EGFR mutations, ALK abnormalities, and PD-L1 expression has become broadly recognized with recent advances in molecular biology. It is now extremely important to investigate tumor oncogene status in each patient at the initial diagnosis. By contrast, the significance of conducting a re-biopsy in the salvage setting has not been systematically reviewed. This review reports that the significance of a re-biopsy varies depending on the clinical situation.

https://ift.tt/2PMxRLS

Unique EMS training opportunity: The Center for Domestic Preparedness

Complete with a mock community and former hospital, the CDP give responders the opportunity to train on emergency and disaster response

https://ift.tt/2NtgDld

SNP interactions of PGC with its neighbor lncRNAs enhance the susceptibility to gastric cancer/atrophic gastritis and influence the expression of involved molecules

Cancer Medicine, EarlyView.


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Functional Outcome Scores With Standard Myoelectric Prostheses In Below-Elbow Amputees

Objective To report normative outcome data of prosthetic hand function in below elbow amputees using four different objective measurements closely related to activities of daily living (ADL). Design Seventeen patients who underwent prosthetic fitting after unilateral below-elbow amputation were enrolled in this study. Global upper extremity function was evaluated using the Action Research Arm Test (ARAT), Southampton Hand Assessment Procedure (SHAP), the Clothespin-Relocation Test (CPRT) and the Box and Block Test (BBT), which monitor hand and extremity function. Results The patients achieved a mean ARAT score of 35.06 ± 4.42 of 57. The average SHAP score was 65.12 ± 13.95 points. The mean time for the CPRT was 22.57 ± 7.50 seconds and the mean score in the BBT was 20.90 ± 5.74. Conclusions In the current economic situation of health care systems, demonstrating the effectiveness and necessity of rehabilitation interventions is of major importance. This study reports outcome data of below-elbow amputees and provides a useful guide for expected prosthetic user performance. Correspondence: Oskar C. Aszmann, MD, Div. of Plastic and Reconstructive Surgery, Dept. of Surgery, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, AUSTRIA, Tel.: 0043 1 40400 69940; Fax.: 0043 1 40400 69880, Email: oskar.aszmann@meduniwien.ac.at Authors Disclosures: The authors have no competing interests to declare. This work was supported by the Christian Doppler Research Foundation a subdivision of the Austrian Federal Ministry of Economy, Family and Youth, the Austrian Council for Research and Technology Development. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Ultrasonographic Imaging for the Diagnosis and Guided Injection of the Lateral Cord of the Plantar Fascia in a Jogger

No abstract available

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The influence of local anesthesia depth on procedural pain during fluoroscopically-guided lumbar transforaminal epidural injections: a randomized clinical trial

Objectives To evaluate the influence of the depth of local anesthesia application on procedural pain during lumbar transforaminal epidural steroid injection (TFESI). Design Sixty-eight patients were enrolled who were scheduled for single-level, unilateral fluoroscopically-guided lumbar TFESI. Patients were randomly allocated to receive either subcutaneous local anesthesia (group S) or deep local anesthesia (group D) for TFESI. The data related to pain and technical performance during the procedure was compared. Additionally, the incidence of injection site soreness was assessed 2 weeks after TFESI. Results Sixty-seven patients completed all assessments (group S, n=33; group D, n=34). There was no significant difference in procedural pain and discomfort level between the groups (P=0.151, P=0.183, respectively). Patients in group D showed lower behavioral pain scores (P=0.017). There was no significant difference in the numbers of needle manipulations, fluoroscopy time, and radiation dose during the procedure between the groups. Two patients in group S and three in group D complained of injection site soreness after TFESI for a few days, but there was no significant difference in its incidence (P=0.667). Conclusions Deep local anesthesia to reduce procedural pain during TFESI appears to have no significant clinical benefit compared with conventional subcutaneous local anesthesia. There is no external funding and no competing interests to declare. This study was registered at ClinicalTrials.gov (ref: NCT03308136). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Morphological differences in the upper trapezius muscle between female office workers with and without trapezius myalgia: facts or fiction? A cross-sectional study

Objective Work-related trapezius myalgia is a common musculoskeletal disorder in office workers. Prolonged low-level muscle activity during office work may lead to morphological changes in the muscle tissue, causing pain and fatigue. The aim of the present study was to investigate differences in muscle morphology between office workers with and without trapezius myalgia. Design Muscle biopsy samples were obtained from the upper trapezius of female office workers with trapezius myalgia (n=17) and healthy controls (n=15). Myosin heavy chain immunohistochemistry and Gomori trichrome stainings were performed to identify differences in muscle fiber type proportion, Feret's diameter and internal nuclear proportion. Results The myalgia group showed significantly more type IIA and IIA/IIX fibers, and less type I and IIX fibers, compared to the control group (P0.05). However, a significantly higher Feret's diameter was found for type I fibers, compared to type II fibers in both groups (P

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Kidney Transplant Outcomes in Recipients with Cognitive Impairment: A National Registry and Prospective Cohort Study

Background Cognitive impairment is common in patients with end-stage renal disease and is associated with poor outcomes on dialysis. We hypothesized that cognitive impairment might be associated with an increased risk of all-cause graft loss (ACGL) in kidney transplant (KT) recipients. Methods Using the Modified Mini-Mental State (3MS) examination, we measured global cognitive function at KT hospital admission in a prospective, two-center cohort of 864 KT candidates (8/2009-7/2016). We estimated the association between pre-KT cognitive impairment and ACGL using Cox regression, adjusting for recipient, donor, and transplant factors. Results In living donor KT (LDKT) recipients, the prevalence was 3.3% for mild impairment (60≤3MS

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International Liver Transplantation Consensus Statement on end-stage liver disease due to nonalcoholic steatohepatitis and liver transplantation

Nonalcoholic steatohepatitis (NASH)-related cirrhosis has become one of the most common indications for liver transplantation (LT), particularly in candidates over the age of 65 years. Typically, NASH candidates have concurrent obesity, metabolic and cardiovascular risks, which directly impact patient evaluation and selection, waitlist morbidity and mortality and eventually posttransplant outcomes. The purpose of these guidelines is to highlight specific features commonly observed in NASH candidates and strategies to optimize pretransplant evaluation and waitlist survival. More specifically, the working group addressed the following clinically-relevant questions providing recommendations based on the GRADE system supported by rigorous systematic reviews and consensus: (1) Is the outcome after LT similar to that of other etiologies of liver disease? (2) Is the natural history of NASH-related cirrhosis different from other etiologies of end-stage liver disease? (3) How should cardiovascular risk be assessed in the candidate for LT? Should the assessment differ from that done in other etiologies? (4) How should comorbidities (hypertension, diabetes, dyslipidemia, obesity, renal dysfunction, etc.) be treated in the candidate for LT? Should treatment and monitoring of these comorbidities differ from that applied in other etiologies? (5) What are the therapeutic strategies recommended to improve the cardiovascular and nutritional status of a NASH patient in the waiting list for LT? (6) Is there any circumstance where obesity should contraindicate LT? (7) What is the optimal time for bariatric surgery: before, during, or after LT? and (8) Donor steatosis: how much relevant is it for LT in NASH patients Contributions: All authors drafted sections of the manuscript and revised the final manuscript for important intellectual content. In addition, MB and ET also drafted some of the sections, combined all the sections in a single manuscript, and revised the final before submission. Conflict of interest: ET: none SN: none YT: none YL: Speaker for Gilead. Grants and Speaker for Novartis. MG: none JK: none MB: Speaker for Novartis, Astellas, Gilead. Grant from Gilead. Correspondence information: Marina Berenguer – MD, La Fe University Hospital, Avenida Fernando Abril Martorell, 106 (Torre F5) – 46026 Valencia (Spain), e-mail: marina.berenguer@uv.es Ciberehd (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas) is partially funded by the Instituto de Salud Carlos III. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Emerin deregulation links nuclear shape instability to metastatic potential

Abnormalities in nuclear shape are a well-known feature of cancer, but their contribution to malignant progression remains poorly understood. Here, we show that depletion of the cytoskeletal regulator Diaphanous related formin 3 (DIAPH3), or the nuclear membrane-associated proteins lamin A/C, in prostate and breast cancer cells, induces nuclear shape instability, with a corresponding gain in malignant properties, including secretion of extracellular vesicles (EV) that contain genomic material. This transformation is characterized by a reduction and/or mislocalization of the inner nuclear membrane protein emerin. Consistent with this, depletion of emerin evokes nuclear shape instability and promotes metastasis. By visualizing emerin localization, evidence for nuclear shape instability was observed in cultured tumor cells, in experimental models of prostate cancer, in human prostate cancer tissues and in circulating tumor cells (CTCs) from patients with metastatic disease. Quantitation of emerin mislocalization discriminated cancer from benign tissue and correlated with disease progression in a prostate cancer cohort. Taken together, these results identify emerin as a mediator of nuclear shape stability in cancer and show that destabilization of emerin can promote metastasis.

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Targeting STAT5 or STAT5-regulated pathways suppresses leukemogenesis of Ph+ acute lymphoblastic leukemia

Combining standard cytotoxic chemotherapy with BCR-ABL1 tyrosine kinase inhibitors (TKI) has greatly improved the upfront treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). However, due to the development of drug resistance through both BCR-ABL1-dependent and -independent mechanisms, prognosis remains poor. The STAT5 transcription factor is activated by BCR-ABL1 and by JAK2-dependent cytokine signaling; therefore, inhibiting its activity could address both mechanisms of resistance in Ph+ ALL. We show here that genetic and pharmacologic inhibition of STAT5 activity suppresses cell growth, induces apoptosis, and inhibits leukemogenesis of Ph+ cell lines and patient-derived newly diagnosed and relapsed/TKI-resistant Ph+ ALL cells ex vivo and in mouse models. STAT5 silencing decreased expression of the growth-promoting PIM-1 kinase, the apoptosis inhibitors MCL-1 and BCL-2, and increased expression of pro-apoptotic BIM protein. The resulting apoptosis of STAT5-silenced Ph+ BV173 cells was rescued by silencing of BIM or restoration of BCL-2 expression. Treatment of Ph+ ALL cells, including samples from relapsed/refractory patients, with the PIM kinase inhibitor AZD1208 and/or the BCL-2 family antagonist Sabutoclax markedly suppressed cell growth and leukemogenesis ex vivo and in mice. Together, these studies indicate that targeting STAT5 or STAT5-regulated pathways may provide a new approach for therapy development in Ph+ ALL, especially the relapsed/TKI-resistant disease.

