We describe a modified technique for percutaneous dilatational tracheostomy using a 15F tube exchanger or Eschmann catheter. A retrospective review of 1180 procedures using this modified technique demonstrated it to be effective with a failure rate of only 0.25% (3 patients). Moreover, it provides an additional safeguard with the ability to rapidly reintroduce the endotracheal tube into the trachea guided by the exchange catheter in the event of accidental extubation during the procedure. This technique needs no additional special devices or equipment (eg, a bronchoscope). However, a prospective study is needed to better define its complication rate. Accepted for publication January 22, 2018. Funding: None. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Ohad Ronen, MD, Department of Otolaryngology, Head and Neck Surgery, Galilee Medical Center, POB 21, Nahariya 2210001, Israel. Address e-mail to ohadr@gmc.gov.il. © 2018 International Anesthesia Research Society
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Τετάρτη 14 Μαρτίου 2018
Intrathecal Drug Delivery Systems for Refractory Pancreatic Cancer Pain: Observational Follow-Up Study Over an 11-Year Period in a Comprehensive Cancer Center
BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer-related death in Europe and the United States. Studies have demonstrated that patients with pancreatic cancer have a high prevalence of pain, with rates varying from 47% to 82%. Analgesia using intrathecal drug delivery systems (IDDS) has been poorly studied specifically in this population. METHODS: The IDDS for pancreatic cancer pain was a follow-up observational study designed to evaluate 11-year results of IDDS for refractory pancreatic cancer pain at the Institut de Cancérologie de L'Ouest, Paul Papin in France. Patients were followed from March 2006 to April 2017. Patients were selected for IDDS based on multidisciplinary meeting discussion. All IDDS-treated patients were prescribed a combined intrathecal analgesics regimen through a catheter placed according to painful metameric level. Postimplant assessment of pain was determined using a numerical rating scale (NRS). Patients were followed via day-hospital visits and telephone calls at least monthly until death. Pain scores were compared using the Wilcoxon signed rank test. Overall survival (OS) was estimated using the Kaplan–Meier method and compared between groups by log rank tests. RESULTS: Ninety-three patients received IDDS, and total therapy duration accounts for 10,300 IDDS days. Implanted patients suffered from severe pain before implantation (median presurgical NRS, 8 [interquartile range, 7–9]) despite a median 360 mg (260–600) oral morphine equivalent daily dose. Median OS in the whole cohort after intrathecal treatment start was 82 days (95% confidence interval, 59–95). Median OS after surgery for implantable pump was 91 days (83–111) and for external pump 27 days (20–49; P
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http://ift.tt/2pdlL2H
Anesthesia for Percutaneous Pulmonary Valve Implantation: A Case Series
BACKGROUND: Twenty percent of patients born with congenital heart disease present with right ventricular outflow tract abnormalities. These patients require multiple surgical procedures in their lifetime. Transcatheter pulmonary valve replacement (TPVR) has become a viable alternative to conventional pulmonary valve and right ventricular outflow tract surgery in pediatric and adult populations. In this retrospective review, we analyze the perioperative management of adult patients who underwent TPVR in our center. METHODS: The study consisted of a chart review of patients who underwent TPVR at Toronto General Hospital between 2006 and 2015. Information about preoperative assessment, intraoperative anesthetic management, and intra- and postprocedural complications was collected. Two types of percutaneous valves have been used for a conduit or valve size between 16 and 28 mm. These procedures are done via the femoral, jugular, or subclavian vein under general anesthesia. RESULTS: Seventy-nine adults (17–68 years of age) who underwent elective TPVR procedures were included. General anesthesia was used in all cases. Defibrillation was necessary in 1 case, and bradycardia was spontaneously resolved in another 1. Eighty-five percent were successfully extubated at the end of the procedure. Five patients required intraoperative inotropic support. Three patients presented self-resolved hemoptysis. Mechanical ventilation for >24 hours was necessary in 3 cases, 2 of which also required concomitant inotropic support. Four failed deployments and 1 case of persistent conduit stenosis were reported. Three patients required reintubation. All patients were discharged home. CONCLUSIONS: Patients undergoing TPVR represent a complex and heterogeneous population. General anesthesia with endotracheal intubation is preferred. Setup for urgent lung isolation and cardiac defibrillation should be considered. Postoperative monitoring and intensive care setting are required. Anesthesiologists with cardiac anesthesia training are probably better suited to manage these patients. Accepted for publication January 22, 2018. Funding: None. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Massimiliano Meineri, MD, Department of Anesthesia and Pain Management, Toronto General Hospital, 200 Elizabeth St, EN3-400, Toronto, ON M5G 2C4, Canada. Address e-mail to massimiliano.meineri@uhn.ca. © 2018 International Anesthesia Research Society
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http://ift.tt/2FVS67V
Smoking and worsening disability in multiple sclerosis: A meta-analysis
Objectives
Multiple sclerosis (MS) is a chronic demyelinating disorder affecting young adults. Environmental factors and lifestyle behaviors are pivotal in MS pathophysiology. Smoking has been considered as an important risk factor in MS. Various recent studies have been conducted to measure the role of smoking on worsening disability in patients with MS, thus we intended to systematically assess effect of smoking on evolution of disability in this study.
Materials & methods
We queried MEDLINE, EMBASE and Cochrane Library with following keywords "Multiple Sclerosis, Smoking, Tobacco Use, Disability" on December 1st 2016. Original articles were included when smoking history was mentioned, disability was measured via expanded disability status scale (EDSS) or multiple sclerosis severity score (MSSS). Studies with insufficient outcome data, non-human, or in other languages than English were excluded.
Results
Through literature review after duplicate removals, 268 articles were retrieved. A total of 56 articles were screened and 15 articles were assessed for eligibility, finally, eleven articles were included in this systematic review and meta-analysis. Ever smoking was significantly associated with increased EDSS (standardized mean difference (SMD) = 0.15, 95% CI = 0.01-0.28), but had no significant association with risk of reaching EDSS 4 (HR = 1.24, 95% CI = 0.89-1.72) or EDSS 6 (HR = 1.17, 95% CI = 0.88-1.57). Smoking had no effect on MSSS (SMD = 0.14, 95% CI = −0.04-0.32) or T2 lesion volume (SMD = 0.07, 95% CI = −0.08-0.22).
Conclusions
This meta-analysis showed smoking increased EDSS, insignificant findings were possibly due to the small number of studies, significant differences in methodologies, and variations in reporting of disability outcomes.
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Painful musculosceletal disorders and depression among working aged migraineurs
Objective
Musculoskeletal disorders and depression are common among migraineurs. The aim of our study was to evaluate the occurrence of these disorders among working aged migraineurs.
Material and Methods
The risk for fibromyalgia, rheumatoid arthritis (RA), osteoarthrosis (OA), sciatic syndrome, and the occurrence of depression was studied among cases who reported about these conditions and migraine in working aged Finnish population in The Health and Social Support Study (HeSSup) based on postal questionnaire in 2012. Group differences were tested by chi-square test. Odds ratios (ORs with 95% CI) adjusted for age, gender, education level and depression were calculated with logistic regression analysis.
Results
Total of 1505 migraineurs (13%) and 8092 controls were included among the 11 596 responders in 2012. Age and gender adjusted ORs, 2.37 (95% CI 1.81-3.09) for fibromyalgia, 1.46 (1.10-1.95) for RA, 1.58 (1.38-1.80) for OA, and 2.09 (1.84-2.37) for sciatic syndrome, were significant. At least moderate depression was more common among migraineurs (7.3%) than among controls (3.4%) (P < .001).
Conclusion
Recognition of comorbid musculoskeletal disorders and mood disorders among migraineurs needs targeted outreach in working aged population. The acute and preventive treatments to control for neuronal sensitization in migraine and comorbid pain disorders may benefit of individual treatment plan and tailored use of antidepressants.
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Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients
Abstract
BACKGROUND
Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects. PATIENTS AND METHODS
In this two-cohort pilot phase I study, 15 advanced cancer patients received two 4-week cycles of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24h with poly-ICLC (Hiltonol), TNF-α and IFN-α. On days +8 and +10 of each cycle, patients received intratumoral image-guided 0.25 mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600 mg/m2 was administered one week before. Six patients received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating PBMCs and serum concentrations of a cytokine panel were sequentially determined before and during treatment. Pre- and post-treatment PBMC from patients achieving durable stable disease were studied by IFNγ ELISPOT-assays responding to tumor-lysate loaded DC and by TCRβ sequencing. RESULTS
Combined treatment was, safe and well tolerated. One heavily pretreated castration-resistant prostate cancer patient experienced a remarkable mixed abscopal response to SABR+immunotherapy. No objective responses were observed, while nine patients presented stable disease (five of them in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-β and IFN-α mRNA in circulating PBMC. DC vaccination increased serum IL-12 and IL-1β concentrations, especially in patients presenting stable disease (SD). IFNγ-ELISPOT reactivity to tumor lysates was observed in two patients experiencing durable SD. CONCLUSIONS
This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and shows immune-associated activity and signs of preliminary clinical efficacy.http://ift.tt/2IpAkIw
RASA1/NF1-Mutant Lung Cancer: Racing to the Clinic?
Although mutation of NF1 has been described in non–small cell lung cancer (NSCLC), co-mutation with RASA1, another Ras-GTPase activating protein (RasGAP), defines a novel genetically defined subclass of NSCLC. RASA1/NF1-mutant cell lines are highly sensitive to MEK inhibitors, warranting clinical evaluation of MAPK inhibition in this subclass of patients. Clin Cancer Res; 24(6); 1243–5. ©2018 AACR.
See related article by Hayashi et al., p. 1436
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CD47 Blockade as an Adjuvant Immunotherapy for Resectable Pancreatic Cancer
Purpose: Patients with pancreatic ductal adenocarcinoma (PDAC) who undergo surgical resection and adjuvant chemotherapy have an expected survival of only 2 years due to disease recurrence, frequently in the liver. We investigated the role of liver macrophages in progression of PDAC micrometastases to identify adjuvant treatment strategies that could prolong survival.
Experimental Design: A murine splenic injection model of hepatic micrometastatic PDAC was used with five patient-derived PDAC tumors. The impact of liver macrophages on tumor growth was assessed by (i) depleting mouse macrophages in nude mice with liposomal clodronate injection, and (ii) injecting tumor cells into nude versus NOD-scid-gamma mice. Immunohistochemistry and flow cytometry were used to measure CD47 ("don't eat me signal") expression on tumor cells and characterize macrophages in the tumor microenvironment. In vitro engulfment assays and mouse experiments were performed with CD47-blocking antibodies to assess macrophage engulfment of tumor cells, progression of micrometastases in the liver and mouse survival.
