Τετάρτη 4 Απριλίου 2018
Methodology of clinical trials evaluating the incorporation of new drugs in the first line treatment of patients with diffuse large B-cell lymphoma (DLBCL): a critical review
Abstract
Purpose
The first line treatment of diffuse large B-cell lymphoma (DLBCL) is the combination of rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy, curing approximately 60% of patients. Many clinical trials have been performed over the last 10 years trying to improve the results of this treatment, but the appropriateness of their planning strategies could be rediscussed. Patients and Methods
Reports of phase 3 trials evaluating the addition of molecularly targeted agents (MTA) or new monoclonal antibodies to the classic R-CHOP backbone in first-line induction or maintenance treatment were reviewed. The trial design, primary end point, number of patients enrolled, patient selection criteria, treatment schedule and results were registered for each one. In addition, the phase1 and 2 trials which preceded these phase 3 trials were also reviewed. Results
Among six phase 3 trials with results, only one trial evaluating lenalidomide maintenance after response to R-CHOP induction was positive and reached its primary endpoint. The other 5 trials did not show an improved outcome with the addition of the new agent. The preceding phase 1 and 2 trials were very heterogeneous in their endpoints and design. Even though most of these trials were considered positive, thus encouraging further investigation, so far they failed to predict the results of the subsequent phase 3 trials. Conclusion
The standard of care for DLBCL is still R-CHOP. Phase 1/2 trials failed to predict the results of subsequent phase 3 trials evaluating non-chemotherapeutic agents added to R-CHOP. The methodology of phase 2 trials evaluating new agents in DLBCL needs to be better defined in the future.https://ift.tt/2GAjsgQ
ADI-PEG 20 Plus Best Supportive Care versus Placebo Plus Best Supportive Care in Patients with Advanced Hepatocellular Carcinoma
Abstract
Background
Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme – arginine deiminase – conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy. Methods and Patients
Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2:1 to ADI-PEG 20 18 mg/m2 vs. placebo intramuscular (IM) injection weekly. The primary endpoint was overall survival (OS), with 93% power to detect a 4 to 5.6 months increase in median OS (1-sided α = 0.025). Secondary endpoints included progression-free survival (PFS), safety, and arginine correlatives. Results
635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 vs 7.4 for placebo (p = 0.88, HR = 1.02) and median PFS 2.6 months vs. 2.6 (p = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in less than 5% of patients. Two patients on ADI-PEG 20 had ≥ grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 vs. 10.4% on placebo, none related to therapy. Post-hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion. Conclusion
ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway. Clinical Trial number
www.clinicaltrials (NCT 01287585)https://ift.tt/2GSD9nw
Functional characterization of the mouse Serpina1 paralog DOM-7
Authors: Jülicher, Karen / Wähner, Annabell / Haase, Kerstin / Barbour, Karen W. / Berger, Franklin G. / Wiehlmann, Lutz / Davenport, Colin / Schuster-Gossler, Karin / Stitz, Jörn / Cantz, Tobias / Eggenschwiler, Reto
https://ift.tt/2GmROb9
Transcytosis of payloads that are non-covalently complexed to bispecific antibodies across the hCMEC/D3 blood-brain barrier model
Authors: Schmid, Daniela / Buntz, Annette / Hanh Phan, Thi Ngoc / Mayer, Klaus / Hoffmann, Eike / Thorey, Irmgard / Niewöhner, Jens / Vasters, Katrin / Sircar, Ranjan / Mundigl, Olaf / Kontermann, Roland E. / Brinkmann, Ulrich
https://ift.tt/2uyv6r8
Hepatitis B virus X protein promotes proliferation of hepatocellular carcinoma cells by upregulating miR-181b via targeting ING5
Authors: Xie, Xuhua / Xu, Xiaopei / Sun, Changyu / Yu, Zujiang
https://ift.tt/2Gzgrl1
Kallikrein-related peptidase 14 is the second KLK protease targeted by the serpin vaspin
Authors: Ulbricht, David / Tindall, Catherine A. / Oertwig, Kathrin / Hanke, Stefanie / Sträter, Norbert / Heiker, John T.
https://ift.tt/2DPHz8Z
The role of (auto)-phosphorylation in the complex activation mechanism of LRRK2
Authors: Athanasopoulos, Panagiotis S. / Heumann, Rolf / Kortholt, Arjan
https://ift.tt/2Fs8xJD
HDAC1 knockdown inhibits invasion and induces apoptosis in non-small cell lung cancer cells
Authors: Zhang, Libin / Bu, Liang / Hu, Jiang / Xu, Zheyuan / Ruan, Libo / Fang, Yan / Wang, Ping
https://ift.tt/2DjKuqw
Prevalent Homozygous Deletions of Type I Interferon and Defensin Genes in Human Cancers Associate with Immunotherapy Resistance
Purpose: Homozygous deletions play important roles in carcinogenesis. The genome-wide screening for homozygously deleted genes in many different cancer types with a large number of patient specimens representing the tumor heterogeneity has not been done. Experimental Design: We performed integrative analyses of the copy number profiles of 10,759 patients across 31 cancer types from The Cancer Genome Atlas project. Results: We found that the Type-I interferon, α- and β-defensin genes were homozygously deleted in 19 cancer types with high frequencies (7%-31%, median = 12%; interquartile range = 10-16.5%). Patients with homozygous deletion of interferons exhibited significantly shortened overall or disease-free survival time in a number of cancer types, whereas patients with homozygous deletion of defensins did not significantly associate with worse overall or disease-free survival. Gene expression analyses suggested that homozygous deletion of interferon and defensin genes could activate genes involved in oncogenic and cell cycle pathways but repress other genes involved in immune response pathways, suggesting their roles in promoting tumorigenesis and helping cancer cells evade immune surveillance. Further analysis of the whole exomes of 109 melanoma patients demonstrated that the homozygous deletion of interferon (P = 0.0029, OR = 11.8) and defensin (P = 0.06, OR = 2.79) genes are significantly associated with resistance to anti-CTLA-4 (Cytotoxic T-Lymphocyte Associated protein 4) immunotherapy. Conclusions: Our analysis reveals that the homozygous deletion of interferon and defensin genes are prevalent in human cancers, and importantly this feature can be used as a novel prognostic biomarker for immunotherapy resistance.
https://ift.tt/2qbVGSr
Inositol trisphosphate receptor type 3-mediated enhancement of EGFR and MET co-targeting efficacy in non-small cell lung cancer detected by 18F-fluorothymidine
Purpose: Our aim was to test whether imaging with 18F-fluorothymidine (18F-FLT) PET/CT was able to detect the combined effects of EGFR and MET inhibitors in oncogene-driven non-small lung cancer (NSCLC) and to elucidate the mechanisms underlying the enhanced efficacy of drug combination. Experimental Design: NSCLC cells bearing MET amplification (H1993 and H820) were treated with EGFR and MET inhibitors either alone or in combination and then tested for cell viability and inhibition of signaling. Nude mice bearing H1993 tumors underwent 18F-FLT PET/CT scan before and after treatment with erlotinib and crizotinib alone or in combination (1:1 ratio) and post-treatment changes of 18F-FLT uptake in tumors were determined. The role of inositol trisphosphate receptor type 3 (IP3R3) in mediating the combined action of EGFR and MET inhibitors was tested by transfecting NSCLC cells with IP3R3-targeted siRNA. Results: Imaging studies showed a significant reduction of 18F-FLT uptake in response to combined treatment with EGFR and MET inhibitors that was higher than that obtained with single agents (ANOVA, F ratio= 6.215, p=0.001). Imaging findings were confirmed by analysis of surgically excised tumors. Levels of IP3R3 were significantly reduced in both cells and tumors after treatment with crizotinib whereas EGFR inhibitors caused a reduction of IP3R3 interaction with K-Ras mainly through dephosphorylation of serine residues of K-Ras. Conclusions: Our findings indicate that 18F-FLT PET/CT is able to detect the enhanced efficacy of EGFR and MET inhibitors in oncogene-driven NSCLC and that such enhancement is mediated by IP3R3 through its interaction with K-Ras.
https://ift.tt/2GBXAlp
Risk assessment after neoadjuvant chemotherapy in luminal breast cancer using a clinico-molecular predictor
Purpose: This study aimed to evaluate a modified EPclin test (mEPclin), a combination of EndoPredict (EP) score, post-neoadjuvant pathological tumor size and nodal status, for predicting the risk of distance recurrence after neoadjuvant chemotherapy (NACT) in patients with residual estrogen-receptor (ER)-positive/HER2-negative breast cancer (BC). We also compared the prognostic power of the mEPclin with that of the CPS-EG score. Experimental Design: 428 formalin-fixed, paraffin-embedded tumor samples from GeparTrio and GeparQuattro studies were evaluated for mRNA expression of eight cancer-related and three reference genes. The mEPclin score was computed using a modified algorithm and predefined cutoff values were used to classify each patient at low or high risk. Primary endpoint was disease-free survival (DFS). Results: A higher continuous mEPclin score was significantly associated with increased risk of relapse (HR=2.16 [95%CI 1.86-2.51]; p<0.001) and death (HR=2.28 [95% CI 1.90-2.75]; p<0.001). Similarly, patients classified at high risk by dichotomous mEPclin showed significantly poorer disease-free and overall survival compared to those at low risk. In contrast to CPS-EG, the mEPclin remained significantly prognostic for DFS in multivariate analysis (HR=2.13 [1.73-2.63]; p<0.001). Combining CPS-EG and other clinicopathological variables with mEPclin yielded a significant improvement of the prognostic power for DFS versus without mEPclin (c-indices: 0.748 vs. 0.660; p<0.001). Conclusions: The mEPclin score independently predicted the risk of distance recurrence and provided additional prognostic information to the CPS-EG score to assess more accurately the prognosis after NACT in the luminal non-pCR patient population. Therefore, this approach can be used to select patients for additional post-neoadjuvant therapies.