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Transcription factor PROX1 suppresses Notch pathway activation via the nucleosome remodeling and deacetylase complex in colorectal cancer stem-like cells

The homeobox transcription factor PROX1 is induced by high Wnt/ß-catenin activity in intestinal adenomas and colorectal cancer (CRC), where it promotes tumor progression. Here we report that in LGR5+ CRC cells, PROX1 suppresses the Notch pathway, which is essential for cell fate in intestinal stem cells. Pharmacological inhibition of Notch in ex vivo 3D organoid cultures from transgenic mouse intestinal adenoma models increased Prox1 expression and the number of PROX1-positive cells. Notch inhibition led to increased proliferation of the PROX1-positive CRC cells but did not affect their ability to give rise to PROX1-negative secretory cells. Conversely, PROX1 deletion increased Notch target gene expression and NOTCH1 promoter activity, indicating reciprocal regulation between PROX1 and the Notch pathway in CRC. PROX1 interacted with the nucleosome remodeling and deacetylase (NuRD) complex to suppress the Notch pathway. Thus, our data suggests that PROX1 and Notch suppress each other and that PROX1-mediated suppression of Notch mediates its stem cell function in CRC.

https://ift.tt/2wpvXJ0

A mutant p53-dependent embryonic stem cell gene signature is associated with augmented tumorigenesis of stem cells

Mutations in the tumor suppressor p53 are the most frequent alterations in human cancer. These mutations include p53-inactivating mutations as well as oncogenic gain-of-function (GOF) mutations that endow p53 with capabilities to promote tumor progression. A primary challenge in cancer therapy is targeting stemness features and cancer stem cells (CSC) that account for tumor initiation, metastasis, and cancer relapse. Here we show that in vitro cultivation of tumors derived from mutant p53 murine bone marrow (BM) mesenchymal stem cells (MSC) gives rise to aggressive tumor lines (TL). These MSC-TL exhibited CSC features as displayed by their augmented oncogenicity and high expression of CSC markers. Comparative analyses between MSC-TL with their parental mutant p53 MSC allowed for identification of the molecular events underlying their tumorigenic properties, including an embryonic stem cell (ESC) gene signature specifically expressed in MSC-TL. Knockout of mutant p53 led to a reduction in tumor development and tumorigenic cell frequency, which was accompanied by reduced expression of CSC markers and the ESC MSC-TL signature. In human cancer, MSC-TL ESC signature-derived genes correlated with poor patient survival and were highly expressed in human tumors harboring p53 hotspot mutations. These data indicate that the ESC gene signature-derived genes may serve as new stemness-based prognostic biomarkers as well as novel cancer therapeutic targets.

https://ift.tt/2PgMvtW

Patient-derived xenograft models reveal intratumor heterogeneity and temporal stability in neuroblastoma

Patient-derived xenografts (PDXs) and the Avatar, a single PDX mirroring an individual patient, are emerging tools in preclinical cancer research. However, the consequences of intratumor heterogeneity for PDX modeling of biomarkers, target identification, and treatment decisions remain underexplored. In this study, we undertook serial passaging and comprehensive molecular analysis of neuroblastoma orthotopic PDXs, which revealed strong intrinsic genetic, transcriptional, and phenotypic stability for more than two years. The PDXs showed preserved neuroblastoma-associated gene signatures that correlated with poor clinical outcome in a large cohort of neuroblastoma patients. Furthermore, we captured spatial intratumor heterogeneity using ten PDXs from a single high-risk patient tumor. We observed diverse growth rates, transcriptional, proteomic, and phospho-proteomic profiles. PDX-derived transcriptional profiles were associated with diverse clinical characteristics in high-risk neuroblastoma patients. These data suggest that high-risk neuroblastoma contains elements of both temporal stability and spatial intratumor heterogeneity, the latter of which complicates clinical translation of personalized PDX-Avatar studies into preclinical cancer research.

https://ift.tt/2MCKxXJ

Inverse Correlation of STAT3 and MEK Signaling Mediates Resistance to RAS Pathway Inhibition in Pancreatic Cancer

Major contributors to therapeutic resistance in pancreatic cancer (PDAC) include Kras mutations, a dense desmoplastic stroma that prevents drug delivery to the tumor, and activation of redundant signaling pathways. We have previously identified a mechanistic rationale for targeting STAT3 signaling to overcome therapeutic resistance in PDAC. In this study, we investigate the molecular mechanisms underlying the heterogeneous response to STAT3 and RAS pathway inhibition in PDAC. Effects of JAK/STAT3 inhibition (STAT3i) or MEK inhibition (MEKi) were established in Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mice and patient-derived xenografts (PDX). Amphiregulin (AREG) levels were determined in serum from human PDAC patients, LSL-KrasG12D/+;Trp53R172H/+;Pdx1Cre/+ (KPC), and PKT mice. MEKi/STAT3i-treated tumors were analyzed for integrity of the pancreas and the presence of cancer stem cells (CSC). We observed an inverse correlation between ERK and STAT3 phosphorylation. MEKi resulted in immediate activation of STAT3, while STAT3i resulted in TACE-induced, AREG-dependent activation of EGFR and ERK. Combined MEKi/STAT3i sustained blockade of ERK, EGFR, and STAT3 signaling, overcoming resistance to individual MEKi or STAT3i. This combined inhibition attenuated tumor growth in PDX and increased survival of PKT mice while reducing serum AREG levels. Furthermore, MEKi/STAT3i altered the PDAC tumor microenvironment by depleting tumor fibrosis, maintaining pancreatic integrity, and downregulating CD44+ and CD133+ CSC. These results demonstrate that resistance to MEKi is mediated through activation of STAT3, while TACE-AREG-EGFR-dependent activation of RAS pathway signaling confers resistance to STAT3 inhibition. Combined MEKi/STAT3i overcomes these resistances and provides a novel therapeutic strategy to target the RAS and STAT3 pathway in PDAC.

https://ift.tt/2wv8t5B

Ribonucleotide excision repair is essential to prevent squamous cell carcinoma of the skin.

Due to imperfect discrimination against ribonucleoside triphosphates by the replicative DNA polymerases, large numbers of ribonucleotides are incorporated into the eukaryotic nuclear genome during S-phase. Ribonucleotides, by far the most common DNA lesion in replicating cells, destabilize the DNA, and an evolutionarily conserved DNA repair machinery, ribonucleotide excision repair (RER), ensures ribonucleotide removal. Whereas complete lack of RER is embryonically lethal, partial loss-of-function mutations in the genes encoding subunits of RNase H2, the enzyme essential for initiation of RER, cause the SLE-related type I interferonopathy Aicardi-Goutières syndrome. Here we demonstrate that selective inactivation of RER in mouse epidermis results in spontaneous DNA damage and epidermal hyperproliferation associated with loss of hair follicle stem cells and hair follicle function. The animals developed keratinocyte intraepithelial neoplasia and invasive squamous cell carcinoma with complete penetrance, despite potent type I interferon production and skin inflammation. These results suggest that compromises to RER-mediated genome maintenance might represent an important tumor-promoting principle in human cancer.

https://ift.tt/2LzrmsG

Spatially resolved transcriptomics enables dissection of genetic heterogeneity in stage III cutaneous malignant melanoma

Cutaneous malignant melanoma (melanoma) is characterized by a high mutational load, extensive inter- and intra-tumoral genetic heterogeneity, and complex tumor microenvironment (TME) interactions. Further insights into the mechanisms underlying melanoma are crucial for understanding tumor progression and responses to treatment. Here we adapted the technology of Spatial Transcriptomics (ST) to melanoma lymph node biopsies and successfully sequenced the transcriptomes of over 2,200 tissue domains. Deconvolution combined with traditional approaches for dimensional reduction of transcriptome-wide data enabled us to both visualize the transcriptional landscape within the tissue and identify gene expression profiles linked to specific histological entities. Our unsupervised analysis revealed a complex spatial intratumoral composition of melanoma metastases that was not evident through morphological annotation. Each biopsy showed distinct gene expression profiles and included examples of the coexistence of multiple melanoma signatures within a single tumor region as well as shared profiles for lymphoid tissue characterized according to their spatial location and gene expression profiles. The lymphoid area in close proximity to the tumor region displayed a specific expression pattern which may reflect the TME, a key component to fully understanding tumor progression. In conclusion, using the ST technology to generate gene expression profiles reveals a detailed landscape of melanoma metastases. This should inspire researchers to integrate spatial information into analyses aiming to identify the factors underlying tumor progression and therapy outcome.

https://ift.tt/2wnIqgx

Intrathecal viral vector delivery of trastuzumab prevents or inhibits tumor growth of human HER2-positive xenografts in mice

Breast cancer brain metastases are a deadly sequela of primary breast tumors that overexpress human epidermal growth factor receptor 2 (HER2); median survival for patients with these tumors is 10-13 months from the time of diagnosis. Current treatments for HER2-positive breast cancer brain metastases are invasive, toxic, and largely ineffective. Here we have developed an adeno-associated virus serotype 9 (AAV9) vector to express the anti-HER2 monoclonal antibody trastuzumab (Herceptin®) in vivo. A single prophylactic intrathecal administration of AAV9.trastuzumab vector in a novel orthotopic Rag1-/- murine xenograft model of HER2-positive breast cancer brain metastases significantly increased median survival, attenuated brain tumor growth, and preserved both the HER2 antigen specificity and the natural killer cell-associated mechanism of action of trastuzumab. When administered as a tumor treatment, AAV9.trastuzumab increased median survival. Dose-escalation studies revealed that higher doses of AAV9.trastuzumab resulted in smaller tumor volumes. Our results indicate that intrathecal AAV9.trastuzumab may provide significant anti-tumor activity in patients with HER2-positive breast cancer brain metastases.

https://ift.tt/2MEKhaM

PTTG and PBF functionally interact with p53 and predict overall survival in head and neck cancer

Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide and poses a significant health burden due to its rising incidence. Although the proto-oncogene pituitary tumor transforming gene 1 (PTTG) predicts poor patient outcome, its mechanisms of action are incompletely understood. We show here that the protein PBF modulates PTTG function, is overexpressed in HNSCC tumors, and correlates with significantly reduced survival. Lentiviral shRNA attenuation of PTTG or PBF expression in HNSCC cells with either wild type or mutant p53, and with and without HPV infection, led to dysregulated expression of p53 target genes involved in DNA repair and apoptosis. Mechanistically, PTTG and PBF affected each other's interaction with p53 and cooperated to reduce p53 protein stability in HNSCC cells independently of HPV. Depletion of either PTTG or PBF significantly repressed cellular migration and invasion and impaired colony formation in HNSCC cells, implicating both proto-oncogenes in basic mechanisms of tumorigenesis. HNSCC patients with high tumoral PBF and PTTG had the poorest overall survival, which reflects a marked impairment of p53-dependent signalling.

https://ift.tt/2Pf64Ts

Exome analysis reveals genomic markers associated with better efficacy of nivolumab in lung cancer patients.

Purpose: Experimental Design: Results: Conclusions:

https://ift.tt/2LBeuSW

Intensive surveillance with bi-annual dynamic contrast-enhanced magnetic resonance imaging downstages breast cancer in BRCA1 mutation carriers

PURPOSE: To establish a cohort of high-risk women undergoing intensive surveillance for breast cancer. METHODS: We performed dynamic contrast-enhanced magnetic resonance imaging (MRI) every 6 months in conjunction with annual mammography (MG). Eligible participants had a cumulative lifetime breast cancer risk ≥ 20% and/or tested positive for a pathogenic mutation in a known breast cancer susceptibility gene. RESULTS: Between 2004-2016, we prospectively enrolled 295 women, including 157 mutation carriers (75 BRCA1, 61 BRCA2); participants' mean age at entry was 43.3 years. Seventeen cancers were later diagnosed: four ductal carcinoma in situ (DCIS) and thirteen early stage invasive breast cancers. Fifteen cancers occurred in mutation carriers (11 BRCA1, 3 BRCA2, 1 CDH1). Median size of the invasive cancers was 0.61 cm. No patients had lymph node metastasis at time of diagnosis and no interval invasive cancers occurred. The sensitivity of bi-annual MRI alone was 88.2% and annual MG plus bi-annual MRI was 94.1%. The cancer detection rate of bi-annual MRI alone was 0.7% per 100 screening episodes, which is similar to the cancer detection rate of 0.7% per 100 screening episodes for annual MG plus bi-annual MRI. The number of recalls and biopsies needed to detect one cancer by bi-annual MRI were 2.8 and 1.7 in BRCA1 carriers, 12.0 and 8.0 in BRCA2 carriers, and 11.7 and 5.0 in non-BRCA1/2 carriers, respectively. CONCLUSIONS: Bi-annual MRI performed well for early detection of invasive breast cancer in genomically stratified high-risk women. No benefit was associated with annual MG screening plus bi-annual MRI screening.