Results: In vivo clodronate depletion experiments and NOD-scid-gamma mouse experiments demonstrated that liver macrophages suppress the progression of PDAC micrometastases. Five patient-derived PDAC cell lines expressed variable levels of CD47. In in vitro engulfment assays, CD47-blocking antibodies increased the efficiency of PDAC cell clearance by macrophages in a manner which correlated with CD47 receptor surface density. Treatment of mice with CD47-blocking antibodies resulted in increased time-to-progression of metastatic tumors and prolonged survival.
Conclusions: These findings suggest that following surgical resection of PDAC, adjuvant immunotherapy with anti-CD47 antibody could lead to substantially improved outcomes for patients. Clin Cancer Res; 24(6); 1415–25. ©2017 AACR.
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Deep Learning-Based Multi-Omics Integration Robustly Predicts Survival in Liver Cancer
Identifying robust survival subgroups of hepatocellular carcinoma (HCC) will significantly improve patient care. Currently, endeavor of integrating multi-omics data to explicitly predict HCC survival from multiple patient cohorts is lacking. To fill this gap, we present a deep learning (DL)–based model on HCC that robustly differentiates survival subpopulations of patients in six cohorts. We built the DL-based, survival-sensitive model on 360 HCC patients' data using RNA sequencing (RNA-Seq), miRNA sequencing (miRNA-Seq), and methylation data from The Cancer Genome Atlas (TCGA), which predicts prognosis as good as an alternative model where genomics and clinical data are both considered. This DL-based model provides two optimal subgroups of patients with significant survival differences (P = 7.13e–6) and good model fitness [concordance index (C-index) = 0.68]. More aggressive subtype is associated with frequent TP53 inactivation mutations, higher expression of stemness markers (KRT19 and EPCAM) and tumor marker BIRC5, and activated Wnt and Akt signaling pathways. We validated this multi-omics model on five external datasets of various omics types: LIRI-JP cohort (n = 230, C-index = 0.75), NCI cohort (n = 221, C-index = 0.67), Chinese cohort (n = 166, C-index = 0.69), E-TABM-36 cohort (n = 40, C-index = 0.77), and Hawaiian cohort (n = 27, C-index = 0.82). This is the first study to employ DL to identify multi-omics features linked to the differential survival of patients with HCC. Given its robustness over multiple cohorts, we expect this workflow to be useful at predicting HCC prognosis prediction. Clin Cancer Res; 24(6); 1248–59. ©2017 AACR.
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Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Metastatic Melanoma
Immune checkpoint inhibitors have revolutionized the treatment of patients with advanced-stage metastatic melanoma, as well as patients with many other solid cancers, yielding long-lasting responses and improved survival. However, a subset of patients who initially respond to immunotherapy, later relapse and develop therapy resistance (termed "acquired resistance"), whereas others do not respond at all (termed "primary resistance"). Primary and acquired resistance are key clinical barriers to further improving outcomes of patients with metastatic melanoma, and the known mechanisms underlying each involves various components of the cancer immune cycle, and interactions between multiple signaling molecules and pathways. Due to this complexity, current knowledge on resistance mechanisms is still incomplete. Overcoming therapy resistance requires a thorough understanding of the mechanisms underlying immune evasion by tumors. In this review, we explore the mechanisms of primary and acquired resistance to immunotherapy in melanoma and detail potential therapeutic strategies to prevent and overcome them. Clin Cancer Res; 24(6); 1260–70. ©2017 AACR.
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Beyond Concurrent Chemoradiation: The Emerging Role of PD-1/PD-L1 Inhibitors in Stage III Lung Cancer
Concurrent chemoradiation (cCRT) with platinum-based chemotherapy is standard-of-care therapy for patients with stage III unresectable non–small cell lung cancer (NSCLC). Although cCRT is potentially curative, 5-year overall survival has hovered around 20%, despite extensive efforts to improve outcomes with increasing doses of conformal radiation and intensification of systemic therapy with either induction or consolidation chemotherapy. PD-1/PD-L1 immune checkpoint inhibitors have demonstrated unprecedented efficacy in patients with stage IV NSCLC. In addition, preclinical and early clinical evidence suggests that chemotherapy and radiation may work synergistically with anti-PD-1/PD-L1 therapy to promote antitumor immunity, which has led to the initiation of clinical trials testing these drugs in patients with stage III NSCLC. A preliminary report of a randomized phase III trial, the PACIFIC trial, demonstrated an impressive increase in median progression-free survival with consolidative durvalumab, a PD-L1 inhibitor, compared with observation after cCRT. Here, we discuss the clinical and translational implications of integrating PD-1/PD-L1 inhibitors in the management of patients with unresectable stage III NSCLC. Clin Cancer Res; 24(6); 1271–6. ©2018 AACR.
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Phase I Study of Chimeric Antigen Receptor-Modified T Cells in Patients with EGFR-Positive Advanced Biliary Tract Cancers
Purpose: This study is an expanded and parallel clinical trial of EGFR-specific chimeric antigen receptor–engineered autologous T (CART) cell immunotherapy (NCT01869166) to assess the safety and activity of CART-EGFR cell therapy in EGFR-positive advanced unresectable, relapsed/metastatic biliary tract cancers (BTC).
Experimental Design: Patients with EGFR-positive (>50%) advanced unresectable, relapsed/metastatic BTCs were enrolled. Well-produced CART-EGFR cells were infused in a manner of dose escalation after the conditioning treatment with nab-paclitaxel (100–250 mg/m2) and cyclophosphamide (15–35 mg/kg).
Results: A total of 19 patients (14 cholangiocarcinomas and 5 gallbladder carcinomas) received one to three cycles of CART-EGFR cell infusion (median CART cell dose, 2.65 x 106/kg; range, 0.8–4.1 x 106/kg) within 6 months. The CART-EGFR cell infusion was tolerated, but 3 patients suffered grade ≥3 acute fever/chill. Grade 1/2 target-mediated toxicities including mucosal/cutaneous toxicities and acute pulmonary edema and grade ≥3 lymphopenia and thrombocytopenia related to the conditioning treatment were observed. Of 17 evaluable patients, 1 achieved complete response and 10 achieved stable disease. The median progression-free survival was 4 months (range, 2.5–22 months) from the first cycle of treatment. Analysis of data indicated that the enrichment of central memory T cells (Tcm) in the infused CART-EGFR cells improved the clinical outcome.
Conclusions: The CART-EGFR cell immunotherapy was a safe and active strategy for EGFR-positive advanced BTCs. The enrichment of Tcm in the infused CART-EGFR cells could predict clinical response. Clin Cancer Res; 24(6); 1277–86. ©2017 AACR.
See related commentary by Kalos, p. 1246
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Expanded Genomic Profiling of Circulating Tumor Cells in Metastatic Breast Cancer Patients to Assess Biomarker Status and Biology Over Time (CALGB 40502 and CALGB 40503, Alliance)
Purpose: We profiled circulating tumor cells (CTCs) to study the biology of blood-borne metastasis and to monitor biomarker status in metastatic breast cancer (MBC).
Methods: CTCs were isolated from 105 patients with MBC using EPCAM-based immunomagnetic enrichment and fluorescence-activated cells sorting (IE/FACS), 28 of whom had serial CTC analysis (74 samples, 2–5 time points). CTCs were subjected to microfluidic-based multiplex QPCR array of 64 cancer-related genes (n = 151) and genome-wide copy-number analysis by array comparative genomic hybridization (aCGH; n = 49).
Results: Combined transcriptional and genomic profiling showed that CTCs were 26% ESR1–ERBB2–, 48% ESR1+ERBB2–, and 27% ERBB2+. Serial testing showed that ERBB2 status was more stable over time compared with ESR1 and proliferation (MKI67) status. While cell-to-cell heterogeneity was observed at the single-cell level, with increasingly stable expression in larger pools, patient-specific CTC expression "fingerprints" were also observed. CTC copy-number profiles clustered into three groups based on the extent of genomic aberrations and the presence of large chromosomal imbalances. Comparative analysis showed discordance in ESR1/ER (27%) and ERBB2/HER2 (23%) status between CTCs and matched primary tumors. CTCs in 65% of the patients were considered to have low proliferation potential. Patients who harbored CTCs with high proliferation (MKI67) status had significantly reduced progression-free survival (P = 0.0011) and overall survival (P = 0.0095) compared with patients with low proliferative CTCs.
Conclusions: We demonstrate an approach for complete isolation of EPCAM-positive CTCs and downstream comprehensive transcriptional/genomic characterization to examine the biology and assess breast cancer biomarkers in these cells over time. Clin Cancer Res; 24(6); 1486–99. ©2018 AACR.
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Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGF{beta}, in Advanced Solid Tumors
Purpose: M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against programmed death ligand 1 (PD-L1) fused to a TGFβ "trap."
Experimental Design: In the 3+3 dose-escalation component of this phase I study (NCT02517398), eligible patients with advanced solid tumors received M7824 at 1, 3, 10, or 20 mg/kg once every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal; in addition, a cohort received an initial 0.3 mg/kg dose to evaluate pharmacokinetics/pharmacodynamics, followed by 10 mg/kg dosing. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include pharmacokinetics, immunogenicity, and best overall response.
Results: Nineteen heavily pretreated patients with ECOG 0–1 have received M7824. Grade ≥3 treatment-related adverse events occurred in four patients (skin infection secondary to localized bullous pemphigoid, asymptomatic lipase increase, colitis with associated anemia, and gastroparesis with hypokalemia). The MTD was not reached. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGFβ1, -β2, and -β3 throughout the dosing period at >1 mg/kg. There were signs of efficacy across all dose levels, including one ongoing confirmed complete response (cervical cancer), two durable confirmed partial responses (PR; pancreatic cancer; anal cancer), one near-PR (cervical cancer), and two cases of prolonged stable disease in patients with growing disease at study entry (pancreatic cancer; carcinoid).
Conclusions: M7824 has a manageable safety profile in patients with heavily pretreated advanced solid tumors. Early signs of efficacy are encouraging, and multiple expansion cohorts are ongoing in a range of tumors. Clin Cancer Res; 24(6); 1287–95. ©2018 AACR.
http://ift.tt/2HANvVS
Statins Synergize with Hedgehog Pathway Inhibitors for Treatment of Medulloblastoma
Purpose: The role of cholesterol biosynthesis in hedgehog pathway activity and progression of hedgehog pathway medulloblastoma (Hh-MB) were examined in vivo. Statins, commonly used cholesterol-lowering agents, were utilized to validate cholesterol biosynthesis as a therapeutic target for Hh-MB.