https://ift.tt/2q6pM9A
Orthoxenografts of testicular germ cell tumors demonstrate genomic changes associated with cisplatin resistance and identify PDMP as a re-sensitizing agent
Purpose: To investigate the genetic basis of cisplatin resistance. Efficacy of cisplatin chemotherapy in the treatment of distinct malignancies is often hampered by intrinsic/ acquired drug resistance of tumors. Experimental design: We produced 14 orthoxenograft transplanting human nonseminomatous (NSE) testicular germ cell tumors (TGCTs) to mice, keeping the primary tumor features (genotype, phenotype and sensitivity to cisplatin). Chromosomal and genetic alterations were evaluated in matched cisplatin-sensitive and their counterpart orthoxenografts that developed resistance to cisplatin in vivo. Results: Comparative genomic hybridization analyses of four matched orthoxenografts identified recurrent chromosomal rearrangements across cisplatin-resistant tumors in three of them, showing gains at 9q32-q33.1 region. We found a clinical correlation between the presence of 9q32-q33.1 gains in cisplatin refractory patients and poorer overall survival in metastatic TGCTs. We study the expression profile of the sixty genes located at that genomic region. POLE3 and AKNA were the only two genes deregulated in resistant tumors harboring the 9q32-q33.1 gain. Other four genes (GCS, ZNF883, CTR1 and FLJ31713) were deregulated in all five resistant tumors independently of the 9q32-q33.1 amplification. RT-PCRs in tumors and functional analyses in C. elegans indicate that the influence of 9q32-q33.1 genes in cisplatin resistance can be driven by either up- or down-regulation. We focused on glucosylceramide synthase (GCS) to demonstrate that the GCS inhibitor DL-threo-PDMP re-sensitizes cisplatin-resistant germline-derived orthoxenografts to cisplatin. Conclusions: Orthoxenografts can be used preclinically to test the efficiency of drugs and also to identify prognosis markers and gene alterations acting as drivers of the acquired cisplatin resistance.
https://ift.tt/2GznG8u
Change in topoisomerase 1 (Top1) positive circulating tumor cells impacts overall survival in patients with advanced breast cancer after treatment with etirinotecan pegol
Purpose: Preplanned exploratory analyses were performed to identify biomarkers in circulating tumor cells (CTCs) predictive of response to the topoisomerase 1 inhibitor etirinotecan pegol (EP). Experimental Design: The BEACON trial treated patients with metastatic breast cancer (MBC) with EP or treatment of physician's choice (TPC). Blood from 656/852 (77%) of patients was processed with ApoStream® to enrich for CTCs. A multiplex immunofluorescence assay measured expression of candidate response biomarkers (Top1, Top2, Ki67, RAD51, ABCG2, H2AX, TUNEL) in CTCs. Patients were classified as Top1 low (Top1Lo) or Top1 high (Top1Hi) based on median CTC Top1 expression. Correlation of CTC biomarker expression at baseline, cycle 2 day 1 (C2D1), and cycle 4 day 1 with overall survival (OS) was investigated using Cox regression and Kaplan-Meier analyses. Results: Overall, 98% of samples were successfully processed, of which 97% had detectable CTCs (median 47-63 CTCs/ml; range 0-2020 CTCs/ml). Top1, Top2, and TUNEL expression was detected in 52%-90% of samples; no significant associations with OS were observed in pre-treatment samples for either group. EP-treated patients with low C2D1Top1+ CTCs had improved OS compared to those with higher positivity (14.1 months vs. 11.0 months, respectively, HR 0.7, P=0.02); this difference was not seen in TPC-treated patients (HR 1.12, P=0.48). Patients whose CTCs decreased from Top1Hi to Top1Lo at C2D1 had the greatest OS benefit from EP (HR 0.57, P=0.01). Conclusions: CTC Top1 expression following EP treatment may identify patients with MBC most likely to have an OS benefit.
https://ift.tt/2q6pL5w
Lessons from the Crypt: HMGA1—Amping up Wnt for Stem Cells and Tumor Progression
High mobility group A1 (HMGA1) chromatin remodeling proteins are enriched in aggressive cancers and stem cells, although their common function in these settings has remained elusive until now. Recent work in murine intestinal stem cells (ISC) revealed a novel role for Hmga1 in enhancing self-renewal by amplifying Wnt signaling, both by inducing genes expressing Wnt agonist receptors and Wnt effectors. Surprisingly, Hmga1 also "builds" a stem cell niche by upregulating Sox9, a factor required for differentiation to Paneth cells; these cells constitute an epithelial niche by secreting Wnt and other factors to support ISCs. HMGA1 is also highly upregulated in colon cancer compared with nonmalignant epithelium and SOX9 becomes overexpressed during colon carcinogenesis. Intriguingly, HMGA1 is overexpressed in diverse cancers with poor outcomes, where it regulates developmental genes. Similarly, HMGA1 induces genes responsible for pluripotency and self-renewal in embryonic stem cells. These findings demonstrate that HMGA1 maintains Wnt and other developmental transcriptional networks and suggest that HMGA1 overexpression fosters carcinogenesis and tumor progression through dysregulation of these pathways. Studies are now needed to determine more precisely how HMGA1 modulates chromatin structure to amplify developmental genes and how to disrupt this process in cancer therapy. Cancer Res; 78(8); 1–8. ©2018 AACR.
https://ift.tt/2GvJgia
Subtle Perturbations of the Maize Methylome Reveal Genes and Transposons Silenced by Chromomethylase or RNA-Directed DNA Methylation Pathways
DNA methylation is a chromatin modification that can provide epigenetic regulation of gene and transposon expression. Plants utilize several pathways to establish and maintain DNA methylation in specific sequence contexts. The chromomethylase (CMT) genes maintain CHG (where H = A, C or T) methylation. The RNA-directed DNA methylation (RdDM) pathway is important for CHH methylation. Transcriptome analysis was performed in a collection of Zea mays lines carrying mutant alleles for CMT or RdDM-associated genes. While the majority of the transcriptome was not affected, we identified sets of genes and transposon families sensitive to context-specific decreases in DNA methylation. Many of the genes that are up-regulated in CMT mutant lines have high levels of CHG methylation, while genes that are differentially expressed in RdDM mutants are enriched for having nearby mCHH islands, implicating context-specific DNA methylation in the regulation of expression for a small number of genes. Many genes regulated by CMTs exhibit natural variation for DNA methylation and transcript abundance in a panel of diverse inbred lines. Transposon families with differential expression in the mutant genotypes show few defining features, though several families up-regulated in RdDM mutants are preferentially in endosperm tissue, highlighting the potential importance for this pathway during reproduction. Together, our findings suggest that while the number of genes and transposon families whose expression are reproducibly affected by mild perturbations in context-specific methylation is small, there are distinct patterns for loci impacted by RdDM and CMT mutants.
https://ift.tt/2GDwmLb
Ultrasound for diagnosing radiographically occult scaphoid fracture
Abstract
Objective
To systematically review the literature on the performance of ultrasound in diagnosing radiographically occult scaphoid fracture.
Methods
A systematic search was performed in the MEDLINE and Embase databases. Original studies investigating the performance of ultrasound in diagnosing radiographically occult scaphoid fracture in more than 10 patients were eligible for inclusion. Studies that included both radiographically apparent and occult scaphoid fractures (at initial radiography) were only included if independent data on radiographically occult fractures were reported. Methodological quality of the studies included was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Accuracy data were extracted. Sensitivity and specificity were pooled with a bivariate random-effects model.
Results
The inclusion criteria were met by 7 studies; total sample size comprised 314 patients. All studies, except 1, included cortical disruption of the scaphoid in their diagnostic criteria. The sensitivity and specificity of ultrasound in diagnosing radiographically occult scaphoid fracture ranged from 77.8% to 100% and from 71.4% to 100% respectively, with pooled estimates of 85.6% (95% CI: 73.9%, 92.6%) and 83.3% % (95% CI: 72.0%, 90.6%) respectively. Exclusion of two studies with a high risk of bias in any QUADAS-2 domain did not affect the pooled results.
Conclusion
Ultrasound can diagnose radiographically occult scaphoid fracture with a fairly high degree of accuracy. Because of its relatively low costs and fairly high sensitivity, ultrasound seems more cost-effective than empiric cast immobilization and may be used when CT and MRI are not readily available.
https://ift.tt/2GUOeEO
Medicare Program Narrows Racial Disparities in Readmissions
WEDNESDAY, April 4, 2018 -- Medicare's Hospital Readmissions Reduction Program is associated with a narrowing of racial disparities in hospital readmissions, according to a study published in the April issue of Health Affairs. José F. Figueroa,...
https://ift.tt/2H9xOWF
Early-Life Epilepsy Should Be Urgently Treated With EBM
WEDNESDAY, April 4, 2018 -- Early-life epilepsy should be treated with the same urgency as pediatric cancer, according to an article published online April 4 in Neurology. Anne T. Berg, Ph.D., and Stewart Goldman, M.D., from the Ann & Robert H....
https://ift.tt/2q8DiJ1
Demoralization Common in Patients With Parkinson's Disease
WEDNESDAY, April 4, 2018 -- Demoralization is common in patients with Parkinson's disease (PD) and is associated with motor dysfunction, according to a study published online April 4 in Neurology. Brian B. Koo, M.D., from Yale University in New...
https://ift.tt/2HbFCr4
Diagnostic Investigation of Lesions Associated with Succinate Dehydrogenase Defects
Horm Metab Res
DOI: 10.1055/a-0586-3710
The mitochondrial enzyme succinate dehydrogenase (SDH) acts as a tumor suppressor. Biallelic inactivation of one of the genes encoding for SDH subunits (collectively named SDHx) leads to complete loss of the protein function and the development of diverse group of tumors. Pheochromocytomas-paragangliomas are the prime example of hereditary tumors caused by SDH deficiency. In this review, we discuss the roles of imaging examinations, and illustrate new insights into genotype-imaging phenotype relationships.
[...]
© Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Abstract | Full text
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Multifocal nitrous oxide cryoballoon ablation with or without EMR for treatment of neoplastic Barrett’s esophagus
Endoscopic cryotherapy can eradicate neoplastic Barrett's esophagus (BE). A new contact cryoballoon focal ablation system (CbFAS)) freezes esophageal mucosa with nitrous oxide. We studied the safety and efficacy of CbFAS for complete eradication of neoplastic Barrett's esophagus.
https://ift.tt/2IuS2tz
Renal histology in a patient with TAFRO Syndrome: A case report
An 84-year-old Japanese man was admitted due to anasarca, thrombocytopenia, systemic inflammation, and progressive renal insufficiency, resistant to diuretics, glucocorticoid therapy and plasma exchange. Renal biopsy showed diffuse endocapillary proliferation and mesangiolysis without any immune deposits. Tocilizumab suppressed systemic inflammation, resulting in improvement of anasarca and renal dysfunction, but thrombocytopenia persisted and platelet-associated IgG antibody was elevated. Though romiplostim was effective for thrombocytopenia, the patient died of aspiration pneumonia after cerebral hemorrhage.
https://ift.tt/2GWYiwX
Expanding the Histomorphologic Spectrum of TFE3 Rearranged PEComas
Perivascular epithelioid tumors (PEComas) are a family of mesenchymal neoplasms that have smooth muscle and melanocytic differentiation. They can be sporadic or associated with Tuberous Sclerosis Complex and commonly present in the kidney as angiomyolipoma or in the lung as pulmonary clear cell sugar tumors or lymphangioleiomyomatosis. However, they can present at any visceral or soft tissue site. They usually have a benign clinical course, but rarely can behave in a malignant fashion. Most PEComas demonstrate abnormalities of TSC2, but a recently described subset harbor TFE3 rearrangements that appear to be mutually exclusive of TSC2 alterations.