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EGFR exon 20 insertion mutations display sensitivity to Hsp90 inhibition in preclinical models and lung adenocarcinomas

Purpose: EGFR exon 20 insertions account for up to 10% of all EGFR mutations in lung adenocarcinomas, representing the third most common cluster of mutations. The management of advanced cancers with these mutations remains elusive, without an approved inhibitor. Experimental Design: Preclinical models of a representative set of EGFR exon 20 insertion mutations to evaluate the efficacy of different inhibitors and description of the clinical outcome of an advanced lung cancer. Results: We show that select first, second and third generation EGFR inhibitors are unable to deter common EGFR exon 20 insertion mutants in concentrations that spare the wild-type kinase. Nonetheless, EGFR exon 20 insertion mutants associate with the heat shock protein 90 (Hsp90) chaperone system. We exploit this vulnerability to show that the non-geldanamycin Hsp90 inhibitor luminespib (formerly AUY922) degrades EGFR exon 20 mutations, downstream targets and induces apoptosis. In addition, a patient whose EGFR inhibitor-insensitive lung adenocarcinoma harbored an EGFR exon 20 insertion mutation had a confirmed radiographic response to luminespib. Conclusions: The report confirms that EGFR exon 20 mutations are dependent on Hsp90 and are readily inhibited by the Hsp90 inhibitor luminespib; a treatment strategy that has been pursued in a confirmatory clinical trial (NCT01854034) for this group of lung adenocarcinomas that currently represent an unmet clinical need in precision oncology.

https://ift.tt/2PNEHka

Gemcitabine synergizes with immune checkpoint inhibitors and overcomes resistance in a preclinical model and mesothelioma patients

Purpose: Combination of immune checkpoint inhibitors with chemotherapy is under investigation for cancer treatment. Experimental design: We studied the rationale of such a combination for treating mesothelioma, a disease with limited treatment options. Results: The combination of gemcitabine and immune checkpoint inhibitors outperformed immunotherapy alone with regard to tumor control and survival in a pre-clinical mesothelioma model; however, the addition of dexamethasone to gemcitabine and immune checkpoint inhibitors nullified the synergistic clinical response. Further, treatment with gemcitabine plus anti-PD-1 resulted in an objective clinical response in two mesothelioma patients, who were resistant to gemcitabine or anti-PD-1 as monotherapy. Conclusion: Thus, treatment of mesothelioma with a combination of gemcitabine with immune checkpoint inhibitors is feasible and results in synergistic clinical response compared to single treatment in the absence of steroids.

https://ift.tt/2LzPdIM

Patients in prehospital transport to the emergency department: a cohort study of risk factors for 7-day mortality

Background Ambulance transfer is the first contact with the healthcare system for many patients in emergency conditions. We aimed to identify prognostic risk factors accessible in the prehospital phase that indicate an increased risk of 7-day mortality. Patients and methods We included patients aged 18 years or older, transferred by ambulance to the emergency department at Odense University Hospital, from 1 April 2012 to 30 September 2014. We carried out multivariate logistic regressions, adjusted for age and sex, to describe the relationship between vital sign values recorded in the prehospital setting and 7-day mortality. Results A total of 32 076 ambulance transfers were recorded. Of these, 20 328 were first-time transfers, including 2692 that received assistance from a physician-staffed mobile emergency care unit (MECU). The 7-day mortality was 5.3% [95% confidence interval (CI): 5.0–5.6]. The risk of death increased with age. The odds ratios (ORs) were 2.0 (95% CI: 1.1–3.5) for ages 30–44 years and 7.3 (95% CI: 4.5–11) for ages 45–69 years compared with the 18–29-year-olds. All abnormal vital sign values were associated with increased 7-day mortality. Glasgow Coma Score of less than 14 had the strongest association (OR: 17, 95% CI: 14.7–19.7). MECU assistance showed an adjusted OR of 5.3 (95% CI: 4.6–6.1). Conclusion The overall 7-day mortality was 5.3%, but differed in the two subgroups, with 15.4% in the MECU-assisted ambulance transfers and 3.8% in non-MECU-assisted transfers. Older age and Glasgow Coma Scores below 14 were the strongest of factors associated significantly with 7-day mortality.

https://ift.tt/2PMAywT

Laryngeal mask airway as a rescue device for failed endotracheal intubation during scene-to-hospital air transport of combat casualties

Background Advanced airway management of combat casualties during scene-to-hospital air transport is challenging. Because of the short transport time, flight physicians of the Israeli military airborne combat evacuation unit are approved for the use of a laryngeal mask airway (LMA) in the event of failed endotracheal intubation (ETI). The aim of this study was to assess the effectiveness of LMA use during scene-to-hospital transport of combat casualties in Israel. Patients and methods A retrospective cohort analysis of all combat casualties treated with ETI during scene-to-hospital transport over a 3-year period was carried out. Successful LMA insertion was defined as satisfactory placement of the device on the basis of adequate chest expansion with bag-mask ventilation. Results The median flight time from scene to hospital was 13 min [interquartile range (IQR): 9–15 min]. Sixty-five casualties underwent ETI attempts, 47 successful and 18 failed. All 18 casualties who had failed ETI underwent LMA insertion as a rescue treatment. Six casualties suffered from traumatic brain injury, six had firearm injuries, two had blast injuries, and two had inhalational injuries. LMA insertion was successful in 16/18 (88.9%) casualties, 14 survived to hospital discharge, whereas two were declared dead upon hospital arrival. Two cases of LMA insertion were unsuccessful, but patients survived to hospital discharge. Among the 16 successful cases, the median oxygen saturation on scene-pickup before LMA insertion and on hospital-handover with LMA in place were 90% (IQR: 84–96%) and 98% (IQR: 96–99%), respectively (P

https://ift.tt/2LzmRyi

Has the Licensing Act 2003 affected violence rates in England and Wales? A systematic review of hospital and police studies

Violence has been declining in the UK for two decades, with most assaults being alcohol related. The Licensing Act 2003 (England and Wales) aimed to reduce alcohol-related crime, giving local authorities control over premises licensing. We performed a systematic review of original research with the primary outcome of change in violence rates since the Act's implementation, including hospital-defined and police-defined measures of violence. Our secondary outcome was temporal distribution of violence. Fifteen studies were included, which were of overall poor quality. Seven found reduced violence rates after the Act's implementation, three found increased rates and five found no significant change. A subset of nine studies analysed temporal distribution, eight finding displacement of incidents later. This is the most complete analysis to date of the effect of this Act on violence, finding a lack of reliable evidence to answer the research question, but little to suggest that the Act has markedly impacted already-declining violence rates.

https://ift.tt/2PMA6ib

Traumatic brain injury in the Netherlands, trends in emergency department visits, hospitalization and mortality between 1998 and 2012

Background Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. The effects of epidemiological changes such as ageing of the population and increased traffic safety on the incidence of TBI are unknown. Objective The objective of this study was to evaluate trends in TBI-related emergency department (ED) visits, hospitalization and mortality in the Netherlands between 1998 and 2012. Design This was a retrospective observational, longitudinal study. Main outcome measures The main outcome measures were TBI-related ED visits, hospitalization and mortality. Results Between 1998 and 2012, there were 500 000 TBI-related ED visits in the Netherlands. In the same period, there were 222 000 TBI-related admissions and 17 000 TBI-related deaths. During this period, there was a 75% increase in ED visits for TBI and a 95% increase for TBI-related hospitalization; overall mortality because of TBI did not change significantly. Despite the overall increase in TBI-related ED visits, this increase was not evenly distributed among age groups or trauma mechanisms. In patients younger than 65 years, a declining trend in ED visits for TBI caused by road traffic accidents was observed. Among patients 65 years or older, ED visits for TBI caused by a fall increased markedly. TBI-related mortality shifted from mainly young (67%) and middle-aged individuals (

https://ift.tt/2wuK9jr

Lung ultrasound in diagnosing pneumonia in the emergency department: a systematic review and meta-analysis

Community-acquired pneumonia (CAP) is one of the most widespread and severe infectious diseases worldwide. In the emergency department (ED), there is still a need for a rapid and accurate tool that can diagnose CAP. Lung ultrasound (LUS) is a recent tool that is increasingly being for this purpose. So far, the LUS has been evaluated on a wide range of patients, but not yet on the specific population in the ED through a meta-analysis. Our aim was to assess the accuracy of the LUS in diagnosing CAP in this setting through a systematic review and a meta-analysis. A systematic research of literature was carried out for all published studies comparing the diagnostic accuracy of the LUS against chest radiography or computerized tomography scan in patients older than 18 years of age with clinical criteria for CAP assessed in the ED. We extracted the descriptive and quantitative data from eligible studies, and calculated the pooled sensitivity, specificity, and diagnostic odds ratio. We defined the summary receiver operating characteristic curve. Our initial search strategy yielded 10 377 studies, of which 17 (0.2%) were eligible. These studies provided a combined sample size of 5108 participants. The general risk of bias of the considered studies was quite low, but some concerns were highlighted. The diagnostic odds ratio was around 181 (I2: 27%). The pooled area under the curve, sensitivity, and specificity were, respectively, 97, 92, and 93%. The LUS was found to be an accurate tool in diagnosing CAP in adult patients in the ED. More methodologically rigorous trials are needed.

https://ift.tt/2PMzZTN

Emergency medicine research and the European Journal of Emergency Medicine

No abstract available

https://ift.tt/2LBI3Ub

Ultrasound-guided pericardiocentesis: a novel parasternal approach

Objective The aim of this study was to evaluate a novel pericardiocentesis technique using an in-plane parasternal medial-to-lateral approach with the use of a high-frequency probe in patients with cardiac tamponade. Background Echocardiography is pivotal in the diagnosis of pericardial effusion and tamponade physiology. Ultrasound guidance for pericardiocentesis is currently considered the standard of care. Several approaches have been described recently, which differ mainly on the site of puncture (subxiphoid, apical, or parasternal). Although they share the use of low-frequency probes, there is absence of complete control of needle trajectory and real-time needle visualization. An in-plane and real-time technique has only been described anecdotally. Methods and results A retrospective analysis of 11 patients (63% men, mean age: 37.7±21.2 years) presenting with cardiac tamponade admitted to the tertiary-care emergency department and treated with parasternal medial-to-lateral in-plane pericardiocentesis was carried out. The underlying causes of cardiac tamponade were different among the population. All the pericardiocentesis were successfully performed in the emergency department, without complications, relieving the hemodynamic instability. The mean time taken to perform the eight-step procedure was 309±76.4 s, with no procedure-related complications. Conclusion The parasternal medial-to-lateral in-plane pericardiocentesis is a new technique theoretically free of complications and it enables real-time monitoring of needle trajectory. For the first time, a pericardiocentesis approach with a medial-to-lateral needle trajectory and real-time, in-plane, needle visualization was performed in a tamponade patient population.

https://ift.tt/2PMzSrl

Partial occlusion, conversion from thoracotomy, undelayed but shorter occlusion: resuscitative endovascular balloon occlusion of the aorta strategy in Japan

Introduction Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a viable alternative to resuscitative thoracotomy (RT) in refractory hemorrhagic patients. We evaluated REBOA strategies using Japanese multi-institutional data. Patients and methods The DIRECT-IABO investigators registered trauma patients requiring REBOA from 18 hospitals. Patients' characteristics, outcomes, and time in initial treatment were collected and analyzed. Results From August 2011 to December 2015, 106 trauma patients were analyzed. The majority of patients were men (67%) (median BMI of 22 kg/m2, 96% blunt injured). REBOA occurred in the field (1.9%, all survived >30 days), emergency department (75%), angiography suite (17%), and operating room (1.9%). Initial deployment was at zone I in 93% and partial occlusion in 70% of cases. RT and REBOA were combined in 30 patients (RT+REBOA group) who showed significantly higher injury severity score (44 vs. 36, P=0.001) and chest abbreviated injury scale (4 vs. 3; P

https://ift.tt/2ww5UPF

Sepsis patients in the emergency department: stratification using the Clinical Impression Score, Predisposition, Infection, Response and Organ dysfunction score or quick Sequential Organ Failure Assessment score?