Experimental Design: Bioinformatic analysis was performed to evaluate the association between cholesterol biosynthesis with hedgehog group medulloblastoma in human biospecimens. Alterations in hedgehog signaling were evaluated in medulloblastoma cells after inhibition of cholesterol biosynthesis. The progression of endogenous medulloblastoma in mice was examined after genetic blockage of cholesterol biosynthesis in tumor cells. Statins alone, or in combination with vismodegib (an FDA-approved Smoothened antagonist), were utilized to inhibit medulloblastoma growth in vivo.
Results: Cholesterol biosynthesis was markedly enhanced in Hh-MB from both humans and mice. Inhibition of cholesterol biosynthesis dramatically decreased Hh pathway activity and reduced proliferation of medulloblastoma cells. Statins effectively inhibited medulloblastoma growth in vivo and functioned synergistically in combination with vismodegib.
Conclusions: Cholesterol biosynthesis is required for Smoothened activity in the hedgehog pathway, and it is indispensable for the growth of Hh-MB. Targeting cholesterol biosynthesis represents a promising strategy for treatment of Hh-MB. Clin Cancer Res; 24(6); 1375–88. ©2018 AACR.
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Identification of a Novel, EBV-Based Antibody Risk Stratification Signature for Early Detection of Nasopharyngeal Carcinoma in Taiwan
Background. Epstein–Barr virus (EBV) is necessary for the development of nasopharyngeal carcinoma (NPC). By adulthood, approximately 90% of individuals test EBV-positive, but only a fraction develop cancer. Factors that identify which individuals are most likely to develop disease, including differential antibody response to the virus, could facilitate detection at early stages when treatment is most effective.
Methods. We measured anti-EBV IgG and IgA antibody responses in 607 Taiwanese individuals. Antibodies were measured using a custom protein microarray targeting 199 sequences from 86 EBV proteins. Variation in response patterns between NPC cases and controls was used to develop an antibody-based risk score for predicting NPC. The overall accuracy [area under the curve (AUC)] of this risk score, and its performance relative to currently used biomarkers, was evaluated in two independent Taiwanese cohorts.
Findings. Levels of 60 IgA and 73 IgG anti-EBV antibodies differed between stage I/IIa NPC cases and controls (P < 0.0002). Risk prediction analyses identified antibody targets that best discriminated NPC status—BXLF1, LF2,BZLF1, BRLF1, EAd, BGLF2, BPLF1, BFRF1, and BORF1. When combined with currently used VCA/EBNA1 IgA biomarkers, the resulting risk score predicted NPC with 93% accuracy (95% CI, 87%–98%) in the general Taiwanese population, a significant improvement beyond current biomarkers alone (82%; 95% CI, 75%–90%, P ≤ 0.01). This EBV-based risk score also improved NPC prediction in genetically high-risk families (89%; 95% CI, 82%–96%) compared with current biomarkers (78%; 95% CI, 66%–90%, P ≤ 0.03).
Interpretation. We identified NPC-related differences in 133 anti-EBV antibodies and developed a risk score using this microarray dataset that targeted immune responses against EBV proteins from all stages of the viral life cycle, significantly improving the ability to predict NPC. Clin Cancer Res; 24(6); 1305–14. ©2017 AACR.
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Therapeutic Challenge with a CDK 4/6 Inhibitor Induces an RB-Dependent SMAC-Mediated Apoptotic Response in Non-Small Cell Lung Cancer
Purpose: The retinoblastoma tumor suppressor (RB), a key regulator of cell-cycle progression and proliferation, is functionally suppressed in up to 50% of non–small cell lung cancer (NSCLC). RB function is exquisitely controlled by a series of proteins, including the CyclinD–CDK4/6 complex. In this study, we interrogated the capacity of a CDK4/6 inhibitor, palbociclib, to activate RB function.
Experimental Design and Results: We employed multiple isogenic RB-proficient and -deficient NSCLC lines to interrogate the cytostatic and cytotoxic capacity of CDK 4/6 inhibition in vitro and in vivo. We demonstrate that while short-term exposure to palbociclib induces cellular senescence, prolonged exposure results in inhibition of tumor growth. Mechanistically, CDK 4/6 inhibition induces a proapoptotic transcriptional program through suppression of IAPs FOXM1 and Survivin, while simultaneously augmenting expression of SMAC and caspase-3 in an RB-dependent manner.
Conclusions: This study uncovers a novel function of RB activation to induce cellular apoptosis through therapeutic administration of a palbociclib and provides a rationale for the clinical evaluation of CDK 4/6 inhibitors in the treatment of patients with NSCLC. Clin Cancer Res; 24(6); 1402–14. ©2018 AACR.
http://ift.tt/2pdyvXn
p53-Reactive T Cells Are Associated with Clinical Benefit in Patients with Platinum-Resistant Epithelial Ovarian Cancer After Treatment with a p53 Vaccine and Gemcitabine Chemotherapy
Purpose: To conduct a phase I trial of a Modified Vaccinia Ankara vaccine delivering wild-type human p53 (p53MVA) in combination with gemcitabine chemotherapy in patients with platinum-resistant ovarian cancer.
Experimental Design: Patients received gemcitabine on days 1 and 8 and p53MVA vaccine on day 15, during the first 3 cycles of chemotherapy. Toxicity was classified using the NCI Common Toxicity Criteria and clinical response assessed by CT scan. Peripheral blood samples were collected for immunophenotyping and monitoring of anti-p53 immune responses.
Results: Eleven patients were evaluated for p53MVA/gemcitabine toxicity, clinical outcome, and immunologic response. Toxicity: there were no DLTs, but 3 of 11 patients came off study early due to gemcitabine-attributed adverse events (AE). Minimal AEs were attributed to p53MVA vaccination. Immunologic and clinical response: enhanced in vitro recognition of p53 peptides was detectable after immunization in both the CD4+ and CD8+ T-cell compartments in 5 of 11 and 6 of 11 patients, respectively. Changes in peripheral T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSC) did not correlate significantly with vaccine response or progression-free survival (PFS). Patients with the greatest expansion of p53-reactive T cells had significantly longer PFS than patients with lower p53-reactivity after therapy. Tumor shrinkage or disease stabilization occurred in 4 patients.
Conclusions: p53MVA was well tolerated, but gemcitabine without steroid pretreatment was intolerable in some patients. However, elevated p53-reactive CD4+ and CD8+ T-cell responses after therapy correlated with longer PFS. Therefore, if responses to p53MVA can be enhanced with alternative agents, superior clinical responses may be achievable. Clin Cancer Res; 24(6); 1315–25. ©2018 AACR.
http://ift.tt/2FBG3Nx
Genetic Ablation of Rbm38 Promotes Lymphomagenesis in the Context of Mutant p53 by Downregulating PTEN
Mutant p53 exerts gain-of-function effects that drive metastatic progression and therapeutic resistance, but the basis for these effects remain obscure. The RNA binding protein RBM38 limits translation of mutant p53 and is often altered in tumors harboring it. Here we show how loss of Rbm38 significantly alters cancer susceptibility in mutant p53 knock-in mice by shortening lifespan, altering tumor incidence, and promoting T-cell lymphomagenesis. Loss of Rbm38 enhanced mutant p53 expression and decreased expression of the tumor suppressor Pten, a key regulator of T-cell development. Furthermore, Rbm38 was required for Pten expression via stabilization of Pten mRNA through an AU-rich element in its 3′UTR. Our results suggest that Rbm38 controls T-cell lymphomagenesis by jointly modulating mutant p53 and Pten, with possible therapeutic implications for treating T-cell malignancies.Significance: An RNA-binding protein controls T-cell lymphomagenesis by jointly modulating mutant p53 and PTEN, with possible therapeutic implications for treating T-cell malignancies. Cancer Res; 78(6); 1511–21. ©2018 AACR.
http://ift.tt/2pdyNNX
Radioresistant Cervical Cancers Are Sensitive to Inhibition of Glycolysis and Redox Metabolism
Highly glycolytic cervical cancers largely resist treatment by cisplatin and coadministered pelvic irradiation as the present standard of care. In this study, we investigated the effects of inhibiting glycolysis and thiol redox metabolism to evaluate them as alternate treatment strategies in these cancers. In a panel of multiple cervical cancer cell lines, we evaluated sensitivity to inhibition of glycolysis (2-deoxyglucose, 2-DG) with or without simultaneous inhibition of glutathione and thioredoxin metabolism (BSO/AUR). Intracellular levels of total and oxidized glutathione, thioredoxin reductase activity, and indirect measures of intracellular reactive oxygen species were compared before and after treatment. Highly radioresistant cells were the most sensitive to 2-DG, whereas intermediate radioresistant cells were sensitive to 2-DG plus BSO/AUR. In response to 2-DG/BSO/AUR treatment, we observed increased levels of intracellular oxidized glutathione, redox-sensitive dye oxidation, and decreased glucose utilization via multiple metabolic pathways including the tricarboxylic acid cycle. 2-DG/BSO/AUR treatment delayed the growth of tumors composed of intermediate radioresistant cells and effectively radiosensitized these tumors at clinically relevant radiation doses both in vitro and in vivo. Overall, our results support inhibition of glycolysis and intracellular redox metabolism as an effective alternative drug strategy for the treatment of highly glycolytic and radioresistant cervical cancers.Significance: This study suggests a simple metabolic approach to strike at an apparent Achilles' heel in highly glycolytic, radioresistant forms of cervical cancers, possibly with broader applications in cancer therapy. Cancer Res; 78(6); 1392–403. ©2018 AACR.