https://ift.tt/2Itfya1
Placentas from women with pregnancy-associated venous insufficiency show villi damage with evidence of hypoxic cellular stress
Lower extremity venous insufficiency (VI) is a complication of pregnancy. The potential association of this venous disease with structural damage of the placenta has not been described. We analyzed the pattern of histopathological lesions and the gene and protein expression of HIF1-α and apoptosis regulatory proteins. A prospective study was carried out on placenta samples from 43 women with pregnancy-associated VI and 24 age-matched pregnant healthy controls (HC). Women with VI showed a significant increase in the number of villi (150.77±42.55 VI versus 122.13±27.74 HC) and in syncytial knots compared to those found in placentas from HC (67.15±31.08 VI versus 42.49±17.36 HC), and an increase in the number of bridges (32.40±2.67 VI versus 22.73±2.37 HC) (P<.05).
https://ift.tt/2GY6ahM
EWSR1-NFATC2 Gene Fusion in a Soft Tissue Tumor with Epithelioid Round Cell Morphology and Abundant Stroma: A Case Report and Review of the Literature
SummaryMesenchymal round cell tumors are a diverse group of neoplasms defined by primitive, often high-grade cytomorphology. The most common molecular alterations detected in these tumors are gene rearrangements involving EWSR1 to one of many fusion partners. Rare EWSR1-NFATC2 gene rearrangements, corresponding to a t(20;22) gene translocation, have been described in mesenchymal tumors with clear round cell morphology and a predilection for the skeleton. We present a case of a tumor harboring the EWSR1-NFATC2 gene fusion arising in the subcutaneous tissue of a young woman.
https://ift.tt/2GCL7Ot
Evaluation of Glioblastoma (GBM) Response to Therapy with Chemical Exchange Saturation Transfer (CEST)
Early determination of Glioblastoma (GBM) response to standard 6-week chemo-radiation may allow for adjusting subsequent therapy in non-responders. Chemical exchange saturation transfer (CEST) probes cellular and metabolic characteristics of the tumor which are more sensitive to treatment-induced changes (compared to tumor size change). CEST was able to identify those tumors that would progress early after treatment completion based on the imaging acquired as early as two weeks into the treatment course. Moreover, certain CEST metrics were able to characterize GBM aggressiveness even before treatment.
https://ift.tt/2q6dUVn
The pATM Immunofluorescence assay: a high-performance radiosensitivity assay to predict post radiotherapy overreactions
A new statistical analysis was performed on 117 patient-specific fibroblasts lines cultured from a skin biopsy in order to assess AUC, sensitivity, specificity, the positive predicted value and the negative predicted value of the pATM Immunofluorescence assay to sort overreactors. The pATM assay shows outstanding predictive performance amongst the available tests.
https://ift.tt/2q6dTRj
Proton stereotactic radiosurgery for brain metastases: a single institution analysis of 370 patients
There is a paucity of data on the use of proton stereotactic radiosurgery (SRS) for brain metastases. This retrospective study analyzed failure, toxicity, and survival outcomes in 370 patients with 815 metastases treated with proton SRS. To the best of our knowledge, this is the first reported series of proton SRS for treatment of brain metastases and our observations suggest that moderate-dose proton SRS is well-tolerated and can achieve good local control outcomes, comparable to those obtained with conventional SRS strategies.
https://ift.tt/2uLbTTh
Stereotactic Body Radiotherapy For Oligometastatic Ovarian Cancer: A Step Towards A Drug Holiday
This study including 82 patients showed that stereotactic radiotherapy for oligometastatic ovarian cancer is feasible, well tolerated and offers high local control. At 1 year, 1 out of 3 patients is free of progression and new treatments.
https://ift.tt/2GBvQNy
Delivering a “New Deal” of Kidney Health Opportunities to Improve Outcomes Within the Veterans Health Administration
Just as the "New Deal" aimed to elevate the "forgotten man" of the Great Depression through governmental relief and reform, so does the Department of Veterans Affairs (VA) health care system aim to improve the health of veterans with the invisible illness of chronic kidney disease through a concerted series of health care delivery reforms. Augmenting its primary care platform with advances in informatics and health service delivery initiatives targeting kidney disease, the VA is changing how nephrology care is provided to veterans with the goal of optimized population kidney health.
https://ift.tt/2uPu7CU
Severe Cardiac Involvement Is Rare in Patients with Late-Onset Pompe Disease and the Common c.-32-13T>G Variant: Implications for Newborn Screening
Based on a review of a large patient cohort, published literature, and 3 newborn screening cohorts, we concluded that children diagnosed through newborn screening with late-onset Pompe disease and the common heterozygous c.-32-13T>G variant require frequent cardiac follow-up with electrocardiography for arrhythmias. However, there is limited evidence for performing repeated echocardiography for cardiomyopathy.
https://ift.tt/2q5wpsV
Maternal Black Race and Persistent Wheezing Illness in Former Extremely Low Gestational Age Newborns: Secondary Analysis of a Randomized Trial
To evaluate the relationship between maternal self-reported race/ethnicity and persistent wheezing illness in former high-risk, extremely low gestational age newborns, and to quantify the contribution of socioeconomic, environmental, and biological factors on this relationship.
https://ift.tt/2GAyZNT
The Key Role of Epigenetics in Human Disease Prevention and Mitigation
New England Journal of Medicine, Volume 378, Issue 14, Page 1323-1334, April 2018.
https://ift.tt/2q3XWLs
Bedside Computer Vision — Moving Artificial Intelligence from Driver Assistance to Patient Safety
New England Journal of Medicine, Volume 378, Issue 14, Page 1271-1273, April 2018.
https://ift.tt/2IvJenb
Change in Overweight from Childhood to Early Adulthood and Risk of Type 2 Diabetes
New England Journal of Medicine, Volume 378, Issue 14, Page 1302-1312, April 2018.
https://ift.tt/2IukCLu
Outpatient Talc Administration by Indwelling Pleural Catheter for Malignant Effusion
New England Journal of Medicine, Volume 378, Issue 14, Page 1313-1322, April 2018.
https://ift.tt/2q3XXPw
Inventing a New Model of Hypertension Care for Black Men
New England Journal of Medicine, Volume 378, Issue 14, Page 1345-1347, April 2018.
https://ift.tt/2IqbJm7
Ultrasound Guidance for Pleural-Catheter Placement
New England Journal of Medicine, Volume 378, Issue 14, April 2018.
https://ift.tt/2IuLAT0
Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer
https://ift.tt/2IsFcf5
Stream of Consciousness
New England Journal of Medicine, Volume 378, Issue 14, Page 1336-1342, April 2018.
https://ift.tt/2q3XPj0
More on Ofatumumab for TTP
New England Journal of Medicine, Volume 378, Issue 14, Page 1364-1365, April 2018.
https://ift.tt/2q5GmX9
4-Year Follow-up in a Child with a Total Autologous Tracheal Replacement
https://ift.tt/2GCeAI8
Cousin Pam
New England Journal of Medicine, Volume 378, Issue 14, Page 1273-1275, April 2018.
https://ift.tt/2q5eYZh
Bouveret’s Syndrome
https://ift.tt/2IsF92T
PCI Strategies in Acute Myocardial Infarction with Cardiogenic Shock
New England Journal of Medicine, Volume 378, Issue 14, Page 1358-1361, April 2018.
https://ift.tt/2q5Ze8H
Promise and Reality of Price Transparency
New England Journal of Medicine, Volume 378, Issue 14, Page 1348-1354, April 2018.
https://ift.tt/2IqdQq7
Groin Hernia Surgery in Low-Resource Settings — A Problem Still Unsolved
New England Journal of Medicine, Volume 378, Issue 14, Page 1357-1358, April 2018.
https://ift.tt/2q5GmGD
Change in Overweight from Childhood to Early Adulthood and Risk of Type 2 Diabetes
New England Journal of Medicine, Volume 378, Issue 14, Page 1302-1312, April 2018.
https://ift.tt/2IukCLu
Outpatient Talc Administration by Indwelling Pleural Catheter for Malignant Effusion
New England Journal of Medicine, Volume 378, Issue 14, Page 1313-1322, April 2018.
https://ift.tt/2q3XXPw
Inventing a New Model of Hypertension Care for Black Men
New England Journal of Medicine, Volume 378, Issue 14, Page 1345-1347, April 2018.
https://ift.tt/2IqbJm7
The Key Role of Epigenetics in Human Disease Prevention and Mitigation
New England Journal of Medicine, Volume 378, Issue 14, Page 1323-1334, April 2018.
https://ift.tt/2q3XWLs
Ultrasound Guidance for Pleural-Catheter Placement
New England Journal of Medicine, Volume 378, Issue 14, April 2018.
https://ift.tt/2IuLAT0
Hand, Foot, and Mouth Disease in an Adult
New England Journal of Medicine, Volume 378, Issue 14, April 2018.
https://ift.tt/2q3XT2e
Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer
New England Journal of Medicine, Volume 378, Issue 14, Page 1362-1364, April 2018.
https://ift.tt/2IsFcf5
Stream of Consciousness
New England Journal of Medicine, Volume 378, Issue 14, Page 1336-1342, April 2018.
https://ift.tt/2q3XPj0
Bedside Computer Vision — Moving Artificial Intelligence from Driver Assistance to Patient Safety
New England Journal of Medicine, Volume 378, Issue 14, Page 1271-1273, April 2018.
https://ift.tt/2IvJenb
More on Ofatumumab for TTP
New England Journal of Medicine, Volume 378, Issue 14, Page 1364-1365, April 2018.
https://ift.tt/2q5GmX9
4-Year Follow-up in a Child with a Total Autologous Tracheal Replacement
New England Journal of Medicine, Volume 378, Issue 14, Page 1355-1357, April 2018.
https://ift.tt/2GCeAI8
Cousin Pam
New England Journal of Medicine, Volume 378, Issue 14, Page 1273-1275, April 2018.
https://ift.tt/2q5eYZh
Bouveret’s Syndrome
New England Journal of Medicine, Volume 378, Issue 14, Page 1335-1335, April 2018.
https://ift.tt/2IsF92T
PCI Strategies in Acute Myocardial Infarction with Cardiogenic Shock
New England Journal of Medicine, Volume 378, Issue 14, Page 1358-1361, April 2018.
https://ift.tt/2q5Ze8H
Promise and Reality of Price Transparency
New England Journal of Medicine, Volume 378, Issue 14, Page 1348-1354, April 2018.
https://ift.tt/2IqdQq7
Groin Hernia Surgery in Low-Resource Settings — A Problem Still Unsolved
New England Journal of Medicine, Volume 378, Issue 14, Page 1357-1358, April 2018.
https://ift.tt/2q5GmGD
Come see Firefly in Booth 2016 at ATA 2018
Join us for ATA18 in Chicago, April 28-May 1, the telehealth industry's premier event for technology innovation and networking. Highlights include more than 150 sessions, including ignite sessions, speakers corners, roundtables, an augmented reality new product showcase, and more.