Objective The aim of this study was to compare the stratification of sepsis patients in the emergency department (ED) for ICU admission and mortality using the Predisposition, Infection, Response and Organ dysfunction (PIRO) and quick Sequential Organ Failure Assessment (qSOFA) scores with clinical judgement assessed by the ED staff. Patients and methods This was a prospective observational study in the ED of a tertiary care teaching hospital. Adult nontrauma patients with suspected infection and at least two Systemic Inflammatory Response Syndrome criteria were included. The primary outcome was direct ED to ICU admission. The secondary outcomes were in-hospital, 28-day and 6-month mortality, indirect ICU admission and length of stay. Clinical judgement was recorded using the Clinical Impression Scores (CIS), appraised by a nurse and the attending physician. The PIRO and qSOFA scores were calculated from medical records. Results We included 193 patients: 103 presented with sepsis, 81 with severe sepsis and nine with septic shock. Fifteen patients required direct ICU admission. The CIS scores of nurse [area under the curve (AUC)=0.896] and the attending physician (AUC=0.861), in conjunction with PIRO (AUC=0.876) and qSOFA scores (AUC=0.849), predicted direct ICU admission. The CIS scores did not predict any of the mortality endpoints. The PIRO score predicted in-hospital (AUC=0.764), 28-day (AUC=0.784) and 6-month mortality (AUC=0.695). The qSOFA score also predicted in-hospital (AUC=0.823), 28-day (AUC=0.848) and 6-month mortality (AUC=0.620). Conclusion Clinical judgement is a fast and reliable method to stratify between ICU and general ward admission in ED patients with sepsis. The PIRO and qSOFA scores do not add value to this stratification, but perform better on the prediction of mortality. In sepsis patients, therefore, the principle of 'treat first what kills first' can be supplemented with 'judge first and calculate later'.

https://ift.tt/2PMgdYE

Prevalence and in-hospital outcome of aspiration in out-of-hospital intubated trauma patients

No abstract available

https://ift.tt/2Lzb5nr

Key performance indicators’ assessment to develop best practices in an Emergency Medical Communication Centre

Introduction Emergency Medical Communication Centre (EMCC) represents a pivotal link in the chain of survival for those requiring rapid response for out-of-hospital medical emergencies. Assessing and grading the performance of EMCCs are warranted as it can affect the health and safety of the served population. Objective The aim of our work was to describe the activity on an EMCC and to explore the associations between different key performance indicators. Methods We carried out our prospective observational study in the EMCC of Nantes, France, from 6 June 2011 to 6 June 2015. The EMCC performance was assessed with the following key performance indicators: answered calls, Quality of Service 20 s (QS20), occupation rate and average call duration. Results A total of 35 073 h of dispatch activity were analysed. 1 488 998 emergency calls were answered. The emergency call incidence varied slightly from 274 to 284 calls/1000 citizens/year between 2011 and 2015. The median occupation rate was 35% (25–44). QS20 was correlated negatively with the occupation rate (Spearman's ρ: −0.78). The structural equation model confirmed that the occupation rate was highly correlated with the QS20 (standardized coefficient: −0.89). For an occupation rate of 26%, the target value estimated by our polynomial model, the probability of achieving a QS20 superior or equal to 95% varied between 56 and 84%. Conclusion The occupation rate appeared to be the most important factor contributing towards the QS20. Our data will be useful to develop best practices and guidelines in the field of emergency medicine communication centres.

https://ift.tt/2PKmy6Z

The superiority of the two-thumb over the two-finger technique for single-rescuer infant cardiopulmonary resuscitation

Objectives The two-finger technique (TFT) using the index-middle fingers of the right hand (TFT-R23) was recently confirmed to produce deeper chest compression depth (CCD) compared with the TFT using any other fingers. This study was carried out to confirm whether the TFT-R23 would be as effective as the two-thumb technique (TTT). In addition, individual finger strengths were measured to identify the reasons why the TTT and TFT-R23 produced deeper CCD than any other methods. Methods This prospective randomized cross-over trial compared TTT with TFT-R23. A total of 37 doctors conducted 2 min single-rescuer cardiopulmonary resuscitation using TTT and TFT-R23 in a random order using a 3-month-old sized infant manikin laid on the floor. The chest compression to ventilation ratio was set to 15 : 2. In addition, finger strengths were measured using a pinch meter. Results The actual CCD of the TTT was significantly deeper than that of the TFT-R23 (41.3±1.3 vs. 39.8±1.5 mm, P

https://ift.tt/2LDr7N4

Super Artifacts: Personal Devices as Intrinsically Multifunctional, Meta-representational Artifacts with a Highly Variable Structure

Abstract

The computer is one of the most complex artifacts ever built. Given its complexity, it can be described from many different points of view. The aim of this paper is to investigate the representational structure and multifunctionality of a particular subset of computers, namely personal devices (PCs, laptops, smartphones, tablets) from a user-centred perspective. The paper also discusses the concept of "cognitive task", as recently employed in some definitions of cognitive artifacts, and investigates the metaphysical properties of such artifacts. From a representational point of view, the article introduces the concepts of artifactual meta-representation and of semi-transparency, two features that personal devices share with some cognitive and non-cognitive artifacts. Recognising the meta-representational nature of personal devices and of other cognitive artifacts, thus overcoming semi-transparency, is important for the understanding of why different artifacts offer us different cognitive affordances as well as different cognitive advantages. In this sense, it is not simply a theoretical achievement, but has some important practical consequences. In our highly technological world we can use different kinds of computers and artifacts for solving the same tasks, and we need to understand why some artifacts are better suited for some tasks than others. The ultimate characterisation of personal devices that emerges from this work is that of a sort of super-artifact. This special status is given to personal devices because of their distinctive features. They are in fact intrinsically multifunctional and meta-representational artifacts, with extremely variable structures. As super-artifacts, personal devices are characterised by macro-functionality and can be easily used as both cognitive artifacts and tools for other functions, depending on the kind of representations they instantiate.

https://ift.tt/2N0q6nc

FDA Promotes Efficient Biosimilar Approval [News in Brief]

Agency's action plan outlines strategies designed to boost innovation and competition, reduce drug costs.

https://ift.tt/2NpxDsv

In Situ Vaccination with a TLR 9 Agonist and Local Low Dose Radiation Induces Systemic Responses in Untreated Indolent Lymphoma [Research Articles]

This multicenter phase 1/2 clinical trial evaluated intratumoral SD-101, a TLR9 agonist, and low-dose radiation in patients with untreated indolent lymphoma. 29 enrolled patients received 4 Gy of radiation followed by five weekly intratumoral injections of SD-101 at a single tumor site. No treatment-related grade 4 or serious adverse events occurred. Nearly all patients had tumor reduction at their treated site. More importantly, 24 patients had tumor reduction at their non-treated sites with 5 patients achieving a partial response and one achieving a complete response. Treatment-related increases of CD8+ and CD4+ effector T-cells and decreases of T Follicular Helper and T regulatory cells (Tregs) were observed in the tumor microenvironment. Low pre-treatment levels of CD4+ Tregs, proliferating CD8+ T-cells, and GranzymeB+ CD8+ T-cells were associated with favorable outcomes. Intratumoral SD-101 in combination with low-dose radiation is well tolerated and results in regression of both treated and untreated sites of disease.

https://ift.tt/2MZil0E

SD-101 in Combination with Pembrolizumab in Advanced Melanoma: Results of a Phase 1b, Multicenter Study [Research Briefs]

PD-1 inhibitors are approved for treating advanced melanoma, but resistance has been observed. This phase 1b trial evaluated intratumoral SD-101, a synthetic CpG-oligonucleotide that stimulates Toll-like receptor 9 (TLR9), in combination with pembrolizumab in patients with unresectable or metastatic malignant melanoma. The most common adverse events related to SD-101 were injection site reactions and transient, mild-to-moderate "flu-like" symptoms. Among the 9 patients naïve to anti-PD-1 therapy, the overall response rate (ORR) was 78%. The estimated 12 month progression free survival (PFS) rate was 88%, and overall survival (OS) rate was 89%. Among 13 patients having prior anti-PD-1 therapy, the ORR was 15%. RNA profiling of tumor biopsies demonstrated increased CD8+ T cells, NK cells, cytotoxic cells, dendritic cells, and B cells. The combination of intratumoral SD-101 and pembrolizumab was well tolerated and induced broad immune activation in the tumor microenvironment with durable tumor responses in both peripheral and visceral lesions.

https://ift.tt/2Nt4Xin

Analysis of Transcription Factor-Related Regulatory Networks Based on Bioinformatics Analysis and Validation in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) accounts for a significant proportion of liver cancer, which has become the second most common cause of cancer-related mortality worldwide. To investigate the potential mechanisms of invasion and progression of HCC, bioinformatics analysis and validation by qRT-PCR were performed. We found 237 differentially expressed genes (DEGs) including EGR1, FOS, and FOSB, which were three cancer-related transcription factors. Subsequently, we constructed TF-gene network and miRNA-TF-mRNA network based on data obtained from mRNA and miRNA expression profiles for analysis of HCC. We found that 42 key genes from the TF-gene network including EGR1, FOS, and FOSB were most enriched in the p53 signaling pathway. The qRT-PCR data confirmed that mRNA levels of EGR1, FOS, and FOSB all were decreased in HCC tissues. In addition, we confirmed that the mRNA levels of CCNB1, CCNB2, and CHEK1, three key markers of the p53 signaling pathway, were all increased in HCC tissues by bioinformatics analysis and qRT-PCR validation. Therefore, we speculated that miR-181a-5p, which was upregulated in HCC tissues, could regulate FOS and EGR1 to promote the invasion and progression of HCC by p53 signaling pathway. Overall, the study provides support for the possible mechanisms of progression in HCC.

https://ift.tt/2woUwpr

Insecticide Resistance and Its Intensity in Populations of Malaria Vectors in Colombia