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Kindlin-1 Promotes Pulmonary Breast Cancer Metastasis
In breast cancer, increased expression of the cytoskeletal adaptor protein Kindlin-1 has been linked to increased risks of lung metastasis, but the functional basis is unknown. Here, we show that in a mouse model of polyomavirus middle T antigen–induced mammary tumorigenesis, loss of Kindlin-1 reduced early pulmonary arrest and later development of lung metastasis. This phenotype relied on the ability of Kindlin-1 to bind and activate β integrin heterodimers. Kindlin-1 loss reduced α4 integrin–mediated adhesion of mammary tumor cells to the adhesion molecule VCAM-1 on endothelial cells. Treating mice with an anti–VCAM-1 blocking antibody prevented early pulmonary arrest. Kindlin-1 loss also resulted in reduced secretion of several factors linked to metastatic spread, including the lung metastasis regulator tenascin-C, showing that Kindlin-1 regulated metastatic dissemination by an additional mechanism in the tumor microenvironment. Overall, our results show that Kindlin-1 contributes functionally to early pulmonary metastasis of breast cancer.Significance: These findings provide a mechanistic proof in mice that Kindin-1, an integrin-binding adaptor protein, is a critical mediator of early lung metastasis of breast cancer. Cancer Res; 78(6); 1484–96. ©2018 AACR.
http://ift.tt/2FCHzzc
Breast Cancer Targeting through Inhibition of the Endoplasmic Reticulum-Based Apoptosis Regulator Nrh/BCL2L10
Drug resistance and metastatic relapse remain a top challenge in breast cancer treatment. In this study, we present preclinical evidence for a strategy to eradicate advanced breast cancers by targeting the BCL-2 homolog Nrh/BCL2L10, which we discovered to be overexpressed in >45% of a large cohort of breast invasive carcinomas. Nrh expression in these tumors correlated with reduced metastasis-free survival, and we determined it to be an independent marker of poor prognosis. Nrh protein localized to the endoplasmic reticulum. Mechanistic investigations showed that Nrh made BH4 domain–dependent interactions with the ligand-binding domain of the inositol-1,4,5-triphosphate receptor (IP3R), a type 1/3 Ca2+ channel, allowing Nrh to negatively regulate ER-Ca2+ release and to mediate antiapoptosis. Notably, disrupting Nrh/IP3R complexes by BH4 mimetic peptides was sufficient to inhibit the growth of breast cancer cells in vitro and in vivo. Taken together, our results highlighted Nrh as a novel prognostic marker and a candidate therapeutic target for late stage breast cancers that may be addicted to Nrh.Significance: These findings offer a comprehensive molecular model for the activity of Nrh/BCL2L10, a little studied antiapoptotic molecule, prognostic marker, and candidate drug target in breast cancer. Cancer Res; 78(6); 1404–17. ©2018 AACR.
http://ift.tt/2pdyXF3
Role of Chromatin Damage and Chromatin Trapping of FACT in Mediating the Anticancer Cytotoxicity of DNA-Binding Small-Molecule Drugs
Precisely how DNA-targeting chemotherapeutic drugs trigger cancer cell death remains unclear, as it is difficult to separate direct DNA damage from other effects in cells. Recent work on curaxins, a class of small-molecule drugs with broad anticancer activity, shows that they interfere with histone–DNA interactions and destabilize nucleosomes without causing detectable DNA damage. Chromatin damage caused by curaxins is sensed by the histone chaperone FACT, which binds unfolded nucleosomes becoming trapped in chromatin. In this study, we investigated whether classical DNA-targeting chemotherapeutic drugs also similarly disturbed chromatin to cause chromatin trapping of FACT (c-trapping). Drugs that directly bound DNA induced both chromatin damage and c-trapping. However, chromatin damage occurred irrespective of direct DNA damage and was dependent on how a drug bound DNA, specifically, in the way it bound chromatinized DNA in cells. FACT was sensitive to a plethora of nucleosome perturbations induced by DNA-binding small molecules, including displacement of the linker histone, eviction of core histones, and accumulation of negative supercoiling. Strikingly, we found that the cytotoxicity of DNA-binding small molecules correlated with their ability to cause chromatin damage, not DNA damage. Our results suggest implications for the development of chromatin-damaging agents as selective anticancer drugs.Significance: These provocative results suggest that the anticancer efficacy of traditional DNA-targeting chemotherapeutic drugs may be based in large part on chromatin damage rather than direct DNA damage. Cancer Res; 78(6); 1431–43. ©2018 AACR.
http://ift.tt/2FzZS89
AMPK-Akt Double-Negative Feedback Loop in Breast Cancer Cells Regulates Their Adaptation to Matrix Deprivation
Cell detachment from the extracellular matrix triggers anoikis. Disseminated tumor cells must adapt to survive matrix deprivation, while still retaining the ability to attach at secondary sites and reinitiate cell division. In this study, we elucidate mechanisms that enable reversible matrix attachment by breast cancer cells. Matrix deprival triggered AMPK activity and concomitantly inhibited AKT activity by upregulating the Akt phosphatase PHLPP2. The resultant pAMPKhigh/pAktlow state was critical for cell survival in suspension, as PHLPP2 silencing also increased anoikis while impairing autophagy and metastasis. In contrast, matrix reattachment led to Akt-mediated AMPK inactivation via PP2C-α-mediated restoration of the pAkthigh/pAMPKlow state. Clinical specimens of primary and metastatic breast cancer displayed an Akt-associated gene expression signature, whereas circulating breast tumor cells displayed an elevated AMPK-dependent gene expression signature. Our work establishes a double-negative feedback loop between Akt and AMPK to control the switch between matrix-attached and matrix-detached states needed to coordinate cell growth and survival during metastasis.Significance: These findings reveal a molecular switch that regulates cancer cell survival during metastatic dissemination, with the potential to identify targets to prevent metastasis in breast cancer. Cancer Res; 78(6); 1497–510. ©2018 AACR.
http://ift.tt/2HB9rjM
KRAS Oncoprotein Expression Is Regulated by a Self-Governing eIF5A-PEAK1 Feed-Forward Regulatory Loop
There remains intense interest in tractable approaches to target or silence the KRAS oncoprotein as a rational therapeutic strategy to attack pancreatic ductal adenocarcinoma (PDAC) and other cancers that overexpress it. Here we provide evidence that accumulation of the KRAS oncoprotein is controlled by a self-regulating feed-forward regulatory loop that utilizes a unique hypusinated isoform of the translation elongation factor eIF5A and the tyrosine kinase PEAK1. Oncogenic activation of KRAS increased eIF5A–PEAK1 translational signaling, which in turn facilitated increased KRAS protein synthesis. Mechanistic investigations show that this feed-forward positive regulatory pathway was controlled by oncogenic KRAS-driven metabolic demands, operated independently of canonical mTOR signaling, and did not involve new KRAS gene transcription. Perturbing eIF5A–PEAK1 signaling, by genetic or pharmacologic strategies or by blocking glutamine synthesis, was sufficient to inhibit expression of KRAS, eIF5A, and PEAK1, to attenuate cancer cell growth and migration, and to block tumor formation in established preclinical mouse models of PDAC. Levels of KRAS, eIF5A, and PEAK1 protein increased during cancer progression with the highest levels of expression observed in metastatic cell populations. Combinatorial targeting of eIF5A hypusination and the RAS–ERK signaling pathway cooperated to attenuate KRAS expression and its downstream signaling along with cell growth in vitro and tumor formation in vivo. Collectively, our findings highlight a new mechanistic strategy to attenuate KRAS expression as a therapeutic strategy to target PDAC and other human cancers driven by KRAS activation.Significance: These findings highlight a new mechanistic strategy to attenuate KRAS expression as a therapeutic strategy to target human cancers driven by KRAS activation. Cancer Res; 78(6); 1444–56. ©2018 AACR.
http://ift.tt/2FGWAff
Antitumor Effects of Blocking Protein Neddylation in T315I-BCR-ABL Leukemia Cells and Leukemia Stem Cells
Imatinib revolutionized the treatment of chronic myeloid leukemia (CML), but drug resistance and disease recurrence remain a challenge. In this study, we suggest a novel strategy based on blocking protein neddylation to address BCR-ABL point mutations and leukemia stem cells (LSC) that lie at the root of imatinib-resistant recurrences. On the basis of the finding that the NEDD8-activating enzyme subunit NAE1 is overexpressed in CML cells, we hypothesized that the function of certain neddylation-dependent protein substrates might be targeted to therapeutic ends in imatinib-resistant CML cells and LSCs. In support of this hypothesis, we demonstrated that the NAE1 inhibitor MLN4924 induced G2–M-phase arrest and apoptosis in bulk CML cells with wild-type p53, regardless of their T315I mutation status in BCR-ABL. Moreover, MLN4924 inhibited the survival and self-renewal of primary human CML CD34+ cells and LSCs in CML-bearing mice via accumulation of p27kip1 in the nucleus. Notably, p27kip1 silencing attenuated the suppressive effect of MLN4924 on the maintenance of LSCs in CML-bearing mice. Taken together, our findings offer a preclinical proof of concept for targeting protein neddylation as a novel therapeutic strategy to override mutational and LSC-derived imatinib resistance in CML.Significance: These findings highlight a mediator of protein neddylation, a type of protein turnover mechanism, as a viable therapeutic target against imatinib-resistant forms of chronic myelogenous leukemia. Cancer Res; 78(6); 1522–36. ©2018 AACR.
http://ift.tt/2HAN5ip
Genetic Mosaicism and Cancer: Cause and Effect
Increasing theoretical and experimental evidence suggests that the genomes of both normal and cancer cells are subject to continuous changes as a result of copying errors during replication, defects in chromosome segregation during mitosis, and direct chemical attacks by reactive oxygen species. The process of cellular genetic diversification begins during embryonic development and continues throughout life, leading to the phenomenon of somatic mosaicism. New information about the genetic diversity of cells composing the body makes us reconsider the existing concepts of cancer etiology and pathogenesis. Here, I suggest that a progressively deteriorating microenvironment ("soil") generates the cancerous "seed" and favors its development. Cancer Res; 78(6); 1375–8. ©2018 AACR.
http://ift.tt/2FCHDyW
A Novel l-Asparaginase with low l-Glutaminase Coactivity Is Highly Efficacious against Both T- and B-cell Acute Lymphoblastic Leukemias In Vivo
Acute lymphoblastic leukemia (ALL) is the most common type of pediatric cancer, although about 4 of every 10 cases occur in adults. The enzyme drug l-asparaginase serves as a cornerstone of ALL therapy and exploits the asparagine dependency of ALL cells. In addition to hydrolyzing the amino acid l-asparagine, all FDA-approved l-asparaginases also have significant l-glutaminase coactivity. Since several reports suggest that l-glutamine depletion correlates with many of the side effects of these drugs, enzyme variants with reduced l-glutaminase coactivity might be clinically beneficial if their antileukemic activity would be preserved. Here we show that novel low l-glutaminase variants developed on the backbone of the FDA-approved Erwinia chrysanthemi l-asparaginase were highly efficacious against both T- and B-cell ALL, while displaying reduced acute toxicity features. These results support the development of a new generation of safer l-asparaginases without l-glutaminase activity for the treatment of human ALL.Significance: A new l-asparaginase–based therapy is less toxic compared with FDA-approved high l-glutaminase enzymes Cancer Res; 78(6); 1549–60. ©2018 AACR.