Featured keynote speaker presentations: Jo Ann Jenkins, CEO, AARP, Lisa Bielamowicz, MD, President and Co-Founder, Gist Healthcare, LLC, and best-selling author, Robert Wachter, MD.
- In the Firefly booth, there will be live demonstrations of:
Visit www.ata18.org to learn more about ATA or to register.
https://ift.tt/2q2Jpi6
Isolation of Human Endothelial Cells from Normal Colon and Colorectal Carcinoma - An Improved Protocol
https://ift.tt/2q5bUMT
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Targeted next-generation sequencing is a time- and cost-efficient approach that is becoming increasingly popular in both disease research and clinical diagnostics. The protocol described here presents the complex workflow required for sequencing and the bioinformatics process used to identify genetic variants that contribute to disease.
https://ift.tt/2uP0MbK
{beta}-Secretase BACE1 Promotes Surface Expression and Function of Kv3.4 at Hippocampal Mossy Fiber Synapses
The β-secretase β-site APP-cleaving enzyme 1 (BACE1) is deemed a major culprit in Alzheimer's disease, but accumulating evidence indicates that there is more to the enzyme than driving the amyloidogenic processing of the amyloid precursor protein. For example, BACE1 has emerged as an important regulator of neuronal activity through proteolytic and, most unexpectedly, also through nonproteolytic interactions with several ion channels. Here, we identify and characterize the voltage-gated K+ channel 3.4 (Kv3.4) as a new and functionally relevant interaction partner of BACE1. Kv3.4 gives rise to A-type current with fast activating and inactivating kinetics and serves to repolarize the presynaptic action potential. We found that BACE1 and Kv3.4 are highly enriched and remarkably colocalized in hippocampal mossy fibers (MFs). In BACE1–/– mice of either sex, Kv3.4 surface expression was significantly reduced in the hippocampus and, in synaptic fractions thereof, Kv3.4 was specifically diminished, whereas protein levels of other presynaptic K+ channels such as KCa1.1 and KCa2.3 remained unchanged. The apparent loss of presynaptic Kv3.4 affected the strength of excitatory transmission at the MF–CA3 synapse in hippocampal slices of BACE1–/– mice when probed with the Kv3 channel blocker BDS-I. The effect of BACE1 on Kv3.4 expression and function should be bidirectional, as predicted from a heterologous expression system, in which BACE1 cotransfection produced a concomitant upregulation of Kv3.4 surface level and current based on a physical interaction between the two proteins. Our data show that, by targeting Kv3.4 to presynaptic sites, BACE1 endows the terminal with a powerful means to regulate the strength of transmitter release.
SIGNIFICANCE STATEMENT The β-secretase β-site APP-cleaving enzyme 1 (BACE1) is infamous for its crucial role in the pathogenesis of Alzheimer's disease, but its physiological functions in the intact nervous system are only gradually being unveiled. Here, we extend previous work implicating BACE1 in the expression and function of voltage-gated Na+ and K+ channels. Specifically, we characterize voltage-gated K+ channel 3.4 (Kv3.4), a presynaptic K+ channel required for action potential repolarization, as a novel interaction partner of BACE1 at the mossy fiber (MF)–CA3 synapse of the hippocampus. BACE1 promotes surface expression of Kv3.4 at MF terminals, most likely by physically associating with the channel protein in a nonenzymatic fashion. We advance the BACE1–Kv3.4 interaction as a mechanism to strengthen the temporal control over transmitter release from MF terminals.
https://ift.tt/2EjNVhf
Swedish Nerve Growth Factor Mutation (NGFR100W) Defines a Role for TrkA and p75NTR in Nociception
Nerve growth factor (NGF) exerts multiple functions on target neurons throughout development. The recent discovery of a point mutation leading to a change from arginine to tryptophan at residue 100 in the mature NGFβ sequence (NGFR100W) in patients with hereditary sensory and autonomic neuropathy type V (HSAN V) made it possible to distinguish the signaling mechanisms that lead to two functionally different outcomes of NGF: trophic versus nociceptive. We performed extensive biochemical, cellular, and live-imaging experiments to examine the binding and signaling properties of NGFR100W. Our results show that, similar to the wild-type NGF (wtNGF), the naturally occurring NGFR100W mutant was capable of binding to and activating the TrkA receptor and its downstream signaling pathways to support neuronal survival and differentiation. However, NGFR100W failed to bind and stimulate the 75 kDa neurotrophic factor receptor (p75NTR)-mediated signaling cascades (i.e., the RhoA-Cofilin pathway). Intraplantar injection of NGFR100W into adult rats induced neither TrkA-mediated thermal nor mechanical acute hyperalgesia, but retained the ability to induce chronic hyperalgesia based on agonism for TrkA signaling. Together, our studies provide evidence that NGFR100W retains trophic support capability through TrkA and one aspect of its nociceptive signaling, but fails to engage p75NTR signaling pathways. Our findings suggest that wtNGF acts via TrkA to regulate the delayed priming of nociceptive responses. The integration of both TrkA and p75NTR signaling thus appears to regulate neuroplastic effects of NGF in peripheral nociception.
SIGNIFICANCE STATEMENT In the present study, we characterized the naturally occurring nerve growth factor NGFR100W mutant that is associated with hereditary sensory and autonomic neuropathy type V. We have demonstrated for the first time that NGFR100W retains trophic support capability through TrkA, but fails to engage p75NTR signaling pathways. Furthermore, after intraplantar injection into adult rats, NGFR100W induced neither thermal nor mechanical acute hyperalgesia, but retained the ability to induce chronic hyperalgesia. We have also provided evidence that the integration of both TrkA- and p75NTR-mediated signaling appears to regulate neuroplastic effects of NGF in peripheral nociception. Our study with NGFR100W suggests that it is possible to uncouple trophic effect from nociceptive function, both induced by wild-type NGF.
https://ift.tt/2Gx64y1
Glutathione Conjugation at the Blood-CSF Barrier Efficiently Prevents Exposure of the Developing Brain Fluid Environment to Blood-Borne Reactive Electrophilic Substances
Exposure of the developing brain to toxins, drugs, or deleterious endogenous compounds during the perinatal period can trigger alterations in cell division, migration, differentiation, and synaptogenesis, leading to lifelong neurological impairment. The brain is protected by cellular barriers acting through multiple mechanisms, some of which are still poorly explored. We used a combination of enzymatic assays, live tissue fluorescence microscopy, and an in vitro cellular model of the blood–CSF barrier to investigate an enzymatic detoxification pathway in the developing male and female rat brain. We show that during the early postnatal period the choroid plexus epithelium forming the blood–CSF barrier and the ependymal cell layer bordering the ventricles harbor a high detoxifying capacity that involves glutathione S-transferases. Using a functional knock-down rat model for choroidal glutathione conjugation, we demonstrate that already in neonates, this metabolic pathway efficiently prevents the penetration of blood-borne reactive compounds into CSF. The versatility of the protective mechanism results from the multiplicity of the glutathione S-transferase isoenzymes, which are differently expressed between the choroidal epithelium and the ependyma. The various isoenzymes display differential substrate specificities, which greatly widen the spectrum of molecules that can be inactivated by this pathway. In conclusion, the blood–CSF barrier and the ependyma are identified as key cellular structures in the CNS to protect the brain fluid environment from different chemical classes of potentially toxic compounds during the postnatal period. This metabolic neuroprotective function of brain interfaces ought to compensate for the liver postnatal immaturity.
SIGNIFICANCE STATEMENT Brain homeostasis requires a stable and controlled internal environment. Defective brain protection during the perinatal period can lead to lifelong neurological impairment. We demonstrate that the choroid plexus forming the blood–CSF barrier is a key player in the protection of the developing brain. Glutathione-dependent enzymatic metabolism in the choroidal epithelium inactivates a broad spectrum of noxious compounds, efficiently preventing their penetration into the CSF. A second line of detoxification is located in the ependyma separating the CSF from brain tissue. Our study reveals a novel facet of the mechanisms by which the brain is protected at a period of high vulnerability, at a time when the astrocytic network is still immature and liver xenobiotic metabolism is limited.
https://ift.tt/2GwWMCi
Cereblon Maintains Synaptic and Cognitive Function by Regulating BK Channel
Mutations in the cereblon (CRBN) gene cause human intellectual disability, one of the most common cognitive disorders. However, the molecular mechanisms of CRBN-related intellectual disability remain poorly understood. We investigated the role of CRBN in synaptic function and animal behavior using male mouse and Drosophila models. Crbn knock-out (KO) mice showed normal brain and spine morphology as well as intact synaptic plasticity; however, they also exhibited decreases in synaptic transmission and presynaptic release probability exclusively in excitatory synapses. Presynaptic function was impaired not only by loss of CRBN expression, but also by expression of pathogenic CRBN mutants (human R419X mutant and Drosophila G552X mutant). We found that the BK channel blockers paxilline and iberiotoxin reversed this decrease in presynaptic release probability in Crbn KO mice. In addition, paxilline treatment also restored normal cognitive behavior in Crbn KO mice. These results strongly suggest that increased BK channel activity is the pathological mechanism of intellectual disability in CRBN mutations.