Insecticide resistance in malaria vectors threatens malaria prevention and control efforts. In Colombia the three primary vectors, Anopheles darlingi, An. nuneztovari s.l., and An. albimanus, have reported insecticide resistance to pyrethroids, organophosphates, carbamates, and DDT; however, the insecticide resistance monitoring is not continuous, and the data on the prevalence of resistance is scarce and geographically limited. We describe the resistance levels and intensity of previously detected resistant populations among primary malaria vectors from the most endemic malaria areas in Colombia. The study was carried out in 10 localities of five states in Colombia. Bioassays were carried out following the methodology of CDC Bottle Bioassay using the discriminating concentration and in order to quantify the intensity the specimens were exposed to 2, 5, and 10X discriminating concentrations. Five insecticides were tested: deltamethrin, lambda-cyhalothrin, alpha-cypermethrin, permethrin, and DDT. The results provide evidence of low resistance intensity and resistance highly localized to pyrethroids and DDT in key malaria vectors in Colombia. This may not pose a threat to malaria control yet but frequent monitoring is needed to follow the evolution of insecticide resistance.

https://ift.tt/2Pe1Zi2

Dynamic Expression of Genes Involved in Proteoglycan/Glycosaminoglycan Metabolism during Skin Development

Glycosaminoglycans are important for cell signaling and therefore for proper embryonic development and adult homeostasis. Expressions of genes involved in proteoglycan/glycosaminoglycan (GAG) metabolism and of genes coding for growth factors known to bind GAGs were analyzed during skin development by microarray analysis and real time quantitative PCR. GAG related genes were organized in six categories based on their role in GAG homeostasis, viz. (1) production of precursor molecules, (2) production of core proteins, (3) synthesis of the linkage region, (4) polymerization, (5) modification, and (6) degradation of the GAG chain. In all categories highly dynamic up- and downregulations were observed during skin development, including differential expression of GAG modifying isoenzymes, core proteins, and growth factors. In two mice models, one overexpressing heparanase and one lacking C5 epimerase, differential expression of only few genes was observed. Data show that during skin development a highly dynamic and complex expression of GAG-associated genes occurs. This likely reflects quantitative and qualitative changes in GAGs/proteoglycans, including structural fine tuning, which may be correlated with growth factor handling.

https://ift.tt/2wkPPgi

Emotional Pain Tied to Health Care-Associated Infections

TUESDAY, Aug. 28, 2018 -- Patients with health care-associated infections (HAIs) suffer social and emotional pain, according to a review published in the August issue of the American Journal of Infection Control. Kay Currie, Ph.D., from Glasgow...

https://ift.tt/2LB8n0W

FDA: Hundreds of Human, Pet Homeopathy Products Recalled

TUESDAY, Aug. 28, 2018 -- Hundreds of Dr. King's water-based homeopathic drugs for children, adults, and pets may be unsafe to use because of high levels of microbial contamination, according to the U.S. Food and Drug Administration. Due to the risk...

https://ift.tt/2PNd8HL

Medical Practices Should Address Negative Online Reviews

TUESDAY, Aug. 28, 2018 -- Medical practice staff can effectively handle negative online reviews by staying calm and positive, looking for solutions, apologizing, and thanking the reviewers, according to an article published in Physicians...

https://ift.tt/2LCplfr

FDA Warning Letters Target Illegal Online Sales of Opioids

TUESDAY, Aug. 28, 2018 -- Four more online networks that operate 21 websites illegally selling potentially dangerous, unapproved, and misbranded versions of opioid pain medications have been told to immediately stop their sales, the U.S. Food and...

https://ift.tt/2PKhK1r

Laryngeal Tube Insertion Beats Endotracheal Intubation in OHCA

TUESDAY, Aug. 28, 2018 -- For patients with out-of-hospital cardiac arrest (OHCA), 72-hour survival is better with initial laryngeal tube (LT) insertion compared to endotracheal intubation (ETI), while a supraglottic airway device (SGA) is no better...

https://ift.tt/2LB8klM

Delayed diagnosis of extrapulmonary tuberculosis presenting as fever of unknown origin in an intermediate-burden country

Tuberculosis (TB), especially extrapulmonary tuberculosis (EPTB), is an important cause of fever of unknown origin (FUO) in TB-burdened areas. Little information is known about patients with EPTB with clinical...

https://ift.tt/2woE2h9

Randomized Quality Improvement Trial of Opting-In Versus Opting-Out to Increase Influenza Vaccination Rates during Pregnancy

AJP Rep 2018; 08: e161-e167
DOI: 10.1055/s-0038-1668566

Introduction Despite strong recommendations, only 40.6% of pregnant women attending two prenatal clinics were vaccinated against influenza during the 2009 pandemic. We tested whether an opting-out approach would improve vaccine uptake. Methods We conducted a randomized quality improvement (QI) trial to compare opting-out with conventional opting-in consent for influenza immunization. Women age ≥ 18 years attending the University of Texas Health Science Center at Houston (UTHealth) or UT-Medical Branch (UTMB) prenatal clinics during the 2010–2011 influenza season, were eligible. Results We enrolled 280 women (140 UTHealth, 140 UTMB). Both groups had similar mean age (26.0 ± 5.5 years), mean gestational age (19.4 ± 9.5 weeks), and percent with underlying health conditions (20.7%). Vaccination rates with opting-in and opting-out were similar among all (83 vs. 84%), UTHealth (87 vs. 93%), and UTMB patients (79 vs.76%) (p > 0.05). In subsamples of patients assessed, consent strategy did not significantly affect maternal recall of information provided. Conclusion While prenatal influenza vaccination uptake doubled from the 2009–2010 influenza season, opting-out did not perform better than opting-in, a conclusion opposite that we would have reached had this been a nonconcurrent trial. Vaccination rates dropped posttrial; hence, continued research is needed to increase the prenatal influenza immunizations.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
Table of contents  |  Abstract  |  open access Full text

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A case report of dengue haemorrhagic fever during the peripartum period: challenges in management and a case of vertical dengue transmission

Incidence of Dengue infection is on the increase in Sri Lanka with it being associated with significant maternal and neonatal morbidity in pregnancy.

https://ift.tt/2LyInTG

Excess mortality related to circulatory system diseases and diabetes mellitus among Italian AIDS patients vs. non-AIDS population: a population-based cohort study using the multiple causes-of-death approach

Chronic diseases, chiefly cancers and circulatory system diseases (CSDs), have become the leading non-AIDS-related causes of death among HIV-infected people, as in the general population. After our previous re...

https://ift.tt/2PM5vkU

Signs, symptoms and diagnosis of necrotizing fasciitis experienced by survivors and family: a qualitative Nordic multi-center study

Necrotizing soft tissue infection is the most serious of all soft tissue infections. The patient's life is dependent on prompt diagnosis and aggressive treatment. Diagnostic delays are related to increased mor...

https://ift.tt/2Ntkw9Z

Antiretroviral resistance in HIV-1 patients at a tertiary medical institute in Saudi Arabia: a retrospective study and analysis

Since the early 90's antiretroviral drugs have been available at King Faisal Specialist Hospital and Research Centre (KFSH&RC), a referral hospital in Riyadh, Saudi Arabia, for the treatment of both adults and...

https://ift.tt/2LBK9mW

ACE I allele is associated with more severe portal hypertension in patients with liver cirrhosis: A pilot study

In liver cirrhosis, the renin-angiotensin-aldosterone system is involved in the pathogenesis of portal hypertension. Its effector, angiotensin II, is generated by angiotensin-converting enzyme (ACE). Serum ACE levels are affected by I/D polymorphism of its gene, with alleles I and D being associated, respectively, with lesser and greater activity of the enzyme. In cirrhotic patients carrying the ACE I allele, an increased risk for gastro-oesophageal varices was observed.

https://ift.tt/2wmSPsz

The transformative journey of chronic myeloid leukemia

International Journal of Hematologic Oncology, Ahead of Print.


https://ift.tt/2Nqm7xe

Fentanyl-resistant gloves help keep EMS workers safe from exposure

MILWAUKEE, Jan. 27, 2018 — A new product is on the market to help protect EMS workers from deadly drug exposure. "Many times, EMS providers go into very unsecured scenes. They don't know what they're getting into," said Rhonda Baliff, of Medline Industries. The big risk when treating the victims is exposure to fentanyl, a synthetic drug found in heroin "The exposure...

https://ift.tt/2Nsvsof

Three roles caregivers must take on to help fight opioid epidemic

NORTHFIELD, Ill., March 29, 2018 — It's troubling what medical personnel are seeing as our country's opioid problem worsens. The CDC just released their latest report on opioid overdoses and emergency departments are working furiously because of the increase – a 30 percent jump in ED visits in 2017 over 2016. We're asking emergency room staff, and paramedics and EMTs...

https://ift.tt/2NqaVkc

Three critical areas to watch in EMS

NORTHFIELD, Ill., May 17, 2018 — Of the more than 13 million calls in Firehouse Magazine's yearly survey of fire departments and EMS agencies nearly nine million needed emergency medical services. The need for EMS is great. We're not just responding to car accidents. We're in post-acute facilities. We're collaborating with hospitals. We're seeing change. Though...

https://ift.tt/2wopSwz

Partnering for public safety: Savvik Buying Group and Medline announce GPO contract

NORTHFIELD, Ill., Aug. 20, 2018 — Medline EMS today announced a new partnership with Savvik Buying Group, one of the largest public safety buying groups in the country representing EMS, fire departments, and law enforcement. With the new bid-approved program, more than 8,800 members can now tap into Medline's offering of: 550,000+ high-quality medical supplies and products (gloves,...

https://ift.tt/2ojiVs6

A Deep Look into the Future of Quantitative Imaging in Oncology: A Statement of Working Principles and Proposal for Change

The rapid growth of quantitative imaging research in recent years has resulted in a number of publications with sub-optimal methods to provide generalizable results. We believe the fields of quantitative imaging and radiomics require renewed focus on optimal study design/reporting practices, standardization, interpretability, data sharing and clinical trials. In this critical review, we propose fundamental changes to the scientific approach to ensure high-impact research and the development of actionable prediction models that will yield more meaningful applications.

https://ift.tt/2BY4m7c

Functional Liver Imaging and Dosimetry to Predict Hepatotoxicity Risk in Cirrhotic Patients with Primary Liver Cancer

This study evaluated the ability of global liver function and functional liver dosimetry derived from pre-radiotherapy [99mTc]-sulfur colloid SPECT/CT imaging to predict hepatotoxicity in primary liver cancer patients with underlying cirrhosis treated with radiotherapy. We identified novel functional dosimetry predictors and constraints that were complementary to conventional clinical metrics and anatomic dosimetry, which has implications for improved patient risk-stratification and precision radiotherapy planning.

https://ift.tt/2NwOHgw

Genomic classifier for guiding treatment of intermediate-risk prostate cancers to dose-escalated image-guided radiotherapy without hormone therapy

We demonstrate the utility of GC over the existing NCCN subclassification for predicting disease outcomes (biochemical recurrence and metastasis) in IR-PCa. We therefore recommend the use of clinicogenomic risk stratification to identify IR-PCa patients who can be treated with DE-IGRT and safely omit combinatorial ADT.

https://ift.tt/2wpmHol

Cardiac-sparing whole lung imrt in patients with pediatric tumors and lung metastasis: Final report of a prospective multicenter clinical trial

A prospective clinical trial was conducted to demonstrate the feasibility of whole lung IMRT, study its dosimetric advantages and assess the short term clinical outcomes in children with lung metastasis. Real time central QA review and pre-approval was obtained. Cardiac sparing IMRT was feasible in all patients and showed improved 4D lung dose coverage and significant reduction in cardiac doses compared to standard techniques. One patient developed cardiac and pulmonary toxicity 5 years after treatment.

https://ift.tt/2wpmNMJ

FDA takes action against 21 websites marketing unapproved opioids as part of agency’s effort to target illegal online sales