http://ift.tt/2HCnoOl
The Balance Players of the Adaptive Immune System
Equilibrium between immune activation and suppression may be necessary to maintain immune homeostasis, because proinflammatory effector T cells (defined as antiregulatory T cells) counteract the functions of regulatory immune cells. These self-reactive T cells recognize human leukocyte antigen (HLA)–restricted epitopes derived from proteins expressed by regulatory immune cells such as IDO, PD-L1, PD-L2, or arginase. The activation of such proinflammatory effector T cells offers a novel way to directly target the tumor microenvironment, potentially giving them considerable clinical value, especially in patients with cancer. Vaccination against genetically stable cells with regular HLA expression is an attractive way to directly target immunosuppressive cells in addition to attracting proinflammatory cells into the tumor microenvironment. Importantly, vaccination toward IDO or PD-L1 to potentiate such T cells have proven safe, with minimal toxicity in the clinical phase I trials conducted thus far.Cancer Res; 78(6); 1379–82. ©2018 AACR.
http://ift.tt/2HClSLV
The Hippo Pathway Component TAZ Promotes Immune Evasion in Human Cancer through PD-L1
The Hippo pathway component WW domain-containing transcription regulator 1 (TAZ) is a transcriptional coactivator and an oncogene in breast and lung cancer. Transcriptional targets of TAZ that modulate immune cell function in the tumor microenvironment are poorly understood. Here, we perform a comprehensive screen for immune-related genes regulated by TAZ and its paralog YAP using NanoString gene expression profiling. We identify the immune checkpoint molecule PD-L1 as a target of Hippo signaling. The upstream kinases of the Hippo pathway, mammalian STE20-like kinase 1 and 2 (MST1/2), and large tumor suppressor 1 and 2 (LATS1/2), suppress PD-L1 expression while TAZ and YAP enhance PD-L1 levels in breast and lung cancer cell lines. PD-L1 expression in cancer cell lines is determined by TAZ activity and TAZ/YAP/TEAD increase PD-L1 promoter activity. Critically, TAZ-induced PD-L1 upregulation in human cancer cells is sufficient to inhibit T-cell function. The relationship between TAZ and PD-L1 is not conserved in multiple mouse cell lines, likely due to differences between the human and mouse PD-L1 promoters. To explore the extent of divergence in TAZ immune-related targets between human and mouse cells, we performed a second NanoString screen using mouse cell lines. We show that many targets of TAZ may be differentially regulated between these species. These findings highlight the role of Hippo signaling in modifying human/murine physiologic/pathologic immune responses and provide evidence implicating TAZ in human cancer immune evasion.Significance: Human-specific activation of PD-L1 by a novel Hippo signaling pathway in cancer immune evasion may have a significant impact on research in immunotherapy. Cancer Res; 78(6); 1457–70. ©2018 AACR.
http://ift.tt/2FEPlbF
International trends in lung cancer incidence from 1973 to 2007
Abstract
Lung cancer is the commonly diagnosed cancer and one of the most important avoidable causes of death around the world. We conducted the study to investigate the pattern of lung cancer incidence worldwide. Joinpoint analysis was used to extend international lung cancer incidence rates by the latest data from Cancer Incidence in Five Continents over the 35-year period 1973–2007 from 24 populations from Americas, Asia, Europe, and Oceania. Age-standardized incidence rates (ASRs) of lung cancer were from 33.3 to 66.8 per 100,000 among males and 10.5 to 37.4 per 100,000 among females in most of Americas, Europe, and Oceania populations during the period 2003–2007. In Asia, ASRs in China (Hong Kong) were the highest, up to 53.3 per 100,000 in males and 21.9 per 100,000 in females during the period 2003–2007. The international trends between 1973 and 2007 showed that ASRs of lung cancer among males were declining in 13 of 18 selected Americas, Oceania, and Europe populations, with AAPC from −0.7% to −2.9%, whereas the rates among females in 18 selected populations were increasing, with AAPC from 1.3% to 5.0%. The increasing and decreasing trends of ASRs of lung cancer in Asia have a geographic variation but no gender differences. Although the decreasing trends in ASRs of lung cancer for males were observed, the ASRs were higher than females. The declining trends in males were mainly attributed to tobacco control, whereas the increasing trends in females should be given more concern and need to be further studied in etiology factors.
The international trends between 1973 and 2007 showed that ASRs of lung cancer among males were declining in 13 of 18 selected Americas, Oceania, and Europe populations, with AAPC from −0.7% to −2.9%. Whereas the rates among females in 18 selected populations were increasing, with AAPC from 1.3% to 5.0%. The increasing and decreasing trends of ASRs of lung cancer in Asia have an geographic variation but no gender differences.
http://ift.tt/2Guoj3V
AAVrh10 Gene Therapy Ameliorates Central and Peripheral Nervous System Disease in Canine Globoid Cell Leukodystrophy (Krabbe Disease)
Human Gene Therapy, Ahead of Print.
http://ift.tt/2GtpEYO
Overexpression of Hepatocyte Growth Factor mRNA Induced by Gene Transfer Attenuates Neointimal Hyperplasia After Balloon Injury
Human Gene Therapy, Ahead of Print.
http://ift.tt/2FIrpQH
Gene Therapy for Bone Repair Using Human Cells: Superior Osteogenic Potential of Bone Morphogenetic Protein 2–Transduced Mesenchymal Stem Cells Derived from Adipose Tissue Compared to Bone Marrow
Human Gene Therapy, Ahead of Print.
http://ift.tt/2FCFJ1g
Preclinical Models in Chimeric Antigen Receptor–Engineered T-Cell Therapy
Human Gene Therapy, Ahead of Print.
http://ift.tt/2DsFj7P
Not “With Her”: How Gendered Political Slogans Affect Conservative Women’s Perceptions of Female Leaders
Abstract
Past research has indicated that women who work in male-dominated fields, such as politics, face discrimination due to a stereotypically perceived poor fit between their gender and occupational expectations. Even when their potential for success is undeniable, these women are typically derogated and viewed as unlikeable for violating prescriptive gender norms. We examined whether conservative U.S. women would respond in this unfavorable manner toward Democratic nominee Hillary Clinton during the 2016 U.S. Presidential Election. Female undergraduates (n = 140) were randomly assigned to watch a set of three campaign ads that included either no slogan, a gender-neutral slogan ("Stronger Together"), or a gendered slogan ("I'm with Her"). Afterwards, they rated Clinton on dimensions related to interpersonal hostility, competency, and overall support. Given its adherence to traditional values and gender roles, we hypothesized that political conservatism would be predictive of critical responses to Clinton, especially when the campaign slogan made her gender-norm violation salient. Results revealed that conservative ideology was more strongly associated with increased ratings of perceived hostility and less support for Clinton within the "I'm with Her" condition than with the comparison groups. These findings point to the social maintenance of political inequality and suggest that female leaders may need to use gender-neutral platforms to diminish the negative effects of their perceived norm violation, at least among conservative voters.
http://ift.tt/2FzYGSd
Corticothalamic axon morphologies and network architecture
Abstract
Recent commentaries on the role of the thalamus consider a wide sphere of influence beyond sensory-motor transformation, to include task-relevant cognitive processes. In this short review, I reconsider known anatomic features of corticothalamic connectivity, primarily for macaque monkey, and discuss these as part of an intricate network architecture consistent with multiple connectional re-combinations and a diversity of functional tasks. Drawing mainly on results from single axon analysis for the two broad classes of corticothalamic (CT) connections, I review the strikingly complementary spatial parameters of their extrinsic CT arbors in relation to intrinsic cortical collaterals. That is, CT neurons in layer 5 (class II) have spatially compact (low divergent) thalamic fields, but highly spatially divergent cortical collaterals. In contrast, CT neurons in layer 6 (class I) have highly divergent thalamic fields, but delimited, low divergent cortical collaterals. CT convergence in the thalamus is technically more difficult to analyze; but one can infer a low convergence of terminations from layer 5, in contrast with CT terminations from layer 6, which are highly convergent. Reciprocating thalamocortical (TC) axons have multiple clustered and divergent arbors. What to conclude from these relationships requires further investigation of activity patterns and networks under different conditions. Specific parameters are suggestive of selective recruitment of distributed postsynaptic networks and ordered activity sequences; but are these separable systems, operating cooperatively or in parallel (L.5 low divergent/low convergent vs. L. 6 high divergent/high convergent)?
This article is protected by copyright. All rights reserved.
http://ift.tt/2FELziv
A Flow Cytometry-Based Phenotypic Screen To Identify Novel Endocytic Factors in Saccharomyces cerevisiae
Endocytosis is a fundamental process for internalizing material from the plasma membrane, including many transmembrane proteins that are selectively internalized depending on environmental conditions. In most cells, the main route of entry is clathrin-mediated endocytosis (CME), a process that involves the coordinated activity of over 60 proteins; however, there are likely as-yet unidentified proteins involved in cargo selection and/or regulation of endocytosis. We performed a mutagenic screen to identify novel endocytic genes in Saccharomyces cerevisiae expressing the methionine permease Mup1 tagged with pHluorin (pHl), a pH-sensitive GFP variant whose fluorescence is quenched upon delivery to the acidic vacuole lumen. We used fluorescence-activated cell sorting to isolate mutagenized cells with elevated fluorescence, resulting from failure to traffic Mup1-pHl cargo to the vacuole, and further assessed subcellular localization of Mup1-pHl to characterize the endocytic defects in 256 mutants. A subset of mutant strains was classified as having general endocytic defects based on mislocalization of additional cargo proteins. Within this group, we identified mutations in four genes encoding proteins with known roles in endocytosis: the endocytic coat components SLA2, SLA1, and EDE1, and the ARP3 gene, whose product is involved in nucleating actin filaments to form branched networks. All four mutants demonstrated aberrant dynamics of the endocytic machinery at sites of CME; moreover, the arp3R346H mutation showed reduced actin nucleation activity in vitro. Finally, whole genome sequencing of two general endocytic mutants identified mutations in conserved genes not previously implicated in endocytosis, KRE33 and IQG1, demonstrating that our screening approach can be used to identify new components involved in endocytosis.
http://ift.tt/2FHZHne
Rapid Multiplex Small DNA Sequencing on the MinION Nanopore Sequencing Platform
Real-time sequencing of short DNA reads has a wide variety of clinical and research applications including screening for mutations, target sequences and aneuploidy. We recently demonstrated that MinION, a nanopore-based DNA sequencing device the size of a USB drive, could be used for short-read DNA sequencing. In this study, an ultra-rapid multiplex library preparation and sequencing method for the MinION is presented and applied to accurately test normal diploid and aneuploidy samples' genomic DNA in under three hours, including library preparation and sequencing. This novel method shows great promise as a clinical diagnostic test for applications requiring rapid short-read DNA sequencing.
http://ift.tt/2pdsQAB
The 2018 Lake Louise Acute Mountain Sickness Score
High Altitude Medicine &Biology, Ahead of Print.