SIGNIFICANCE STATEMENT Cereblon (CRBN), a well known target of the immunomodulatory drug thalidomide, was originally identified as a gene that causes human intellectual disability when mutated. However, the molecular mechanisms of CRBN-related intellectual disability remain poorly understood. Based on the idea that synaptic abnormalities are the most common factor in cognitive dysfunction, we monitored the synaptic structure and function of Crbn knock-out (KO) animals to identify the molecular mechanisms of intellectual disability. Here, we found that Crbn KO animals showed cognitive deficits caused by enhanced BK channel activity and reduced presynaptic glutamate release. Our findings suggest a physiological pathomechanism of the intellectual disability-related gene CRBN and will contribute to the development of therapeutic strategies for CRBN-related intellectual disability.
https://ift.tt/2EjiKmf
QI Project Reduces Unnecessary Peds Inpatient Electrolyte Testing
WEDNESDAY, April 4, 2018 -- A quality improvement initiative rapidly reduced unnecessary electrolyte testing among hospitalized pediatric patients, according to a study published online April 4 in Pediatrics. Michael J. Tchou, M.D., from the...
https://ift.tt/2uMzItB
CDC: Aggressive Action Needed to Contain Antibiotic Resistance
WEDNESDAY, April 4, 2018 -- Early aggressive action should be taken to prevent the spread of bacteria harboring unusual resistance genes, according to a report published April 3 by the U.S. Centers for Disease Control and Prevention. According to...
https://ift.tt/2Jjb1YZ
Breast Cancer Diagnosis, Therapy Differ in Women With Implants
WEDNESDAY, April 4, 2018 -- Method of diagnosis, stage, and treatment are not affected by type of breast implant or anatomic location, according to research published in the April issue of Plastic and Reconstructive Surgery. Michael Sosin, M.D.,...
https://ift.tt/2uLAur7
Metabolic Abnormalities Seen in Testicular Cancer Survivors
WEDNESDAY, April 4, 2018 -- Testicular cancer survivors (TCS) have metabolic abnormalities characterized by hypertension and increased low-density lipoprotein (LDL) and total cholesterol, according to a study published in the March 1 issue of the...
https://ift.tt/2JiDfTP
Variations Identified in Free-Text Directions in E-Prescriptions
WEDNESDAY, April 4, 2018 -- There is considerable variation in the quality of free-text patient directions (Sig) in electronic prescriptions (e-prescriptions), according to a study published online April 2 in the Journal of Managed Care &...
https://ift.tt/2IwvFnA
Caffeine Citrate Helps Reduce Acute Kidney Injury in Preemies
WEDNESDAY, April 4, 2018 -- Caffeine administration in preterm neonates is associated with reduced incidence and severity of acute kidney injury (AKI) in the first week after birth, according to a study published online April 2 in JAMA...
https://ift.tt/2JiCN85
Depressive Symptoms Tied to Diabetes Self-Management
WEDNESDAY, April 4, 2018 -- Changes in depressive symptoms can predict improvement in self-efficacy and adherence to diabetes management, according to a study published online March 27 in Diabetes Care. Hyunsung Oh, Ph.D., from Arizona State...
https://ift.tt/2IrEq20
Docs Engage Little to Coordinate Medicare Home Health Care
WEDNESDAY, April 4, 2018 -- Physicians do not meaningfully engage with skilled home health care (SHHC) agencies in the certification of Medicare beneficiaries' plans of care, according to a study published online April 3 in the Annals of Internal...
https://ift.tt/2JkMYsH
Marijuana Legalization May Reduce Opioid Use
WEDNESDAY, April 4, 2018 -- State implementation of medical marijuana laws is associated with a reduction in the rate of opioid prescribing, according to a study published online April 2 in JAMA Internal Medicine. Hefei Wen, Ph.D., from the...
https://ift.tt/2IvrHLL
Eating Veggies Found to Protect Against Atherosclerosis in Women
WEDNESDAY, April 4, 2018 -- Eating more vegetables may prevent subclinical atherosclerosis in elderly women, according to a study published online April 4 in the Journal of the American Heart Association. Lauren C. Blekkenhorst, from Edith Cowan...
https://ift.tt/2HazDmg
Perfusable Vascular Network with a Tissue Model in a Microfluidic Device
https://ift.tt/2GxdvW2
Novel bacterial diversity is enriched with chloroperoxidase-reacted organic matter under anaerobic conditions
Abstract
Fungal chloroperoxidases (CPOs) are one class of enzymes that produce natural organochlorides in soils. The microbial degradation of these organochlorides is not well known, though has implications for bioremediation, microbial ecology and natural chlorine and carbon cycling. In this study, Illumina-based 16S rRNA gene sequencing and real-time quantitative PCR (qPCR) was used to characterize the bacterial community enriched from an amendment of organic matter reacted with CPO under conditions conducive towards chlorination (CPO-OM). In total, 17 bacterial groups were enriched in triplicate microcosms inoculated with creek sediment and amended with CPO-OM. These bacterial groups were neither enriched with amendments of non-reacted organic matter extract, with or without oxidative stress induced by H2O2, nor with amendments of organic matter reacted with CPO under non-chlorinating conditions. Of these, only two represented genera with known organohalide respiring bacteria—Dehalogenimonas and Dehalobacter. The genus Acetobacterium was also found to be enriched but the other 14 groups of enriched bacteria do not currently have any close phylogenetically related isolates. This study highlights a gap in the current understanding of the microbiology involved in natural organochloride turnover and suggests that CPO-OM could be used for isolating and culturing strains from novel bacteria genera.https://ift.tt/2uM65J5
eDNA from roots: a robust tool for determining Phytophthora communities in natural ecosystems
Abstract
Proper isolation and identification of Phytophthora species is critical due to their broad distribution and huge impact on natural ecosystems throughout the world. In this study, five different sites were sampled and seven methods were compared to determine the Phytophthora community. Three traditional isolation methods were conducted (i) soil baiting, (ii) filtering of the bait water and (iii) isolation from field roots using Granny Smith apples. These were compared to four sources of eDNA used for metabarcoding using Phytophthora-specific primers on (i) sieved field soil, (ii) roots from field, (iii) filtered baiting water and (iv) roots from bait plants grown in the glasshouse in soil collected from these sites. Six Phytophthora species each were recovered by soil baiting using bait leaves and from the filtered bait water. No Phytophthora species were recovered from Granny Smith apples. eDNA extracted from field roots detected the highest number of Phytophthora species (25). These were followed by direct DNA isolation from filters (24), isolation from roots from bait plants grown in the glasshouse (19), and DNA extraction from field soil (13). Therefore, roots were determined to be the best substrate for detecting Phytophthora communities using eDNA.https://ift.tt/2q4dmiq
Iron limitation effects on nitrogen-fixing organisms with possible implications for cyanobacterial blooms
Abstract
Cyanobacteria-dominated harmful algal blooms are increasing in occurrence. Many of the taxa contributing to these blooms are capable of fixing atmospheric nitrogen and should be favored under conditions of low nitrogen availability. Yet, synthesizing nitrogenase, the enzyme responsible for nitrogen fixation, is energetically expensive and requires substantial concentrations of iron. Phosphorus addition to nitrogen poor streams should promote nitrogen fixation, but experimental results so far have been inconclusive, suggesting that other factors may be involved in controlling this process. With iron potentially limited in many streams, we examined the influence of phosphorus-iron colimitation on the community structure of nitrogen-fixing organisms. In stream microcosms, using microscopic and molecular sequence data, we observed: (i) the greatest abundance of heterocyst forming nitrogen-fixing cyanobacteria in low nitrogen treatments with high phosphorus and iron and (ii) greater abundance of non-photosynthetic nitrogen-fixing bacteria in treatments with nitrogen compared to those without it. We also found that comparisons between molecular results and those obtained from microscopic identification provided complementary information about cyanobacterial communities. Our investigation indicates the potential for phosphorus-iron colimitation of stream nitrogen-fixing organisms.https://ift.tt/2uLReOL
Streptococcus gordonii Challisin protease is required for sensing cell--cell contact with Actinomyces oris
Abstract
The ability of microorganisms to regulate gene expression is thought to be critical for survival and growth during the development of polymicrobial biofilms such as dental plaque. The commensal dental plaque colonizer, Streptococcus gordonii, responds to cell--cell contact (coaggregation) with Actinomyces oris by regulating >20 genes, including those involved in arginine biosynthesis. We hypothesized that an S. gordonii extracellular protease is critical for sensing by providing amino acids that modulate gene expression. S. gordonii coaggregated strongly with A. oris in buffer, saliva or chemically defined medium (CDM). In wild-type S. gordonii, expression of arginine biosynthesis genes argC and argG increased within two hours' growth in CDM in monocultures, but not following coaggregation with A. oris. By contrast, coaggregation of A. oris with an S. gordonii mutant lacking sgc, encoding the extracellular protease Challisin, resulted in increases in argC and argG gene expression that were similar to monocultures. Genetic complementation of sgc restored the ability of S. gordonii to sense coaggregation with A. oris. Coaggregation enabled growth of S. gordonii in low/no arginine and disruption of sgc did not affect this ability. We propose that extracellular bacterial proteases may be key mediators of cell--cell contact sensing by diverse microbial species.https://ift.tt/2q4LsD6
Community structure and distribution of benthic cyanobacteria in Antarctic lacustrine microbial mats
Abstract
The terrestrial Antarctic Realm has recently been divided into 16 Antarctic Conservation Biogeographic Regions (ACBRs) based on environmental properties and the distribution of biota. Despite their prominent role in the primary production and nutrient cycling in Antarctic lakes, cyanobacteria were only poorly represented in the biological dataset used to delineate these ACBRs. Here, we provide a first high-throughput sequencing insight into the spatial distribution of benthic cyanobacterial communities in Antarctic lakes located in four distinct, geographically distant ACBRs and covering a range of limnological conditions. Cyanobacterial community structure differed between saline and freshwater lakes. No clear bioregionalization was observed, as clusters of community similarity encompassed lakes from distinct ACBRs. Most phylotypes (77.0%) were related to cyanobacterial lineages (defined at ≥99.0% 16S rRNA gene sequence similarity) restricted to the cold biosphere, including lineages potentially endemic to Antarctica (55.4%). The latter were generally rare and restricted to a small number of lakes, while more ubiquitous phylotypes were generally abundant and present in different ACBRs. These results point to a widespread distribution of some cosmopolitan cyanobacterial phylotypes across the different Antarctic ice-free regions, but also suggest the existence of dispersal barriers both within and between Antarctica and the other continents.https://ift.tt/2uLReyf
Biofilm growth and control in cooling water industrial systems
Abstract
Matrix-embedded, surface-attached microbial communities, known as biofilms, profusely colonise industrial cooling water systems, where the availability of nutrients and organic matter favours rapid microbial proliferation and their adhesion to surfaces in the evaporative fill material, heat exchangers, water reservoir and cooling water sections and pipelines. The extensive growth of biofilms can promote micro-biofouling and microbially induced corrosion (MIC) as well as pose health problems associated with the presence of pathogens like Legionella pneumophila. This review examines critically biofilm occurrence in cooling water systems and the main factors potentially affecting biofilm growth, biodiversity and structure. A broad evaluation of the most relevant biofilm monitoring and control strategies currently used or potentially useful in cooling water systems is also provided.https://ift.tt/2q4LlYc
Antibiotic resistance genes show enhanced mobilization through suspended growth and biofilm-based wastewater treatment processes
Abstract