August 28, 2018 -- The U.S. Food and Drug Administration today announced it has warned four more online networks, operating a total of 21 websites, illegally marketing potentially dangerous, unapproved, and misbranded versions of opioid medications,...

https://ift.tt/2MWDrNo

Predictors of Prolonged Breast Milk Provision to Very Low Birth Weight Infants

To identify factors associated with prolonged maternal breast milk (BM) provision in very low birth weight (VLBW) infants.

https://ift.tt/2NskjDV

Trends in Hospital Treatment of Empyema in Children in the United States

To evaluate trends in procedures used to treat children hospitalized in the US with empyema during a period that included the release of guidelines endorsing chest tube placement as an acceptable first-line alternative to video-assisted thoracoscopic surgery.

https://ift.tt/2wmFWPd

Reply

We would like to thank Degraeuwe for his comments. We agree that the neonatal Early-Onset Sepsis (EOS) calculator was not designed to be applied to a subpopulation of infants such as those exposed to clinical chorioamnionitis. We agree that the calculator was not meant to be used as a diagnostic tool. Unfortunately, many physicians across the country are using it for this purpose, as evidenced by several published papers, quality improvement projects, and surveys of physician practice.1-4 However, even when it is applied appropriately to assess the risk of early-onset sepsis in all infants born ≥34 weeks of gestation, it still performs poorly as a screening tool for sepsis.

https://ift.tt/2BXZTRW

Perinatal Transmission of Hepatitis C Virus: Defining the Cascade of Care

The US National Viral Hepatitis Action Plan calls for major efforts to expand hepatitis C virus (HCV) diagnosis and treatment; prenatal care settings are potential venues for expanding HCV testing. We aimed to characterize the HCV diagnostic cascade for women and infants and investigate factors associated with linkage and follow-up.

https://ift.tt/2NsuPef

Factors affecting delirium after pediatric cardiac surgery

I read with interest the report by Alvarez et al.1 The authors performed an observational study on 99 patients undergoing cardiac surgery and concluded that delirium is common in patients in the pediatric cardiac intensive care unit and is associated with longer length of stay. The authors should be congratulated for their well-designed study on an important topic in hospitalized subjects.2,3 In addition, the current emphasis on the need to reduce healthcare costs by reducing length of stay makes the topic relevant in perioperative medicine.

https://ift.tt/2woUkqe

Slow Steps Toward Transition

It was just over 35 years ago that Giulio Barbero, MD, a pediatrician, penned a letter in the Annals of Internal Medicine encouraging internists to concede that they might learn something from pediatricians and exhorting pediatricians to trust their patients to internists.1 At that time, transition was described as occurring by default, rather than by design.2 Surgeon General C. Everett Koop at a conference in 1984 in Wayzata, Minnesota, and then a follow-up convocation in 1989 in Jekyll Island, Georgia, addressed some of the shortfalls of transition, not the least of which was a recognition that there was a lack of research on the developmental milestones to direct the optimal time for transition between the child-focused care setting and the adult world.

https://ift.tt/2wmp775

A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9

This protocol presents a method to evaluate the proteolytic activity of an intrinsically low-activity, single turnover protease in a cellular context. Specifically, this method is applied to evaluate the proteolytic activity of PCSK9, a key driver of lipid metabolism whose proteolytic activity is required for its ultimate hypercholesterolemic function.

https://ift.tt/2PMsU5R

Heterogeneous mutation pattern in tumor tissue and circulating tumor DNA warrants parallel NGS panel testing

Abstract

Liquid biopsy by genotyping circulating tumor DNA (ctDNA) has provided a non-invasive approach in assessing tumor genomic alterations in clinical oncology. However, emerging evidence in clinical settings has shown significant discordance in the genomic alterations between matched tumor tissue and blood ctDNA samples, and even between the same set of blood samples analyzed on different testing platforms. Thus, it is necessary to study underlying causes of discrepancies in these studies by genotyping tumor tissue and ctDNA in parallel using next generation sequencing (NGS) panels based on the same technology. Here we enrolled 56 non-small-cell lung cancer (NSCLC) patients and evaluated tumor tissue genotyping and ctDNA based liquid biopsy by parallel NGS panel testing and compared different sample preparation conditions. Somatic mutations in plasma cell-free DNA (cfDNA) were detected in 63.6% patients with early-stage NSCLC and 60% patients with advanced-stage NSCLC. The overall concordance between matched formalin-fixed paraffin-embedded sample and cfDNA was 54.6% in early-stage NSCLC patients and 80% in advanced-stage NSCLC patients. The positive concordance rate was 44.4% and 71.4% in early-stage and advanced-stage patients, respectively. Using fresh frozen tumor samples did not improve the overall concordance rate between matched tumor tissue and cfDNA. Processing blood samples beyond 4 h after blood draw significantly decreased the detection rate of somatic mutations in cfDNA. Thus, the concordance rate between tumor tissue-based and ctDNA-based genotyping in clinical samples can be affected by multiple pre-analytical, analytical and biologic factors. Parallel NGS panel testing on both sample types for each patient may be warranted for effective guidance of cancer targeted therapies and possible early detection of cancer.

https://ift.tt/2LyLhrI

Physicians Lack Knowledge About Serogroup MenB Vaccination

TUESDAY, Aug. 28, 2018 -- U.S. pediatricians and family physicians (FPs) have considerable knowledge gaps regarding serogroup B meningococcal (MenB) vaccination, according to a study published online Aug. 20 in Pediatrics. Allison Kempe, M.D.,...

https://ift.tt/2NsLJcA

Buprenorphine/Naloxone Rx Fills Up With Medicaid Expansion

TUESDAY, Aug. 28, 2018 -- There was an increase in buprenorphine with naloxone fills in expansion versus nonexpansion counties after Medicaid expansion, according to a study published online Aug. 17 in JAMA Network Open. Brendan Saloner, Ph.D., from...

https://ift.tt/2woBcbU

Alcohol Is Leading Risk Factor for Global Disease Burden

TUESDAY, Aug. 28, 2018 -- Globally, alcohol use is a leading risk factor for disease burden, according to research published online Aug. 23 in The Lancet. Max G. Griswold, from the Institute for Health Metrics and Evaluation in Seattle, and...

https://ift.tt/2NoZ2e1

Experts Address Loss of the National Guideline Clearinghouse

TUESDAY, Aug. 28, 2018 -- The demise of the National Guideline Clearinghouse (NGC) in July 2018 is likely to impact evidence-based health care around the world, according to an Ideas and Opinions piece published online Aug. 28 in the Annals of...

https://ift.tt/2wo1oUb

Cardiovascular Health Tied to Brain Function in Younger Adults

TUESDAY, Aug. 28, 2018 -- Having a greater number of modifiable cardiovascular risk factors at recommended levels is associated with higher cerebral vessel density and caliber, higher cerebral blood flow, and fewer white matter hyperintensities...

https://ift.tt/2MViLoQ

Poor Shared Decision-Making for Lung Cancer Screening

TUESDAY, Aug. 28, 2018 -- The quality of shared decision-making (SDM) about the initiation of lung cancer screening (LCS) is poor, according to a study published online Aug. 13 in JAMA Internal Medicine. Alison T. Brenner, Ph.D., M.P.H., from the...

https://ift.tt/2NsJPsL

Cannabinoid in Breast Milk Up to Six Days After Marijuana Use

TUESDAY, Aug. 28, 2018 -- Most breast milk samples have measurable Δ-9-tetrahydrocannabinol (Δ9-THC) up to about six days after maternal use, according to a study published online Aug. 27 in Pediatrics. Kerri A. Bertrand, M.P.H., from the...

https://ift.tt/2NpPm37

Skin Microbiota Differ for Obese, Non-Obese Undergoing C-Section

TUESDAY, Aug. 28, 2018 -- After cesarean delivery (CD), the incision site harbors a higher bacterial biomass in obese women than in non-obese women, according to a study recently published in Scientific Reports. Kara M. Rood, M.D., from The Ohio...

https://ift.tt/2wkV1kA

Artificial Intelligence Holds Promise in Medicine

TUESDAY, Aug. 28, 2018 -- Artificial intelligence (AI) in health care offers opportunities for early detection and triage, diagnostics and personalized medicine, and medical decision-making, according to an article published in Managed Healthcare...

https://ift.tt/2NoYW69

Retinal Abnormalities May Indicate Preclinical Alzheimer's

TUESDAY, Aug. 28, 2018 -- Retinal microvascular abnormalities are identified in cognitively healthy individuals who have biomarkers positive for Alzheimer's disease (AD), according to a study published online Aug. 23 in JAMA Ophthalmology. Bliss...

https://ift.tt/2N2U3CS

Preparation of a High-quality Primary Cell Culture from Fish Pituitaries

Here we describe a protocol to prepare and maintain primary pituitary cell cultures from medaka (Oryzias latipes). The optimized conditions in this protocol take important parameters such as temperature, osmolality, and pH into consideration by mimicking the physiological conditions of the fish, thereby enabling physiologically more meaningful results.

https://ift.tt/2ohqy2k

A Proximal Culture Method to Study Paracrine Signaling Between Cells

Paracrine and juxtacrine cellular interactions play an important role in many biological processes, including tumor progression, immune responses, angiogenesis, and development. Here, a proximal culture method is used to study paracrine signaling where the localized concentrations of the secreted factors are maintained while preventing direct cellular contact.

https://ift.tt/2BVqXB5

Isolating and Incorporating Light-Harvesting Antennas from Diatom Cyclotella Meneghiniana in Liposomes with Thylakoid Lipids

Here, we present a protocol to isolate fucoxanthin chlorophyll a/c binding proteins (FCP) from diatoms and incorporate them into liposomes with natural lipid compositions to study excitation energy transfer upon ion composition changes.

https://ift.tt/2oj649k

Tox and Hound – Narcan’t

by Sarah Shafer     You're taking care of a 4-year-old who got into some medication. His pupils are small, his heart rate is slow, and he's more drowsy than a resident at a late night party. Toxidrome fluent, you give him a slug of naloxone . . . and . . . nothing happens. […]

EMCrit Project by Tox & Hound.

https://ift.tt/2MVPZo5

Tox and Hound – Narcan’t

by Sarah Shafer     You're taking care of a 4-year-old who got into some medication. His pupils are small, his heart rate is slow, and he's more drowsy than a resident at a late night party. Toxidrome fluent, you give him a slug of naloxone . . . and . . . nothing happens. […]

EMCrit Project by Tox & Hound.

https://ift.tt/2MVPZo5

Long non-coding RNA DSCR8 acts as a molecular sponge for miR-485-5p to activate Wnt/β-catenin signal pathway in hepatocellular carcinoma

Long non-coding RNA DSCR8 acts as a molecular sponge for miR-485-5p to activate Wnt/β-catenin signal pathway in hepatocellular carcinoma

Long non-coding RNA DSCR8 acts as a molecular sponge for miR-485-5p to activate Wnt/β-catenin signal pathway in hepatocellular carcinoma, Published online: 28 August 2018; doi:10.1038/s41419-018-0937-7

Long non-coding RNA DSCR8 acts as a molecular sponge for miR-485-5p to activate Wnt/β-catenin signal pathway in hepatocellular carcinoma

https://ift.tt/2PMINcD

Essential role of Ahnak in adipocyte differentiation leading to the transcriptional regulation of Bmpr1α expression

Essential role of Ahnak in adipocyte differentiation leading to the transcriptional regulation of Bmpr1α expression