http://ift.tt/2GsweP9
PRRT2 controls neuronal excitability by negatively modulating Na+ channel 1.2/1.6 activity
Abstract
Proline-rich transmembrane protein 2 (PRRT2) is the causative gene for a heterogeneous group of familial paroxysmal neurological disorders that include seizures with onset in the first year of life (benign familial infantile seizures), paroxysmal kinesigenic dyskinesia or a combination of both. Most of the PRRT2 mutations are loss-of-function leading to haploinsufficiency and 80% of the patients carry the same frameshift mutation (c.649dupC; p.Arg217Profs*8), which leads to a premature stop codon. To model the disease and dissect the physiological role of PRRT2, we studied the phenotype of neurons differentiated from induced pluripotent stem cells from previously described heterozygous and homozygous siblings carrying the c.649dupC mutation. Single-cell patch-clamp experiments on induced pluripotent stem cell-derived neurons from homozygous patients showed increased Na+ currents that were fully rescued by expression of wild-type PRRT2. Closely similar electrophysiological features were observed in primary neurons obtained from the recently characterized PRRT2 knockout mouse. This phenotype was associated with an increased length of the axon initial segment and with markedly augmented spontaneous and evoked firing and bursting activities evaluated, at the network level, by multi-electrode array electrophysiology. Using HEK-293 cells stably expressing Nav channel subtypes, we demonstrated that the expression of PRRT2 decreases the membrane exposure and Na+ current of Nav1.2/Nav1.6, but not Nav1.1, channels. Moreover, PRRT2 directly interacted with Nav1.2/Nav1.6 channels and induced a negative shift in the voltage-dependence of inactivation and a slow-down in the recovery from inactivation. In addition, by co-immunoprecipitation assays, we showed that the PRRT2-Nav interaction also occurs in brain tissue. The study demonstrates that the lack of PRRT2 leads to a hyperactivity of voltage-dependent Na+ channels in homozygous PRRT2 knockout human and mouse neurons and that, in addition to the reported synaptic functions, PRRT2 is an important negative modulator of Nav1.2 and Nav1.6 channels. Given the predominant paroxysmal character of PRRT2-linked diseases, the disturbance in cellular excitability by lack of negative modulation of Na+ channels appears as the key pathogenetic mechanism.http://ift.tt/2HAEA6L
Comment on ‘BAG-1 as a biomarker in early breast cancer prognosis: a systematic review with meta-analyses'
Comment on 'BAG-1 as a biomarker in early breast cancer prognosis: a systematic review with meta-analyses'
Comment on 'BAG-1 as a biomarker in early breast cancer prognosis: a systematic review with meta-analyses', Published online: 15 March 2018; doi:10.1038/s41416-018-0023-z
Comment on 'BAG-1 as a biomarker in early breast cancer prognosis: a systematic review with meta-analyses'
http://ift.tt/2paZhzE
WSB-1 regulates the metastatic potential of hormone receptor negative breast cancer
WSB-1 regulates the metastatic potential of hormone receptor negative breast cancer
WSB-1 regulates the metastatic potential of hormone receptor negative breast cancer, Published online: 15 March 2018; doi:10.1038/s41416-018-0056-3
WSB-1 regulates the metastatic potential of hormone receptor negative breast cancer
http://ift.tt/2pd9YBL
Automatic detection of image manipulations in the biomedical literature
Automatic detection of image manipulations in the biomedical literature
Automatic detection of image manipulations in the biomedical literature, Published online: 14 March 2018; doi:10.1038/s41419-018-0430-3
Automatic detection of image manipulations in the biomedical literaturehttp://ift.tt/2Dt0W7I
Myocardial Bmp2 gain causes ectopic EMT and promotes cardiomyocyte proliferation and immaturity
Myocardial Bmp2 gain causes ectopic EMT and promotes cardiomyocyte proliferation and immaturity
Myocardial Bmp2 gain causes ectopic EMT and promotes cardiomyocyte proliferation and immaturity, Published online: 14 March 2018; doi:10.1038/s41419-018-0442-z
Myocardial Bmp2 gain causes ectopic EMT and promotes cardiomyocyte proliferation and immaturityhttp://ift.tt/2FVq24z
Decreased autophagy induced by β1-adrenoceptor autoantibodies contributes to cardiomyocyte apoptosis
Decreased autophagy induced by β1-adrenoceptor autoantibodies contributes to cardiomyocyte apoptosis
Decreased autophagy induced by β<sub>1</sub>-adrenoceptor autoantibodies contributes to cardiomyocyte apoptosis, Published online: 14 March 2018; doi:10.1038/s41419-018-0445-9
Decreased autophagy induced by β1-adrenoceptor autoantibodies contributes to cardiomyocyte apoptosishttp://ift.tt/2FVpVpF
circHECTD1 promotes the silica-induced pulmonary endothelial–mesenchymal transition via HECTD1
circHECTD1 promotes the silica-induced pulmonary endothelial–mesenchymal transition via HECTD1
circHECTD1 promotes the silica-induced pulmonary endothelial–mesenchymal transition via HECTD1, Published online: 14 March 2018; doi:10.1038/s41419-018-0432-1
circHECTD1 promotes the silica-induced pulmonary endothelial–mesenchymal transition via HECTD1http://ift.tt/2HAUa2q
MicroRNA-30a-5p inhibits gallbladder cancer cell proliferation, migration and metastasis by targeting E2F7
MicroRNA-30a-5p inhibits gallbladder cancer cell proliferation, migration and metastasis by targeting E2F7
MicroRNA-30a-5p inhibits gallbladder cancer cell proliferation, migration and metastasis by targeting E2F7, Published online: 14 March 2018; doi:10.1038/s41419-018-0444-x
MicroRNA-30a-5p inhibits gallbladder cancer cell proliferation, migration and metastasis by targeting E2F7http://ift.tt/2pd43MZ
Histone deacetylase 3 promotes liver regeneration and liver cancer cells proliferation through signal transducer and activator of transcription 3 signaling pathway
Histone deacetylase 3 promotes liver regeneration and liver cancer cells proliferation through signal transducer and activator of transcription 3 signaling pathway
Histone deacetylase 3 promotes liver regeneration and liver cancer cells proliferation through signal transducer and activator of transcription 3 signaling pathway, Published online: 14 March 2018; doi:10.1038/s41419-018-0428-x
Histone deacetylase 3 promotes liver regeneration and liver cancer cells proliferation through signal transducer and activator of transcription 3 signaling pathwayhttp://ift.tt/2FQVMYD
Kaempferol targeting on the fibroblast growth factor receptor 3-ribosomal S6 kinase 2 signaling axis prevents the development of rheumatoid arthritis
Kaempferol targeting on the fibroblast growth factor receptor 3-ribosomal S6 kinase 2 signaling axis prevents the development of rheumatoid arthritis
Kaempferol targeting on the fibroblast growth factor receptor 3-ribosomal S6 kinase 2 signaling axis prevents the development of rheumatoid arthritis, Published online: 14 March 2018; doi:10.1038/s41419-018-0433-0
Kaempferol targeting on the fibroblast growth factor receptor 3-ribosomal S6 kinase 2 signaling axis prevents the development of rheumatoid arthritishttp://ift.tt/2Dt0RRs
Myeloid derived-suppressor cells: their role in cancer and obesity
Suzanne Ostrand-Rosenberg
http://ift.tt/2FC1xKj
A Patient-Driven Model for Cancer Research [News in Brief]
The Metastatic Prostate Cancer Project aims to engage thousands of patients to create rich research database.
http://ift.tt/2Hz9uwf
CSPG4 Shows Promise for Glioblastoma CAR T Therapy [News in Brief]
T cells transduced to express the antigen shrink brain cancer in mouse models—with no signs of tumor escape.
http://ift.tt/2Dsvo20
Direct-to-Consumer Test for BRCA Mutations Authorized [News in Brief]
The 23andMe test can detect three BRCA1/BRCA2 mutations most commonly found in women of Ashkenazi Jewish descent.
http://ift.tt/2FRmOPp
Survivin Monoclonal Antibodies Detect Survivin Cell Surface Expression and Inhibit Tumor Growth in vivo
Purpose: Survivin is an inhibitor of apoptosis protein (IAP) that is highly expressed in many cancers and represents an attractive molecule for targeted cancer therapy. Although primarily regarded as an intracellular protein with diverse actions, survivin has also been identified in association with circulating tumor exosomes. Experimental Design: We have reported that active specific vaccination with a long peptide surviving immunogen leads to the development of survivin-specific CD8-mediated tumor cell lysis and prolongation of survival in tumor-bearing mice. In addition to cellular antitumor responses, circulating anti-survivin antibodies are detected in the serum of mice and human glioblastoma patients following vaccination with the survivin immunogen. Results: Here we demonstrate that survivin is present on the outer cell membrane of a wide variety of cancer cell types, including both murine and human glioma cells. In addition, antibodies to surviving that are derived from the immunogen display antitumor activity against murine GL261 gliomas in both flank and intracranial tumor models and against B16 melanoma as well. Conclusion: In addition to immunogen-induced, CD8-mediated tumor cell lysis, antibodies to the survivin immunogen have antitumor activity in vivo. Cell-surface survivin could provide a specific target for antibody-mediated tumor immunotherapeutic approaches.
http://ift.tt/2tPz1PS
STAT3/HOTAIR signaling axis regulates HNSCC growth in an EZH2-dependent manner
Purpose: Phosphotidylinositol-3-kinase (PI3K)and signal transducers and activators of transcription 3 (STAT3) are frequently activated in cancer progression. However, little is known about the underlying mechanisms by which PI3K and STAT3 regulate HNSCC growth. The lncRNA HOX transcript antisense RNA (HOTAIR) was found to modulate the progression of head and neck squamous cell cancer (HNSCC). In this study, we attempted to establish the correlation of PI3K-STAT3-HOTAIR signaling with the progression of HNSCC and its sensitivity towards platinum-based and targeted anti-EGFR combination therapy. Experimental Design: We first analyzed the STAT3/HOTAIR and PI3K/AKT level in human HNSCC samples. We then activated or suppressed STAT3/HOTAIR and determined the effects on HNSCC cell proliferation in vitro and the growth of UM1 xenograft tumor, an orthotopic model of HNSCC. The sensitivity of HNSCC cells towards cisplatin and cetuximab was determined by in vitro assays. Results: HNSCC samples showed significantly robust expression/activation of STAT3, HOTAIR, PI3K, and AKT, compared with normal squamous epithelium. STAT3 inhibition with WP1066 decreased HOTAIR level and sensitized HNSCC to cisplatin or cetuximab. STAT3 promoted HOTAIR transcription and its interaction with pEZH2-S21, resulting in enhanced growth of HNSCC cells. In addition, overexpression of HOTAIR promoted the growth of UM1 xenograft tumors in vivo. Conclusions: Our results suggest that STAT3 signaling promotes HNSCC progression via regulating HOTAIR and pEZH2-S21 in HNSCC with PI3K overexpression/activation. These findings provide a rationale to target the STAT3/HOTAIR/pEZH2-S21 regulatory axis for treating patients with HNSCC.