Wastewater treatment plants (WWTPs) are known to harbor antibiotic resistance genes (ARGs) that are disseminated into the environment via effluent. However, few studies have compared abundance, mobilization and selective pressures for ARGs in WWTPs as a function of variations in secondary treatment bioprocesses. We used shotgun metagenomics to provide a comprehensive analysis of ARG composition, relationship to mobile genetic elements and co-occurrences with antibiotic production genes (APGs) throughout two full-scale municipal WWTPs, one of which employs biofilm-based secondary treatment and another that uses a suspended growth system. Results showed that abundances of ARGs declined by over 90% per genome equivalent in both types of wastewater treatment processes. However, the fractions of ARGs associated with mobile genetic elements increased substantially between influent and effluent in each plant, indicating significant mobilization of ARGs throughout both treatment processes. Strong positive correlations between ARGs and APGs were found for the aminoglycoside antibiotic class in the suspended growth system and for the streptogramin antibiotic class in the biofilm system. The biofilm and suspended growth WWTPs exhibited similarities in ARG abundances, composition and mobilization trends. However, clear differences were observed for within-plant ARG persistence. These findings suggest that both biofilm and suspended growth-based WWTPs may promote genetic mobilization of persistent ARGs that are then disseminated in effluent to receiving water bodies.https://ift.tt/2GBde0r
Coexistence of two distinct Sulfurospirillum populations respiring tetrachloroethene—genomic and kinetic considerations
Abstract
Two anaerobic bacterial consortia, each harboring a distinct Sulfurospirillum population, were derived from a 10 year old consortium, SL2, previously characterized for the stepwise dechlorination of tetrachloroethene (PCE) to cis-dichloroethene (cis-DCE) via accumulation of trichloroethene (TCE). Population SL2-1 dechlorinated PCE to TCE exclusively, while SL2-2 produced cis-DCE from PCE without substantial TCE accumulation. The reasons explaining the long-term coexistence of the populations were investigated. Genome sequencing revealed a novel Sulfurospirillum species, designated 'Candidatus Sulfurospirillum diekertiae', whose genome differed significantly from other Sulfurospirillum spp. (78%–83% ANI). Genome-wise, SL2-1 and SL2-2 populations are almost identical, but differences in their tetrachloroethene reductive dehalogenase sequences explain the distinct dechlorination patterns. An extended series of batch cultures were performed at PCE concentrations of 2–200 μM. A model was developed to determine their dechlorination kinetic parameters. The affinity constant and maximal growth rate differ between the populations: the affinity is 6- to 8-fold higher and the growth rate 5-fold lower for SL2-1 than SL2-2. Mixed cultivation of the enriched populations at 6 and 30 μM PCE showed that a low PCE concentration could be the driving force for both functional diversity of reductive dehalogenases and niche specialization of organohalide-respiring bacteria with overlapping substrate ranges.https://ift.tt/2qb3TpZ
Attention Selectively Gates Afferent Signal Transmission to Area V4
Selective attention allows focusing on only part of the incoming sensory information. Neurons in the extrastriate visual cortex reflect such selective processing when different stimuli are simultaneously present in their large receptive fields. Their spiking response then resembles the response to the attended stimulus when presented in isolation. Unclear is where in the neuronal pathway attention intervenes to achieve such selective signal routing and processing. To investigate this question, we tagged two equivalent visual stimuli by independent broadband luminance noise and used the spectral coherence of these behaviorally irrelevant signals with the field potential of a local neuronal population in male macaque monkeys' area V4 as a measure for their respective causal influences. This new experimental paradigm revealed that signal transmission was considerably weaker for the not-attended stimulus. Furthermore, our results show that attention does not need to modulate responses in the input populations sending signals to V4 to selectively represent a stimulus, nor do they suggest a change of the V4 neurons' output gain depending on their feature similarity with the stimuli. Our results rather imply that selective attention uses a gating mechanism comprising the synaptic "inputs" that transmit signals from upstream areas into the V4 neurons. A minimal model implementing attention-dependent routing by gamma-band synchrony replicated the attentional gating effect and the signals' spectral transfer characteristics. It supports the proposal that selective interareal gamma-band synchrony subserves signal routing and explains our experimental finding that attention selectively gates signals already at the level of afferent synaptic input.
SIGNIFICANCE STATEMENT Depending on the behavioral context, the brain needs to channel the flow of information through its networks of massively interconnected neurons. We designed an experiment that allows to causally assess routing of information originating from an attended object. We found that attention "gates" signals at the interplay between afferent fibers and the local neurons. A minimal model demonstrated that coherent gamma-rhythmic activity (~60 Hz) between local neurons and their afferent-providing input neurons can realize the gating. Importantly, the attended signals did not need to be amplified already in an earlier processing stage, nor did they get amplified by a simple output response modulation. The method provides a useful tool to study mechanisms of dynamic network configuration underlying cognitive processes.
https://ift.tt/2GzbVD2
Can Serial Dependencies in Choices and Neural Activity Explain Choice Probabilities?
During perceptual decisions the activity of sensory neurons covaries with choice, a covariation often quantified as "choice-probability". Moreover, choices are influenced by a subject's previous choice (serial dependence) and neuronal activity often shows temporal correlations on long (seconds) timescales. Here, we test whether these findings are linked. Using generalized linear models, we analyze simultaneous measurements of behavior and V2 neural activity in macaques performing a visual discrimination task. Both, decisions and spiking activity show substantial temporal correlations and cross-correlations but seem to reflect two mostly separate processes. Indeed, removing history effects using semipartial correlation analysis leaves choice probabilities largely unchanged. The serial dependencies in choices and neural activity therefore cannot explain the observed choice probability. Rather, serial dependencies in choices and spiking activity reflect two predominantly separate but parallel processes, which are coupled on each trial by covariations between choices and activity. These findings provide important constraints for computational models of perceptual decision-making that include feedback signals.
SIGNIFICANCE STATEMENT Correlations, unexplained by the sensory input, between the activity of sensory neurons and an animal's perceptual choice ("choice probabilities") have received attention from both a systems and computational neuroscience perspective. Conversely, whereas temporal correlations for both spiking activity ("non-stationarities") and for a subject's choices in perceptual tasks ("serial dependencies") have long been established, they have typically been ignored when measuring choice probabilities. Some accounts of choice probabilities incorporating feedback predict that these observations are linked. Here, we explore the extent to which this is the case. We find that, contrasting with these predictions, choice probabilities are largely independent of serial dependencies, which adds new constraints to accounts of choice probabilities that include feedback.
https://ift.tt/2q6Rd2e
Role of Rostral Fastigial Neurons in Encoding a Body-Centered Representation of Translation in Three Dimensions
Many daily behaviors rely critically on estimates of our body motion. Such estimates must be computed by combining neck proprioceptive signals with vestibular signals that have been transformed from a head- to a body-centered reference frame. Recent studies showed that deep cerebellar neurons in the rostral fastigial nucleus (rFN) reflect these computations, but whether they explicitly encode estimates of body motion remains unclear. A key limitation in addressing this question is that, to date, cell tuning properties have only been characterized for a restricted set of motions across head-re-body orientations in the horizontal plane. Here we examined, for the first time, how 3D spatiotemporal tuning for translational motion varies with head-re-body orientation in both horizontal and vertical planes in the rFN of male macaques. While vestibular coding was profoundly influenced by head-re-body position in both planes, neurons typically reflected at most a partial transformation. However, their tuning shifts were not random but followed the specific spatial trajectories predicted for a 3D transformation. We show that these properties facilitate the linear decoding of fully body-centered motion representations in 3D with a broad range of temporal characteristics from small groups of 5–7 cells. These results demonstrate that the vestibular reference frame transformation required to compute body motion is indeed encoded by cerebellar neurons. We propose that maintaining partially transformed rFN responses with different spatiotemporal properties facilitates the creation of downstream body motion representations with a range of dynamic characteristics, consistent with the functional requirements for tasks such as postural control and reaching.
SIGNIFICANCE STATEMENT Estimates of body motion are essential for many daily activities. Vestibular signals are important contributors to such estimates but must be transformed from a head- to a body-centered reference frame. Here, we provide the first direct demonstration that the cerebellum computes this transformation fully in 3D. We show that the output of these computations is reflected in the tuning properties of deep cerebellar rostral fastigial nucleus neurons in a specific distributed fashion that facilitates the efficient creation of body-centered translation estimates with a broad range of temporal properties (i.e., from acceleration to position). These findings support an important role for the rostral fastigial nucleus as a source of body translation estimates functionally relevant for behaviors ranging from postural control to perception.
https://ift.tt/2q5S1oZ
Heteromeric KV2/KV8.2 Channels Mediate Delayed Rectifier Potassium Currents in Primate Photoreceptors
Silent voltage-gated potassium channel subunits (KVS) interact selectively with members of the KV2 channel family to modify their functional properties. The localization and functional roles of these silent subunits remain poorly understood. Mutations in the KVS subunit, KV8.2 (KCNV2), lead to severe visual impairment in humans, but the basis of these deficits remains unclear. Here, we examined the localization, native interactions, and functional properties of KV8.2-containing channels in mouse, macaque, and human photoreceptors of either sex. In human retina, KV8.2 colocalized with KV2.1 and KV2.2 in cone inner segments and with KV2.1 in rod inner segments. KV2.1 and KV2.2 could be coimmunoprecipitated with KV8.2 in retinal lysates indicating that these subunits likely interact directly. Retinal KV2.1 was less phosphorylated than cortical KV2.1, a difference expected to alter the biophysical properties of these channels. Using voltage-clamp recordings and pharmacology, we provide functional evidence for Kv2-containing channels in primate rods and cones. We propose that the presence of KV8.2, and low levels of KV2.1 phosphorylation shift the activation range of KV2 channels to align with the operating range of rod and cone photoreceptors. Our data indicate a role for KV2/KV8.2 channels in human photoreceptor function and suggest that the visual deficits in patients with KCNV2 mutations arise from inadequate resting activation of KV channels in rod and cone inner segments.
SIGNIFICANCE STATEMENT Mutations in a voltage-gated potassium channel subunit, KV8.2, underlie a blinding inherited photoreceptor dystrophy, indicating an important role for these channels in human vision. Here, we have defined the localization and subunit interactions of KV8.2 channels in primate photoreceptors. We show that the KV8.2 subunit interacts with different Kv2 channels in rods and cones, giving rise to potassium currents with distinct functional properties. Our results provide a molecular basis for retinal dysfunction in patients with mutations in the KCNV2 gene encoding KV8.2.
https://ift.tt/2JjJRl1
Quantification of Site-specific Protein Lysine Acetylation and Succinylation Stoichiometry Using Data-independent Acquisition Mass Spectrometry
https://ift.tt/2GCz8jP
Tumour lysis in newborn: spontaneous or secondary to antenatal steroids?