Essential role of Ahnak in adipocyte differentiation leading to the transcriptional regulation of Bmpr1α expression, Published online: 28 August 2018; doi:10.1038/s41419-018-0873-6

Essential role of Ahnak in adipocyte differentiation leading to the transcriptional regulation of Bmpr1α expression

https://ift.tt/2LBj4jY

ARD1 contributes to IKKβ-mediated breast cancer tumorigenesis

ARD1 contributes to IKKβ-mediated breast cancer tumorigenesis

ARD1 contributes to IKKβ-mediated breast cancer tumorigenesis, Published online: 28 August 2018; doi:10.1038/s41419-018-0921-2

ARD1 contributes to IKKβ-mediated breast cancer tumorigenesis

https://ift.tt/2PMJNNA

Novel AF1q/MLLT11 favorably affects imatinib resistance and cell survival in chronic myeloid leukemia

Novel AF1q/MLLT11 favorably affects imatinib resistance and cell survival in chronic myeloid leukemia

Novel AF1q/MLLT11 favorably affects imatinib resistance and cell survival in chronic myeloid leukemia, Published online: 28 August 2018; doi:10.1038/s41419-018-0900-7

Novel AF1q/MLLT11 favorably affects imatinib resistance and cell survival in chronic myeloid leukemia

https://ift.tt/2NpET7W

ID1-induced p16/IL6 axis activation contributes to the resistant of hepatocellular carcinoma cells to sorafenib

ID1-induced p16/IL6 axis activation contributes to the resistant of hepatocellular carcinoma cells to sorafenib

ID1-induced p16/IL6 axis activation contributes to the resistant of hepatocellular carcinoma cells to sorafenib, Published online: 28 August 2018; doi:10.1038/s41419-018-0926-x

ID1-induced p16/IL6 axis activation contributes to the resistant of hepatocellular carcinoma cells to sorafenib

https://ift.tt/2PMIy1d

Overexpression of homeodomain-interacting protein kinase 2 (HIPK2) attenuates sepsis-mediated liver injury by restoring autophagy

Overexpression of homeodomain-interacting protein kinase 2 (HIPK2) attenuates sepsis-mediated liver injury by restoring autophagy

Overexpression of homeodomain-interacting protein kinase 2 (HIPK2) attenuates sepsis-mediated liver injury by restoring autophagy, Published online: 28 August 2018; doi:10.1038/s41419-018-0838-9

Overexpression of homeodomain-interacting protein kinase 2 (HIPK2) attenuates sepsis-mediated liver injury by restoring autophagy

https://ift.tt/2NqjTO9

Low level of isocitrate dehydrogenase 1 predicts unfavorable postoperative outcomes in patients with clear cell renal cell carcinoma

Abstract

Background

The purpose of this study was to investigate the role of isocitrate dehydrogenase 1 (IDH1) expression on prognosis of patients with clear cell renal cell carcinoma (ccRCC) following nephrectomy.

Methods

We retrospectively enrolled 358 ccRCC patients undergoing nephrectomy in Renji Hospital. Clinicopathologic features, overall survival (OS) and recurrence-free survival (RFS) of ccRCC patents were all collected. IDH1 expression level was assessed by immunohistochemistry and its association with clinicopathologic features and outcomes were also evaluated. Kaplan-Meier method with the log-rank test was applied to compare survival curves. Multivariate cox regression models were applied to analyze the prognostic value of each factor on OS and RFS of ccRCC patients. Moreover, two nomograms with factors selected by multivariate analysis were constructed to evaluate the prognosis of ccRCC patients, and the calibration plots were built to assess the predictive accuracy of nomograms.

Results

Our data indicated that IDH1 expression level was down-regulated in ccRCC tissues, and it negatively correlated with tumor Fuhrman grade (p = 0.025). Low IDH1 expression was associated with worse OS and RFS for cccRCC patients (OS, p = 0.004; RFS, p = 0.03). In addition, IDH1 could significantly stratify patients' OS and RFS in intermediate/high risk patients (UISS score ≥ 4) (p = 0.049 and p = 0.004, respectively). Furthermore, incorporating IDH1 with other prognostic factors could predict ccRCC patients' OS and RFS (OS, c-index = 0.779; RFS, c-index = 0.798) and perform better than TNM and SSIGN system.

Conclusions

Low IDH1 expression level might be an adverse prognostic biomarker for clinical outcomes of ccRCC patients, and two nomograms with IDH1 are potential effective prognostic models for ccRCC.

https://ift.tt/2Lybkz7

BrightOcular® Cosmetic Iris Implant: A Spectrum from Tolerability to Severe Morbidity

Purpose: The BrightOcular® implants are the newest model of cosmetic iris devices that are currently advertised as safe. The previous generation known as NewColorIris® have had severe ocular side effects and were subsequently withdrawn from the market. There is little literature on the safety profile of BrightOcular® implants. Case Report: Herein we describe two cases with varying degrees of ocular tolerability. The first case had a normal ocular exam 1 year after implantation, whereas the second case had unilateral severe corneal edema requiring explantation of the iris device and Descemet membrane endothelial keratoplasty 9 months after bilateral implantation. Conclusions: These two cases attest to the unpredictability of the results of these cosmetic surgeries. Patients should be counseled about the vision-threatening complications of iris implants.
Case Rep Ophthalmol 2018;9:395–400

https://ift.tt/2MZvIOy

A Case of Focal Choroidal Excavation Development Associated with Multiple Evanescent White Dot Syndrome

Focal choroidal excavation (FCE) is described as an excavated lesion of the choroid that can be detected by optical coherence tomography (OCT). While the exact pathogenesis of FCE remains unclear, it has been proposed in some cases that there is an association with the inflammation in the outer retina. We present a case of FCE development that was detected by spectral domain OCT (SD-OCT) and found to be associated with multiple evanescent white dot syndrome (MEWDS). A 40-year-old Japanese woman was diagnosed with MEWDS based on multiple white dots observed from the posterior pole to the midperiphery, along with yellow granularity in the fovea. SD-OCT revealed separation between the retinal pigment epithelium (RPE) and Bruch's membrane (BM) and discontinuations of the ellipsoid zone, RPE, and BM. At 4 weeks after onset, several of the white dots disappeared, the yellow granularity in the fovea became small, and we detected nonconforming choroidal excavation under the central fovea. The choroidal excavation gradually deepened and changed to a conforming pattern. These findings suggest that the degree of the impairment caused by inflammation and the plasticity of the BM and RPE complex may be associated with different types of acquired FCE.
Case Rep Ophthalmol 2018;9:388–394

https://ift.tt/2Lva67S

Identifying Coronary Artery Calcification on Non-gated Computed Tomography Scans

Here, we present a protocol to reliably and systematically identify coronary artery calcification (CAC) on non-gated computed tomography (CT) scans of the chest or abdomen. CAC provides an objective measure of coronary artery disease for both research and clinical purposes.

https://ift.tt/2MXdDkc

A Standard and Reliable Method to Fabricate Two-Dimensional Nanoelectronics

The article aims to introduce a standard and reliable fabrication procedure for the development of future low dimensional nanoelectronics.

https://ift.tt/2NwabtW

The c-Myc-regulated lncRNA NEAT1 and paraspeckles modulate imatinib-induced apoptosis in CML cells

Abstract

Chronic myeloid leukemia (CML) is a clonal disease characterized by the presence of the constitutively active tyrosine kinase BCR-ABL oncoprotein. Although BCR-ABL is crucially important for pathogenesis and treatment response, it is thought that some additional factors might be involved in the regulation of these processes. Aberrant expression of long noncoding RNAs (lncRNAs) has recently been identified to be involved in various diseases including cancer, suggesting that lncRNAs may play a role in BCR-ABL-mediated CML. In this study, we found that nuclear-enriched abundant transcript 1 (NEAT1), a lncRNA essential for the formation of nuclear body paraspeckles, is significantly repressed in primary CML cells. NEAT1 expression could be restored by inhibiting BCR-ABL expression or its kinase activity in K562 cells. We also demonstrated that NEAT1 is regulated by c-Myc. Knockdown of NEAT1 could promote imatinib (IM)-induced apoptosis, and we demonstrated that the NEAT1-binding paraspeckle protein splicing factor proline/glutamine-rich (SFPQ) is required for NEAT1-mediated apoptosis in K562 cells. RNA-seq analysis revealed that SFPQ regulates cell growth and death pathway-related genes, confirming its function in IM-induced apoptosis. Collectively, these results assign a biological function to the NEAT1 lncRNA in CML apoptosis and may lead to fuller understanding of the molecular events leading to CML.

https://ift.tt/2PbSLTO

Efficient Production and Identification of CRISPR/Cas9-generated Gene Knockouts in the Model System Danio rerio

Targeted genome editing in the model system Danio rerio (zebrafish) has been greatly facilitated by the emergence of CRISPR-based approaches. Herein, we describe a streamlined, robust protocol for generation and identification of CRISPR-derived nonsense alleles that incorporates the heteroduplex mobility assay and identification of mutations using next-generation sequencing.

https://ift.tt/2LB1bSm

Prognostic significance of tumor-infiltrating lymphocytes in patients with operable tongue cancer

Abstract

Background

Our aim was to investigate the prognostic significance of tumor-infiltrating lymphocytes (TILs) in operable tongue cancer patients.

Methods

The presence of CD3⁺, CD4⁺, CD8⁺, and forkhead box protein P3-positive (FOXP3⁺) TILs in tumor tissues obtained from 93 patients during surgery was examined using immunohistochemistry.

Results

The 3-year overall survival (OS) of patients with a low CD8/FOXP3 ratio was significantly lower than that of patients with a high CD8/FOXP3 ratio (63.8% vs. 87.3%, p = 0.001). Patients with high FOXP3 had a significantly lower 3-year regional recurrence-free survival (RRFS) than did patients with low FOXP3 (49.3% vs. 87.3%, univariate log rank p = 0.000). A low CD4/FOXP3 ratio (68.4% vs. 93.7%, univariate log rank p = 0.002) was significantly unfavorable prognostic factors for 3-year distant metastasis-free survival (DMFS).

Conclusions

In addition to clinicopathological characteristics, TIL markers represent prognosticators for clinical outcomes.

https://ift.tt/2BXji5q

Event‐related deep brain stimulation of the subthalamic nucleus affects conflict processing

Annals of Neurology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2wn4WGp

Cerebrospinal fluid vasopressin and symptom severity in children with autism

Annals of Neurology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2Pddwyk

Survival benefit of multimodal local therapy for repeat recurrence of thoracic esophageal squamous cell carcinoma after esophagectomy

Abstract

Background

This study was performed to clarify the optimal therapeutic strategy for recurrent disease after esophagectomy.

Methods

We investigated the prognosis of 37 patients who developed recurrence among 128 patients who underwent curative thoracoscopic esophagectomy (TE) at Kanazawa University Hospital. The prognostic factors after recurrence were examined by univariate and multivariate analyses.