http://ift.tt/2FXASqV
MPO promoter polymorphism rs2333227 enhances malignant phenotypes of colorectal cancer by altering the binding affinity of AP-2{alpha}
Myeloperoxidase (MPO) promoter single nucleotide polymorphisms (SNPs) rs2243828 (-764T>C) and rs2333227 (G-463A) program malignant phenotypes by regulating MPO transcriptional activity. In this study, we enrolled a total of 1,175 controls and 1,078 colorectal cancer (CRC) patients with comprehensive clinical and survival information to assess whether these SNPs could affect the susceptibility and development of CRC. The MPO rs2333227 TT genotype significantly increased the risk of CRC and decreased the overall survival time of patients. CRC cells with the rs2333227 TT genotype exhibited enhanced proliferation, migration, and invasion capacity in vitro and in vivo. Mechanistically, we found that MPO SNP rs2333227 C to T mutation altered the binding affinity of the transcription factors AP-2α to the rs2333227 mutation region, sequentially enhancing expression levels of MPO and activating further IL23A-MMP9 axis-mediated oncogenic signaling. Taken together, our findings indicate that MPO SNP rs2333227 serves as a marker of enhanced risk for development of CRC.
http://ift.tt/2pfFkql
Prevalence of Multimorbidity Among Older Adults with Advanced illness Visits to U.S. Subspecialty Clinics
Multimorbidity, often defined as three or more coexisting conditions, is associated with lower functional status and greater symptom burden.1 The complexity of care for older adults with advanced illness who also have multimorbidity requires coordination of care between primary care providers and subspecialists.2 Studies to date have not reported what proportion of subspecialty visits involves the population with advanced illness and multimorbidity. This information is important in order to tailor care coordination efforts and plan workflows for more complex clinical decision-making.
http://ift.tt/2Dtz8jC
Reply
We thank Dr Degraeuwe for the opportunity to respond to his concerns regarding our study. The author states that the attending physicians might not have been blinded to the magnetic resonance imaging (MRI) results when deciding on redirection of care. Although it is true that the results of MRI were taken into consideration when making decisions on redirection of care in cohort 1, this was not the case for cohort 2. Because the predictive value and ORs are comparable between cohorts 1 and 2, this finding shows that the predictive value is reliable and not subject to a self-fulfilling prophecy.
http://ift.tt/2HC2bUF
Reduction of chlorhexidine-induced chemical burns in extremely preterm infants by using 0.2% chlorhexidine-acetate as a skin disinfectant
We read with interest the article by Neri et al in which they present 5 very low birth weight infants in whom serious chemical burns occurred within their first 2 days of life, caused by the use of different chlorhexidine (CHG) skin disinfectants (concentrations ranging from 0.5% to 2.0%).1 The authors strongly discourage the use of alcohol-based disinfectants in extremely preterm infants and suggest using solutions containing the lowest effective CHG concentration possible, preferably <1%, during the first week of life.
http://ift.tt/2FR71A7
The long-term effects of direct amoxicillin in acute otitis media
We read with interest the report by Shaikh et al1 regarding the most cost-effective strategy for the management of children less than 2 years of age with acute otitis media (AOM) and no recent antibiotic exposure. According to their analysis this is immediate amoxicillin therapy. We value their well-conducted analysis in which they weighed many different factors. The editorial by Harrison shares this opinion and states that the study supports the American guidelines on AOM. However, we feel that some long-term effects have been given too little attention.
http://ift.tt/2DpxsYl
Delaying and Averting Dialysis Treatment: Patient Protection or Moral Hazard?
In talking with patients about the prospect of kidney failure, it can be useful to frame the problem as deciding what to do "if you outlive your kidneys." For patients and nephrologists alike, this is the dominant challenge of advanced chronic kidney disease (CKD): to anticipate the evolution of illness from declining kidney function, choose the best treatment for the individual patient, and implement it not too early, not too late, but just at the right time.
http://ift.tt/2pb7xiK
A Comparative Analysis of Sepsis Identification Methods in an Electronic Database*
Objectives: To evaluate the relative validity of criteria for the identification of sepsis in an ICU database. Design: Retrospective cohort study of adult ICU admissions from 2008 to 2012. Setting: Tertiary teaching hospital in Boston, MA. Patients: Initial admission of all adult patients to noncardiac surgical ICUs. Interventions: Comparison of five different algorithms for retrospectively identifying sepsis, including the Sepsis-3 criteria. Measurements and Main Results: 11,791 of 23,620 ICU admissions (49.9%) met criteria for the study. Within this subgroup, 59.9% were suspected of infection on ICU admission, 75.2% of admissions had Sequential Organ Failure Assessment greater than or equal to 2, and 49.1% had both suspicion of infection and Sequential Organ Failure Assessment greater than or equal to 2 thereby meeting the Sepsis-3 criteria. The area under the receiver operator characteristic of Sequential Organ Failure Assessment (0.74) for hospital mortality was consistent with previous studies of the Sepsis-3 criteria. The Centers for Disease Control and Prevention, Angus, Martin, Centers for Medicare & Medicaid Services, and explicit coding methods for identifying sepsis revealed respective sepsis incidences of 31.9%, 28.6%, 14.7%, 11.0%, and 9.0%. In-hospital mortality increased with decreasing cohort size, ranging from 30.1% (explicit codes) to 14.5% (Sepsis-3 criteria). Agreement among the criteria was acceptable (Cronbach's alpha, 0.40–0.62). Conclusions: The new organ dysfunction-based Sepsis-3 criteria have been proposed as a clinical method for identifying sepsis. These criteria identified a larger, less severely ill cohort than that identified by previously used administrative definitions. The Sepsis-3 criteria have several advantages over prior methods, including less susceptibility to coding practices changes, provision of temporal context, and possession of high construct validity. However, the Sepsis-3 criteria also present new challenges, especially when calculated retrospectively. Future studies on sepsis should recognize the differences in outcome incidence among identification methods and contextualize their findings according to the different cohorts identified.http://ift.tt/2pc6Dmg
Renal Tubular Cell Mitochondrial Dysfunction Occurs Despite Preserved Renal Oxygen Delivery in Experimental Septic Acute Kidney Injury
Objective: To explain the paradigm of significant renal functional impairment despite preserved hemodynamics and histology in sepsis-induced acute kidney injury. Design: Prospective observational animal study. Setting: University research laboratory. Subjects: Male Wistar rats. Intervention: Using a fluid-resuscitated sublethal rat model of fecal peritonitis, changes in renal function were characterized in relation to global and renal hemodynamics, and histology at 6 and 24 hours (n = 6–10). Sham-operated animals were used as comparison (n = 8). Tubular cell mitochondrial function was assessed using multiphoton confocal imaging of live kidney slices incubated in septic serum. Measurements and Main Results: By 24 hours, serum creatinine was significantly elevated with a concurrent decrease in renal lactate clearance in septic animals compared with sham-operated and 6-hour septic animals. Renal uncoupling protein-2 was elevated in septic animals at 24 hours although tubular cell injury was minimal and mitochondrial ultrastructure in renal proximal tubular cells preserved. There was no significant change in global or renal hemodynamics and oxygen delivery/consumption between sham-operated and septic animals at both 6- and 24-hour timepoints. In the live kidney slice model, mitochondrial dysfunction was seen in proximal tubular epithelial cells incubated with septic serum with increased production of reactive oxygen species, and decreases in nicotinamide adenine dinucleotide and mitochondrial membrane potential. These effects were prevented by coincubation with the reactive oxygen species scavenger, 4-hydroxy-2,2,6,6-tetramethyl-piperidin-1-oxyl. Conclusions: Renal dysfunction in sepsis occurs independently of hemodynamic instability or structural damage. Mitochondrial dysfunction mediated by circulating mediators that induce local oxidative stress may represent an important pathophysiologic mechanism.http://ift.tt/2HCzkjd
Delay Within the 3-Hour Surviving Sepsis Campaign Guideline on Mortality for Patients With Severe Sepsis and Septic Shock*
Objectives: To specify when delays of specific 3-hour bundle Surviving Sepsis Campaign guideline recommendations applied to severe sepsis or septic shock become harmful and impact mortality. Design: Retrospective cohort study. Setting: One health system composed of six hospitals and 45 clinics in a Midwest state from January 01, 2011, to July 31, 2015. Patients: All adult patients hospitalized with billing diagnosis of severe sepsis or septic shock. Interventions: Four 3-hour Surviving Sepsis Campaign guideline recommendations: 1) obtain blood culture before antibiotics, 2) obtain lactate level, 3) administer broad-spectrum antibiotics, and 4) administer 30 mL/kg of crystalloid fluid for hypotension (defined as "mean arterial pressure" 4). Measurements and Main Results: To determine the effect of t minutes of delay in carrying out each intervention, propensity score matching of "baseline" characteristics compensated for differences in health status. The average treatment effect in the treated computed as the average difference in outcomes between those treated after shorter versus longer delay. To estimate the uncertainty associated with the average treatment effect in the treated metric and to construct 95% CIs, bootstrap estimation with 1,000 replications was performed. From 5,072 patients with severe sepsis or septic shock, 1,412 (27.8%) had in-hospital mortality. The majority of patients had the four 3-hour bundle recommendations initiated within 3 hours. The statistically significant time in minutes after which a delay increased the risk of death for each recommendation was as follows: lactate, 20.0 minutes; blood culture, 50.0 minutes; crystalloids, 100.0 minutes; and antibiotic therapy, 125.0 minutes. Conclusions: The guideline recommendations showed that shorter delays indicates better outcomes. There was no evidence that 3 hours is safe; even very short delays adversely impact outcomes. Findings demonstrated a new approach to incorporate time t when analyzing the impact on outcomes and provide new evidence for clinical practice and research.http://ift.tt/2FUesGF
Culture-Negative Septic Shock Compared With Culture-Positive Septic Shock: A Retrospective Cohort Study