Malignancies are rare in the early neonatal period. Common congenital tumours include malignant teratoma and neuroblastomas. Tumour lysis syndrome is a serious condition usually seen after commencement of chemotherapy for a malignancy. Rare case reports of spontaneous tumour lysis have been reported though not in the newborn period. We report here an instance of tumour lysis syndrome in a newborn with congenital rhabdoid tumour, where the cause was either spontaneous or related to antenatal steroid exposure.
https://ift.tt/2IpjwQY
Surprising cause of a hoarse voice
Description
A 78-year-old woman presented to our otorhinolaryngology clinic with a 5-year history of gradually progressive, worsening dysphonia, associated with some recent weight loss. She denied any dysphagia, odynophagia, otalgia, dyspnoea or neck lumps. She had a significant cardiovascular history and was a non-smoker with no alcohol intake. Using the grade–roughness–breathiness–asthenicity–strain scale, the patient scored a 2/3 for grade and breathiness, 1/3 for roughness and 3/3 for strain. On examination, there was a large left-sided posterior pharyngeal wall swelling occluding most of the oropharynx (figure 1). It was firm, non-pulsatile and non-tender, with a normal overlying mucosal appearance. Flexible nasoendoscopy demonstrated that this swelling extended from the level of the soft palate to just below the level of the epiglottis, with laryngeal displacement to the right. However, there was no airway compression, and the patient had normal, mobile true vocal cords bilaterally. Videolaryngostroboscopy was not possible with...
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Distal versus proximal intestinal short-chain fatty acid release in man
Several recent studies published in Gut highlight the potential of prebiotics and short-chain fatty acids (SCFAs) to improve obesity and its associated metabolic disorders. Catry and colleagues1 demonstrated that inulin-type fructans improve endothelial dysfunction, and Roager et al2 showed that a whole grain-rich diet reduced body weight and inflammation. Li et al3 reported that butyrate administration reduced appetite and activated brown adipose tissue in mice, and Chambers and colleagues4 showed that targeted propionate delivery to the human colon reduced energy intake and body weight gain.
In light of these important effects of SCFA, insight into their fate after bacterial production and/or intestinal absorption will help to improve the development of nutritional strategies aiming at modulation of intestinal SCFA. We addressed this issue by assessing SCFA release in the proximal intestines (jejunum, ileum and proximal colon) versus the distal intestines (descending colon, sigmoid and rectum)...
https://ift.tt/2Gzc7Cg
Impact of thiopurines on the natural history and surgical outcome of ulcerative colitis: a cohort study
Objective
Thiopurines are used as maintenance therapy in ulcerative colitis (UC), but whether these drugs influence the natural history of the disease is unknown. We aimed to assess the effect of thiopurines in terms of colectomy, hospital admission, progression in disease extent and anti-tumour necrosis factor (TNF) therapy within 10 years from initiation.
DesignPatients diagnosed with UC within the Örebro University Hospital catchment area, during 1963–2010, who initiated thiopurines (n=253) were included. To overcome the risk of confounding by indication, we compared patients who stopped treatment within 12 months because of an adverse reaction (n=76) with patients who continued therapy or discontinued due to other reasons (n=177) and assessed long-term outcomes using Cox regression with adjustment for potential confounding factors.
ResultsThe cumulative probability of colectomy within 10 years was 19.5% in tolerant patients compared with 29.0% in intolerant (adjusted HR 0.49; 95% CI 0.21 to 0.73). The probability of hospital admission was 34.0% in tolerant versus 56.2% in intolerant patients (adjusted HR 0.36; 95% CI 0.23 to 0.56). The risk for progression in disease extent was 20.4% in tolerant patients compared with 48.8% in intolerant (adjusted HR 0.47; 95% CI 0.21 to 1.06). Within 10 years, 16.1% of tolerant and 27.5% of intolerant patients received anti-TNF therapy (adjusted HR 0.49; 95% CI 0.26 to 0.92).
ConclusionBased on the novel approach of comparing patients tolerant and intolerant to thiopurines, we reveal that thiopurines have a profound beneficial impact of the natural history and long-term colectomy rates of UC.
https://ift.tt/2q6Cq7U
Cell-centred meta-analysis reveals baseline predictors of anti-TNF{alpha} non-response in biopsy and blood of patients with IBD
Objective
Although anti-tumour necrosis factor alpha (anti-TNFα) therapies represent a major breakthrough in IBD therapy, their cost–benefit ratio is hampered by an overall 30% non-response rate, adverse side effects and high costs. Thus, finding predictive biomarkers of non-response prior to commencing anti-TNFα therapy is of high value.
DesignWe analysed publicly available whole-genome expression profiles of colon biopsies obtained from multiple cohorts of patients with IBD using a combined computational deconvolution—meta-analysis paradigm which allows to estimate immune cell contribution to the measured expression and capture differential regulatory programmes otherwise masked due to variation in cellular composition. Insights from this in silico approach were experimentally validated in biopsies and blood samples of three independent test cohorts.
ResultsWe found the proportion of plasma cells as a robust pretreatment biomarker of non-response to therapy, which we validated in two independent cohorts of immune-stained colon biopsies, where a plasma cellular score from inflamed biopsies was predictive of non-response with an area under the curve (AUC) of 82%. Meta-analysis of the cell proportion-adjusted gene expression data suggested that an increase in inflammatory macrophages in anti-TNFα non-responding individuals is associated with the upregulation of the triggering receptor expressed on myeloid cells 1 (TREM-1) and chemokine receptor type 2 (CCR2)-chemokine ligand 7 (CCL7) –axes. Blood gene expression analysis of an independent cohort, identified TREM-1 downregulation in non-responders at baseline, which was predictive of response with an AUC of 94%.
ConclusionsOur study proposes two clinically feasible assays, one in biopsy and one in blood, for predicting non-response to anti-TNFα therapy prior to initiation of treatment. Moreover, it suggests that mechanism-driven novel drugs for non-responders should be developed.
https://ift.tt/2GzcAV2
Microbial activity during a coastal phytoplankton bloom on the Western Antarctic Peninsula in late summer
Abstract
Phytoplankton biomass during the austral summer is influenced by freezing and melting cycles, as well as oceanographic processes that enable nutrient redistribution in the West Antarctic Peninsula (WAP). Microbial functional capabilities, metagenomic and metatranscriptomic activities, as well as inorganic 13C- and 15N-assimilation rates were studied in the surface waters of Chile Bay during two contrasting summer periods in 2014. Concentrations of Chlorophyll a (Chla) varied from 0.3 mg m−3 in February to a maximum of 2.5 mg m−3 in March, together with a decrease in nutrients, however nutrients were never depleted. The microbial community composition remained similar throughout both sampling periods, however, microbial abundance and activity changed with Chla levels. An increased biomass of Bacillariophyta, Haptophyceae, Cryptophyceae was observed along with night-grazing activity of Dinophyceae and ciliates (Alveolates). During high Chla conditions, HCO3− uptake rates during daytime incubations increased 5-fold (>2516 nmol C L−1 d−1), and increased photosynthetic transcript numbers that were mainly associated with cryptophytes; meanwhile night time NO3− (>706 nmol N L−1 d−1) and NH4+ (41.7 nmol N L−1 d−1) uptake rates were 2- and 3-fold higher, respectively, due to activity from alpha-/gamma-Proteobacteria and Bacteroidetes (Flavobacteriia). Due to a projected acceleration in climate change in the WAP, this information is valuable for predicting the composition and functional changes in Antarctic microbial communities.https://ift.tt/2EjJcw1
Bacterial machineries for the assembly of membrane-embedded β-barrel proteins
Abstract
The outer membrane (OM) of Gram-negative bacteria is an essential organelle that protects cells from external aggressions and mediates the secretion of virulence factors. Efficient assembly of integral outer membrane β-barrel proteins (OMPs) is crucial for the correct functioning of the OM. Biogenesis of OMPs occurs in a step-wise manner that is finalized by the β-barrel assembly machinery (BAM complex). Some OMPs further require the translocation and assembly module (TAM) for efficient and correct integration into the OM. Both the BAM complex and the TAM contain a protein of the Omp85 superfamily and distinct interacting factors. Their mechanism of action, however, remains largely elusive. We summarize and discuss recent structural and biochemical analyses that are helping to elucidate the molecular pathways of OMP assembly.https://ift.tt/2JllTWn
Climate Change and One Health
Abstract
The journal The Lancet recently published a countdown on health and climate change. Attention was focused solely on humans. However, animals, including wildlife, livestock and pets, may also be impacted by climate change. Complementary to the high relevance of awareness rising for protecting humans against climate change, here we present a One Health approach, which aims at the simultaneous protection of humans, animals and the environment from climate change impacts (climate change adaptation). We postulate that integrated approaches save human and animal lives and reduce costs when compared to public and animal health sectors working separately. A One Health approach to climate change adaptation may significantly contribute to food security with emphasis on animal source foods, extensive livestock systems, particularly ruminant livestock, environmental sanitation, and steps towards regional and global integrated syndromic surveillance and response systems. The cost of outbreaks of emerging vector borne zoonotic pathogens may be much lower if they are detected early in the vector or in livestock rather than later in humans. Therefore, integrated community-based surveillance of zoonoses is a promising avenue to reduce health effects of climate change.https://ift.tt/2q5UWx9
Antibiotic resistance phenotypes and virulence-associated genes in Escherichia coli isolated from animals and animal food products in Tunisia
Abstract
Livestock and food products of animal origin constitute important reservoirs of intestinal and extraintestinal pathogenic Escherichia coli including antibiotic-resistant E. coli isolates. To assess potential risks to public health related to E. coli strains of animal origin in Tunisia, 65 E. coli isolates recovered from healthy animals and food products of animal origin were studied. Antimicrobial susceptibility was determined according to CLSI guidelines and genes encoding antibiotic resistance as well as virulence factors were investigated by PCR. High rates of antibiotic resistance were observed to kanamycin (78.4%), gentamicin (75.3%), and streptomycin (75.3%; encoded by strA-strB (7 isolates)), amoxicillin (64.6%), amoxicillin/clavulanic acid (60%), tetracycline (44.6%; tetA (8 isolates) and tetB (7 isolates)), nalidixic acid (27.6%; qnrS (3 isolates), qnrB (2 isolates), and qnrA (one isolate)), and sulfonamides (36.9%; sul1 (1 isolate), sul2 (4 isolates), and sul3 (1 isolate)). Virulotypes classified some isolates as STEC (3%), MNEC (1.5%), and atypical EPEC (1.5%). This study demonstrated high rates of antimicrobial resistance and the presence of some pathogenic pathovars from animal origins that are a cause of concern for public health.https://ift.tt/2JgpeWK
First evaluation of alkylpyrazine application as a novel method to decrease microbial contaminations in processed meat products
Every year about 20% of the globally produced meat gets lost due to microbial spoilage. Nevertheless, the demand for processed meat is constantly rising and producers are searching for novel strategies to redu...
https://ift.tt/2H89Ivk
Gene regulatory network state estimation from arbitrary correlated measurements
Advancements in gene expression technology allow acquiring cheap and abundant data for analyzing cell behavior. However, these technologies produce noisy, and often correlated, measurements on the transcriptio...
https://ift.tt/2GBvJ4I
Ethanol ablation for refractory bile leakage after complex hepatectomy
British Journal of Surgery, EarlyView.