Results

Of these 37 recurrences, 29 patients underwent local therapy (surgery, 10 patients; surgery followed by radiation, 2 patients; radiation, 17 patients). Radiation includes intensity-modulated radiation therapy, chemoradiation, and simple radiation therapy. Seventeen patients (58.6%) were considered to have undergone successful therapy by disappearance or diminishment of the targeted region without regrowth. Eleven of 17 patients (64.7%) showed repeat recurrence at another site. Multiple local therapy was performed for repeat recurrence or uncontrollable first therapy. Finally, 57 local therapies were performed. Using multimodal local therapy, 37 (64.9%) of 57 recurrences were successfully managed. The 12 patients treated by surgery as the initial therapy showed the most favorable survival. Seventeen patients who underwent successful initial therapy showed better survival than others. Multiple or miscellaneous organ metastasis, abdominal lymphatic recurrence and best supportive care at recurrence were statistically significant negative variables for survival after recurrence. Performance of surgery and successful therapy as the initial recurrence were statistically significant positive variables for survival after recurrence. Multivariate analysis showed that successful therapy at the initial recurrence was the only independent variable for survival after recurrence.

Conclusions

Multimodal local therapy for repeat recurrence after TE contributes to the improvement of survival after recurrence.

https://ift.tt/2PIjWGC

Leveraging PET to image folate receptor α therapy of an antibody-drug conjugate

Abstract

Background

The folate receptor α (FRα)-targeting antibody-drug conjugate (ADC), IMGN853, shows great antitumor activity against FRα-expressing tumors in vivo, but patient selection and consequently therapy outcome are based on immunohistochemistry. The aim of this study is to develop an antibody-derived immuno-PET imaging agent strategy for targeting FRα in ovarian cancer as a predictor of treatment success.

Methods

We developed [⁸⁹Zr]Zr-DFO-M9346A, a humanized antibody-based radiotracer targeting tumor-associated FRα in the preclinical setting. [⁸⁹Zr]Zr-DFO-M9346A's binding ability was tested in an in vitro uptake assay using cell lines with varying FRα expression levels. The diagnostic potential of [⁸⁹Zr]Zr-M9346A was evaluated in KB and OV90 subcutaneous xenografts. Following intravenous injection of [⁸⁹Zr]Zr-DFO-M9346A (~90 μCi, 50 μg), PET imaging and biodistribution studies were performed. We determined the blood half-life of [⁸⁹Zr]Zr-DFO-M9346A and compared it to the therapeutic, radioiodinated ADC [¹³¹I]-IMGN853. Finally, in vivo studies using IMG853 as a therapeutic, paired with [⁸⁹Zr]Zr-DFO-M9346A as a companion diagnostic were performed using OV90 xenografts.

Results

DFO-M9346A was labeled with Zr-89 at 37 °C within 60 min and isolated in labeling yields of 85.7 ± 5.7%, radiochemical purities of 98.0 ± 0.7%, and specific activities of 3.08 ± 0.43 mCi/mg. We observed high specificity for binding FRα positive cells in vitro. For PET and biodistribution studies, [⁸⁹Zr]Zr-M9346A displayed remarkable in vivo performance in terms of excellent tumor uptake for KB and OV xenografts (45.8 ± 29.0 %IA/g and 26.1 ± 7.2 %IA/g), with low non-target tissue uptake in other organs such as kidneys (4.5 ± 1.2 %IA/g and 4.3 ± 0.7 %IA/g). A direct comparison of the blood half life of [⁸⁹Zr]Zr-M9346A and [¹³¹I]-IMGN853 corroborated the equivalency of the radiopharmaceutical and the ADC, paving the way for a companion PET imaging study.

Conclusions

We developed a new folate receptor-targeted ⁸⁹Zr-labeled PET imaging agent with excellent pharmacokinetics in vivo. Good tumor uptake in subcutaneous KB and OV90 xenografts were obtained, and ADC therapy studies were performed with the precision predictor.

https://ift.tt/2BWXkQ0

Non-canonical NF-κB Antagonizes STING Sensor-Mediated DNA Sensing in Radiotherapy

It is known that the NF-κB pathway plays a crucial role in supporting tumor initiation, progression, and the radioresistance of tumor cells. Hou et al. demonstrate that the deficiency of non-canonical NF-κB, but not canonical NF-κB, promotes radiation-induced anti-tumor immunity by regulating the STING-mediated type I IFN expression.

https://ift.tt/2wssAjJ

The Chemokine Receptor CCR8 Promotes the Migration of Dendritic Cells into the Lymph Node Parenchyma to Initiate the Allergic Immune Response

Migration of dendritic cells (DCs) into the lymph node (LN) initiates adaptive immunity and is thought to be solely dependent on CCR7. Sokol et al. show that in a cutaneous type 2 immune response, CCR8 synergizes with CCR7 and is necessary to promote the entry of allergen-activated DCs into the LN parenchyma, which is required for Th2 differentiation.

https://ift.tt/2NrNgj6

A Map of Toll-like Receptor Expression in the Intestinal Epithelium Reveals Distinct Spatial, Cell Type-Specific, and Temporal Patterns

Price et al. generate five strains of reporter mice to visualize the expression of individual TLRs on intestinal epithelial cells (IECs). Their findings reveal unexpected diversity in the temporal and spatial patterns of TLR expression and in the responsiveness of IECs to microbial stimuli.

https://ift.tt/2PIiwfo

Lung γδ T Cells Mediate Protective Responses during Neonatal Influenza Infection that Are Associated with Type 2 Immunity

Influenza infection causes mortality in infants and protective immunity in this population is poorly understood. Guo et al. find that γδ T cells are required for recovery after neonatal influenza infection. γδ T cell-derived IL-17A is associated with the tissue repair response orchestrated by IL-33, ILC2s, and amphiregulin, and IL-17A correlates with improved disease outcomes in influenza-infected children.

https://ift.tt/2MUfUfQ

Gasdermin D Restrains Type I Interferon Response to Cytosolic DNA by Disrupting Ionic Homeostasis

Gasdermin D is a pore-forming protein, which upon activation by inflammasome complexes mediates pyroptotic cell death and IL-1 release. Banerjee et al. demonstrate a previously unknown regulatory role for gasdermin D-driven K+ efflux in reining in cGAS-dependent type I interferon response to cytosolic DNA.

https://ift.tt/2MZBr6M

Procalcitonin (PCT) Predicts Worse Outcome in Patients with Chronic Heart Failure with Reduced Ejection Fraction (HFrEF)

Introduction. Procalcitonin (PCT) is an excellent marker of sepsis but was not extensively studied in cardiology. The present study investigated PCT plasma concentration in patients with chronic heart failure with reduced ejection fraction (HFrEF) and its prognostic value during 24-month follow-up. Material and Methods. Study group consisted of 130 patients with HFrEF (LVEF ≤ 45%) and 32 controls. PCT level was assessed on admission in all patients. Telephone follow-up was performed every three months over a period of 2 years. Endpoints were death of all causes and readmission for HFrEF exacerbation. Results. HFrEF patients had significantly higher PCT concentration than controls (166.95 versus 22.15 pg/ml; ). Individuals with peripheral oedema had increased PCT comparing to those without oedema (217.07 versus 152.12 pg/ml; ). In ROC analysis, PCT turned out to be a valuable diagnostic marker of HFrEF (AUC 0.91; ). Kaplan-Meier survival curves revealed that patients with PCT in the 4th quartile had significantly lower probability of survival than those with PCT in the 1st and 2nd quartiles. In univariate, but not multivariate, analysis, procalcitonin turned out to be a significant predictor of death during 24-month follow-up. (; 95% CI 1.000–1.003; ). Conclusions. Elevated PCT concentration may serve as another predictor of worse outcome in patients with HFrEF.

https://ift.tt/2okHCnX

Is ibrutinib associated with disseminated cryptococcosis with CNS involvement?

.


https://ift.tt/2LzooUN

ELF3 is an antagonist of oncogenic-signalling-induced expression of EMT-TF ZEB1

.


https://ift.tt/2wtvu91

ENBD tube guided scope insertion technique for internal drainage in a case of difficult selective biliary duct guiding

Digestive Endoscopy, Volume 0, Issue ja, -Not available-.


https://ift.tt/2ogr6p3

Use of probe‐based confocal laser endomicroscopy for colon adenomas with topical application of acrinol drops

Digestive Endoscopy, Volume 0, Issue ja, -Not available-.


https://ift.tt/2LxCJ4r

Activation of orexin 1 receptors in the ventrolateral periaqueductal gray matter (vlPAG) modulates pulpal nociception and the induction of substance P in vlPAG and trigeminal nucleus caudalis

International Endodontic Journal, Volume 0, Issue ja, -Not available-.


https://ift.tt/2N2qNfS

The effect of central administration of alpha‐pinene on capsaicin‐induced dental pulp nociception

International Endodontic Journal, Volume 0, Issue ja, -Not available-.


https://ift.tt/2NoELFK

Cure in metastatic disease: how to manage and who is the right patient in GIST

Summary

Gastrointestinal stromal tumors (GISTs) are a rare type of cancer and a heterogeneous disease. The tyrosine kinase receptors KIT and the platelet-derived growth factor receptor alpha PDGFRA are the most common mutant genes of GIST. Mutation analysis is a diagnostic standard and is crucial for drug therapy with tyrosine kinase inhibitors (TKI). About 10% of patients already have metastases at first diagnosis. R0 resection is the only curative option in GIST and is therefore the therapy for localized tumors. In case of locally advanced primary tumors, neoadjuvant therapy should be offered. Recurrent, metastatic and locally advanced disease can be treated with TKI; in select cases surgical therapy may be added. The role of surgery in metastatic disease is controversial.

https://ift.tt/2NrmhUX

HSP90AA1-mediated autophagy promotes drug resistance in osteosarcoma

Abstract

Background

Osteosarcoma is the most common primary bone tumor in children and adolescents. Unfortunately, osteosarcoma treatments often fail due to the development of chemoresistance, of which the underlying molecular mechanisms still remain unclear. In this study, we demonstrated that HSP90AA1 gene is responsible for drug resistance in osteosarcoma through an autophagy-related mechanism.

Methods

shRNAs were transfected into osteosarcoma cells for knockdown of HSP90AA1 gene. Stable HSP90AA1 overexpressing osteosarcoma cell lines were obtained by lentivirus infection. mRNA and protein expressions of HSP90AA1 in osteosarcoma cells were tested by quantitative real-time PCR and western blot, respectively. Autophagy of osteosarcoma cells was detected by western blot of LC3, transmission electron microscopy and fluorescence microscope. mRFP-GFP-LC3 lentiviral transfection was also performed to detect autophagic flux. NOD/SCID mices were inoculated with MG-63 tumor cells transfected with HSP90AA1 specific shRNA. TUNEL and LC3 staining were performed to detect apoptosis and autophagy of resected tumor tissues.

Results

Doxorubicin, cisplatin, and methotrexate, which are commonly used in chemotherapy, each induced HSP90AA1 upregulation in human osteosarcoma cells. Suppression of HSP90AA1 restored the sensitivity of osteosarcoma cells to chemotherapy both in vivo and in vitro. Mechanism study indicated that autophagy is responsible for the chemoresistance in osteosarcoma cells. HSP90AA1 increased drug resistance by inducing autophagy and inhibiting apoptosis. Suppression of HSP90AA1 diminished autophagic protection in response to chemotherapy in osteosarcoma cells. Moreover, HSP90AA1 promotes autophagy through PI3K/Akt/mTOR pathway and inhibits apoptosis through JNK/P38 pathway.

Conclusion

We showed that chemotherapy agents can induce HSP90AA1 expression in osteosarcoma cells. And HSP90AA1, acting as an important regulator of autophagy, is a critical factor in the development of osteosarcoma chemoresistance both in vitro and in vivo. HSP90AA1 provides a novel therapeutic target for improving osteosarcoma treatment.

https://ift.tt/2PIMu2V