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Using in vivo fluorescence lifetime imaging to detect HER2-positive tumors
Abstract
Background
Assessment of the status of tumor biomarkers in individual patients would facilitate personalizing treatment strategy, and continuous monitoring of those biomarkers and their binding process to the therapeutic drugs would provide a means for early evaluation of the efficacy of therapeutic intervention. Fluorescent probes can accumulate inside the tumor region due to the leakiness of its vascularization and this can make it difficult to distinguish if the measured fluorescence intensity is from probes bound to target receptors or just accumulated unbound probes inside the tumor. In this paper, we have studied the fluorescence lifetime as a means to distinguish bound HER2 specific affibody probes to HER2 receptors.
Our imaging system is a time-resolved fluorescence system using a Ti-Sapphire femtosecond pulse laser as source and Time correlated Single photon Counting (TCSPC) system as detector for calculating the lifetime of the contrast agent. HER2-specific Affibody (His6-ZHER2:GS-Cys) (Affibody, Stockholm, Sweden) conjugated with a Dylight750 fluorescent probe (Thermo-Fisher-Scientific, Waltham, Massachusetts) was used as contrast agent and six human cancer cell lines, BT-474, SKOV-3, NCI-N87, MDA-MB-361, MCF-7, and MDA-MB-468, known to express different levels of HER2/neu, are used in athymic mice xenografts.
Results
By comparing the lifetime of unbound contrast agent (at the contralateral site) to the fluorescence lifetime at the tumor site, our results show that the fluorescence lifetime decreases as HER2 specific Affibody probes bind to the tumor receptors. A decrease of ~15% (100ps) in tumor fluorescence lifetime was observed in tumors with mid to high HER2 expression. Smaller decreases were observed in tumors with low-level of HER2 receptors and no change was observed in the non-HER2-expressing tumors.
Conclusions
Using HER2-specific Affibody conjugated with the Dylight750 fluorescent probe as contrast agent, we demonstrated in live animals that change in fluorescence lifetime of the bound contrast agent can be used to assess the high to mid-level expression of HER2 expressing tumors in-vivo in only one measurement. The rationale is that the fluorescence lifetime of our specific probe is sensitive to affinity to, and specific interaction with, other molecules.
https://ift.tt/2Eh3177
Hallmarks in prostate cancer imaging with Ga68-PSMA-11-PET/CT with reference to detection limits and quantitative properties
Abstract
Background
Gallium-68-labeled prostate-specific antigen positron emission tomography/computed tomography imaging (Ga68-PSMA-11-PET/CT) has emerged as a potential gold standard for prostate cancer (PCa) diagnosis. However, the imaging limitations of this technique at the early state of PCa recurrence/metastatic spread are still not well characterized. The aim of this study was to determine the quantitative properties and the fundamental imaging limits of Ga68-PSMA-11-PET/CT in localizing small PCa cell deposits.
Methods
The human PCa LNCaP cells (PSMA expressing) were grown and collected as single cell suspension or as 3D-spheroids at different cell numbers and incubated with Ga68-PSMA-11. Thereafter, human HCT116 cells (PSMA negative) were added to a total cell number of 2 × 105 cells per tube. The tubes were then pelleted and the supernatant aspirated. A whole-body PET/CT scanner with a clinical routine protocol was used for imaging the pellets inside of a cylindrical water phantom with increasing amounts of background activity. The actual activity bound to the cells was also measured in an automatic gamma counter. Imaging detection limits and activity recovery coefficients as a function of LNCaP cell number were obtained. The effect of Ga68-PSMA-11 mass concentration on cell binding was also investigated in samples of LnCaP cells incubated with increasing concentrations of radioligand.
Results
A total of 1 × 104 LNCaP cells mixed in a pellet of 2 × 105 cells were required to reach a 50% detection probability with Ga68-PSMA-11-PET/CT without background. With a background level of 1 kBq/ml, between 4 × 105 and 1 × 106 cells are required. The radioligand equilibrium dissociation constant was 27.05 nM, indicating high binding affinity. Hence, the specific activity of the radioligand has a profound effect on image quantification.
Conclusions
Ga68-PSMA-11-PET detects a small number of LNCaP cells even when they are mixed in a population of non-PSMA expressing cells and in the presence of background. The obtained image detection limits and characteristic quantification properties of Ga68-PSMA-11-PET/CT are essential hallmarks for the individualization of patient management. The use of the standardized uptake value for Ga68-PSMA-11-PET/CT image quantification should be precluded.
https://ift.tt/2Gwigz2
Comparative efficacy of Chinese herbal injections for treating acute cerebral infarction: a network meta-analysis of randomized controlled trials
Chinese herbal injections (CHIs) are prepared by extracting and purifying effective substances from herbs (or decoction pieces) using modern scientific techniques and methods. CHIs combined with aspirin + anti...
https://ift.tt/2uNofKn
Purification and MIC analysis of antimicrobial proteins from Cucumis sativus L. seeds
Cucumis sativus L. (cucumber), from the family Cucurbitaceae, is a therapeutic plant with various pharmacological benefits, broadly utilized as a part of complementary medicine (e.g., Unani, Ayurveda, Siddha, and...
https://ift.tt/2q4G7f7
A Chinese herbal decoction, Jian-Pi-Yi-Shen, regulates the expressions of erythropoietin and pro-inflammatory cytokines in cultured cells
A Chinese herbal formula, namely Jian-Pi-Yi-Shen (JPYS), has been clinically prescribed for patients with chronic kidney disease associated-anemia, and which can improve the patient's immunological system. How...
https://ift.tt/2uM1Ayi
Mortality and detailed characteristics of pre-ICU qSOFA-negative patients with suspected sepsis: an observational study
Recent studies have suggested that quick Sequential Organ Failure Assessment (qSOFA) scores have limited utility in early prognostication in high-mortality populations. The purpose of this study was to investi...
https://ift.tt/2H7Unek
Options and Limitations in Clinical Investigation of Bacterial Biofilms [Reviews]
SUMMARY
Bacteria can form single- and multispecies biofilms exhibiting diverse features based upon the microbial composition of their community and microenvironment. The study of bacterial biofilm development has received great interest in the past 20 years and is motivated by the elegant complexity characteristic of these multicellular communities and their role in infectious diseases. Biofilms can thrive on virtually any surface and can be beneficial or detrimental based upon the community's interplay and the surface. Advances in the understanding of structural and functional variations and the roles that biofilms play in disease and host-pathogen interactions have been addressed through comprehensive literature searches. In this review article, a synopsis of the methodological landscape of biofilm analysis is provided, including an evaluation of the current trends in methodological research. We deem this worthwhile because a keyword-oriented bibliographical search reveals that less than 5% of the biofilm literature is devoted to methodology. In this report, we (i) summarize current methodologies for biofilm characterization, monitoring, and quantification; (ii) discuss advances in the discovery of effective imaging and sensing tools and modalities; (iii) provide an overview of tailored animal models that assess features of biofilm infections; and (iv) make recommendations defining the most appropriate methodological tools for clinical settings.
https://ift.tt/2GBlPQN
Behavioral Strategies More Effective Than Persuasion in Promoting Vaccination
Faced with outbreaks of influenza and other vaccine-preventable diseases, parents, educators, healthcare providers, and policymakers around the world often want to know how to persuade people to get their vaccinations. But a comprehensive review of the scientific findings from research on vaccination behavior shows that the most effective interventions focus directly on shaping patients' and parents' behavior instead of trying to change their minds.
"A common myth is that it's easy to persuade people to get vaccinated," says researcher Noel T. Brewer of the University of North Carolina, first author on the report. "But when was the last time hearing a fact one time led you to exercise regularly, lose weight, or quit smoking? It's the same for vaccination."
The findings, published in Psychological Science in the Public Interest, a journal of the Association for Psychological Science, suggest that although vaccination campaigns commonly focus on changing people's perceptions and attitudes about vaccines, there is little evidence that these campaigns are effective.
To understand the factors that underlie vaccination-related behavior, Brewer and coauthors Gretchen B. Chapman (Carnegie Mellon University), Alexander J. Rothman (University of Minnesota), Julie Leask (University of Sydney), and Allison Kempe (University of Colorado Anschutz Medical Campus) examined the latest findings from a variety of fields, including psychological science, public health, medicine, nursing, sociology, and behavioral economics.
The report is accompanied by a commentary by Victor J. Dzau, President of the United States National Academy of Medicine.
"As Brewer and colleagues note, psychological science offers insight into why people engage in health behaviors including vaccination," Dzau writes in his commentary. In publishing this report, the authors "are performing a service to society by integrating the disconnected literature on psychological theories and vaccination, which can inform practical interventions to address the challenges of vaccination."
One of the challenges of vaccination is that uptake varies across vaccines. Childhood vaccination generally has strong public support, with the majority of infants in most countries receiving recommended vaccines. In contrast, many adults forego vaccines such as the seasonal flu shot.
"Vaccination is one of the greatest public health achievements in the past century. Yet, vaccine uptake is well below optimal for some vaccines, and healthcare providers routinely face parents and patients who are hesitant about receiving vaccines," explains Chapman. "Accessing the full benefits of vaccination entails facilitating behavior, and the insight for doing that comes from psychological science."
The best available data indicate that the percentage of people who actively refuse all vaccines is incredibly small and that neither vaccine refusal nor delay is on the rise. These findings contradict the media-fueled narrative that an increasing number of people is rejecting immunizations.
In reality, most people receive most vaccines in line with their doctors' recommendations. Many others have favorable attitudes toward vaccination but do not always follow through to receive vaccines in full or on time. The researchers find that the most effective vaccination interventions build on these favorable intentions, employing behavioral strategies to:
- Facilitate action by providing patients with reminders and prompts
- Reduce barriers by setting default orders and appointments
- Shape behavior by developing incentives, sanctions, and requirements
"Our main message to policy makers and providers is that, surprisingly, the strongest evidence supports impacting vaccination directly by leveraging, but not trying to change, what people think and feel," Chapman says.
In some cases, people encounter false or misleading information about vaccines. Research shows that the best way to correct this misinformation is to reiterate the facts clearly and in a way that fits with people's intuitive beliefs.
These conclusions are supported by multiple sources of evidence, but the researchers note that much of the available research on vaccination behavior is limited in quality or quantity. Studies investigating vaccination attitudes and behavior over time are rare and few studies examine the specific mechanisms or components that make for effective interventions.
Despite these limitations, cross-continent studies are increasingly converging on some common findings. In general, these studies show that vaccine acceptance tends to be high, vaccine hesitancy exists around the world, and the factors that motivate vaccination are similar across countries.
Vaccination is a public health issue, with psychological science providing a lens for understanding the factors that motivate vaccination. The interventions that stand to have the greatest impact are those based on psychological theory and behavioral evidence.
The full report and commentary are available to the public online.
https://ift.tt/2Gx8j4n
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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