Objectives: To determine the clinical characteristics and outcomes of culture-negative septic shock in comparison with culture-positive septic shock. Design: Retrospective nested cohort study. Setting: ICUs of 28 academic and community hospitals in three countries between 1997 and 2010. Subjects: Patients with culture-negative septic shock and culture-positive septic shock derived from a trinational (n = 8,670) database of patients with septic shock. Interventions: None. Measurements and Main Results: Patients with culture-negative septic shock (n = 2,651; 30.6%) and culture-positive septic shock (n = 6,019; 69.4%) were identified. Culture-negative septic shock compared with culture-positive septic shock patients experienced similar ICU survival (58.3% vs 59.5%; p = 0.276) and overall hospital survival (47.3% vs 47.1%; p = 0.976). Severity of illness was similar between culture-negative septic shock and culture-positive septic shock groups ([mean and SD Acute Physiology and Chronic Health Evaluation II, 25.7 ± 8.3 vs 25.7 ± 8.1]; p = 0.723) as were serum lactate levels (3.0 [interquartile range, 1.7–6.1] vs 3.2 mmol/L [interquartile range, 1.8–5.9 mmol/L]; p = 0.366). As delays in the administration of appropriate antimicrobial therapy after the onset of hypotension increased, patients in both groups experienced congruent increases in overall hospital mortality: culture-negative septic shock (odds ratio, 1.56; 95% CI [1.47–1.66]; phttp://ift.tt/2FPxmyL
Early Identification of Acute Respiratory Distress Syndrome in the Absence of Positive Pressure Ventilation: Implications for Revision of the Berlin Criteria for Acute Respiratory Distress Syndrome
Objectives: To assess whether patients breathing spontaneously under standard oxygen could be recognized early as acute respiratory distress syndrome patients according to the current Berlin definition. Design: A post hoc analysis from two prospective studies. Setting: Twenty-three French ICUs. Patients: All patients admitted for acute hypoxemic respiratory failure and treated with noninvasive ventilation were analyzed. Patients with cardiogenic pulmonary edema, acute exacerbation of chronic obstructive pulmonary disease, or hypercapnia were excluded. Interventions: None. Measurements and Main Results: The PaO2/FIO2 ratio was estimated at admission under standard oxygen and then under noninvasive ventilation 1 hour after initiation and within the first 24 hours. Among the 219 patients treated with noninvasive ventilation for acute hypoxemic respiratory failure, 180 (82%) had bilateral infiltrates including 161 patients with PaO2/FIO2 less than or equal to 300 mm Hg under standard oxygen. Among them, 127 were treated with positive end-expiratory pressure of at least 5 cm H2O, and 120 (94%) fulfilled criteria for acute respiratory distress syndrome within the first 24 hours. The mortality rate of patients with bilateral infiltrates and PaO2/FIO2 less than or equal to 300 mm Hg under standard oxygen was 29%, a rate very close to that of intubated patients with acute respiratory distress syndrome in the Berlin definition. Conclusions: Almost all patients with pulmonary bilateral infiltrates and a PaO2/FIO2 less than or equal to 300 mm Hg under standard oxygen fulfilled the acute respiratory distress syndrome criteria under noninvasive ventilation within the first 24 hours. Their mortality rate was similar to that reported in the Berlin definition of acute respiratory distress syndrome. Therefore, spontaneous breathing patients with the acute respiratory distress syndrome criteria could be identified early without positive pressure ventilation.http://ift.tt/2FQTuIS
Temporal Trends in Healthcare Costs and Outcome Following ICU Admission After Traumatic Brain Injury
Objective: To assess temporal trends in 1-year healthcare costs and outcome of intensive care for traumatic brain injury in Finland. Design: Retrospective observational cohort study. Setting: Multicenter study including four tertiary ICUs. Patients: Three thousand fifty-one adult patients (≥ 18 yr) with significant traumatic brain injury treated in a tertiary ICU during 2003–2013. Intervention: None. Measurements and Main Results : Total 1-year healthcare costs included the index hospitalization costs, rehabilitation unit costs, and social security reimbursements. All costs are reported as 2013 U.S. dollars ($). Outcomes were 1-year mortality and permanent disability. Multivariate regression models, adjusting for case-mix, were used to assess temporal trends in costs and outcome in predefined Glasgow Coma Scale (3–8, 9–12, and 13–15) and age (18–40, 41–64, and ≥ 65 yr) subgroups. Overall 1-year survival was 76% (n = 2,304), and of 1-year survivors, 37% (n = 850) were permanently disabled. Mean unadjusted 1-year healthcare cost was $39,809 (95% CI, $38,144–$41,473) per patient. Adjusted healthcare costs decreased only in the Glasgow Coma Scale 13–15 and 65 years and older subgroups, due to lower rehabilitation costs. Adjusted 1-year mortality did not change in any subgroup (phttp://ift.tt/2DsoTfC
An Interpretable Machine Learning Model for Accurate Prediction of Sepsis in the ICU
Objectives: Sepsis is among the leading causes of morbidity, mortality, and cost overruns in critically ill patients. Early intervention with antibiotics improves survival in septic patients. However, no clinically validated system exists for real-time prediction of sepsis onset. We aimed to develop and validate an Artificial Intelligence Sepsis Expert algorithm for early prediction of sepsis. Design: Observational cohort study. Setting: Academic medical center from January 2013 to December 2015. Patients: Over 31,000 admissions to the ICUs at two Emory University hospitals (development cohort), in addition to over 52,000 ICU patients from the publicly available Medical Information Mart for Intensive Care-III ICU database (validation cohort). Patients who met the Third International Consensus Definitions for Sepsis (Sepsis-3) prior to or within 4 hours of their ICU admission were excluded, resulting in roughly 27,000 and 42,000 patients within our development and validation cohorts, respectively. Interventions: None. Measurements and Main Results: High-resolution vital signs time series and electronic medical record data were extracted. A set of 65 features (variables) were calculated on hourly basis and passed to the Artificial Intelligence Sepsis Expert algorithm to predict onset of sepsis in the proceeding T hours (where T = 12, 8, 6, or 4). Artificial Intelligence Sepsis Expert was used to predict onset of sepsis in the proceeding T hours and to produce a list of the most significant contributing factors. For the 12-, 8-, 6-, and 4-hour ahead prediction of sepsis, Artificial Intelligence Sepsis Expert achieved area under the receiver operating characteristic in the range of 0.83–0.85. Performance of the Artificial Intelligence Sepsis Expert on the development and validation cohorts was indistinguishable. Conclusions: Using data available in the ICU in real-time, Artificial Intelligence Sepsis Expert can accurately predict the onset of sepsis in an ICU patient 4–12 hours prior to clinical recognition. A prospective study is necessary to determine the clinical utility of the proposed sepsis prediction model.http://ift.tt/2FVinTR
Prevalence of Anxiety and Depression Symptomatology in Adolescents Faced With the Hospitalization of a Loved One in the ICU*
Objective: ICU experience is linked to anxiety and depression symptomatology in family members of patients. Minors may be forbidden from visiting. To bring practices in line with evidence, we determined the prevalence of anxiety and depression symptomatology in adolescents visiting a relative in the ICU. Design: One-year prospective observational monocenter study. Setting: Medical-surgical ICU, University Hospital of Martinique. Patients: Forty-one patients intubated for more than 2 days; 53 adolescents (12–17 yr) first- to third-degree relatives in regular contact (minimum once a month) with patient before hospitalization. Interventions: Adolescents with unrestricted ICU access completed a satisfaction survey, anxiety history questionnaire, and psychometric evaluation (Hospital Anxiety and Depression Scale) before the patient's 15th day of hospitalization and extubation. Measurements and Main Results: Forty adolescents (75.5%) visited their relative. Possible and probable anxiety and depression symptomatology prevalence was 35.9% and 18.9%, respectively, with no significant difference according to ICU visiting status. Most (80%) reported a lack of information, 40% insufficient consideration, and 27.5% misunderstood the reason for hospitalization. Two (5%) regretted visiting. Probable anxiety and depression symptomatology was associated with first-degree relationship (odds ratio, 9.1 [95% CI, 1.1–78.9]; p = 0.045), past exposure to a traumatic event (odds ratio, 8.7 [1.1–69.0]; p = 0.040) and past sense of threat (odds ratio, 10.4 [1.1–94.5]; p = 0.038). Conclusions: Anxiety and depression symptomatology is common in adolescent family members of ICU patients. An open visiting policy for adolescents is recommended, with visit planning, information meetings, and individual support from ICU staff.http://ift.tt/2HCFKyS
Impact of Tobacco Smoking on Mutational Landscape in HPV-Associated Oropharyngeal Cancer
Oropharyngeal cancer (OPC) is now the most common form of head and neck cancer in many western countries due to HPV. Patients with HPV-related (HPV+) OPC have clearly better outcomes after treatment. This has led to a strong wish to individualize treatment for these patients, aiming to minimize morbidity as well as to increase survival. However, patients with HPV+ OPC and a significant history of former or current tobacco smoking (HPV+ smokers) have increased risk of locoregional failure and increased cancer mortality after radiation therapy-based treatment than do non-smokers with HPV+ OPC.
http://ift.tt/2ItcnjC
Development of Care Pathway Models to Standardize and Optimally Integrate Multidisciplinary Services in the Management of Head and Neck Cancer
Multidisciplinary care is a cornerstone of head and neck cancer (HNC) management, with prior studies highlighting improved functional and survival outcomes when utilizing an integrated approach. While the National Comprehensive Cancer Network (NCCN) guidelines recommend that "all patients need access to the full range of support services and specialists with expertise" in the management of HNC, the timing and frequency of these interventions has not been clearly defined. The Care Pathway Model (CPM) is a clinical roadmap that defines and standardizes the patient care experience throughout treatment and survivorship, permitting predictable and consistent prescription of multidisciplinary services.
http://ift.tt/2Itcc7W
Apply an Oligometastatic Paradigm for Nodal Recurrence
Contemporary data show that patients with nodal involvement have potential for long-term survival (1, 2) and that radiation is associated with improved survival (3, 4). With new imaging techniques allowing accurate identification of sites of involvement, there is enthusiasm for potentially altering outcomes for oligometastatic disease (5). For this specific scenario, a small series albeit with limited follow-up suggests potential for positive outcomes (6); otherwise, the management of oligo-recurrent disease is an area of active clinical investigation (7).
http://ift.tt/2pew1Ha
Periocular Nonmelanoma Skin Cancers: Outcome in 86 Cases Treated With High Dose Rate Electronic Brachytherapy
To determine the clinical outcome of patients treated with radiation therapy for periocular nonmelanoma skin cancer (NMSC).
http://ift.tt/2IslBMU
Head and Neck Squamous Cell Carcinoma in Organ Transplant Recipients: A Single Institutional Experience
Immune suppression following solid organ transplantation with antimetabolites and other antirejection medications is a risk factor for the development of squamous cell carcinoma. While outcomes of cutaneous squamous cell cancers in organ transplant recipients (OTRs) have been reported, there is a paucity of such data in those patients who develop mucosal squamous cell carcinomas of the head and neck (HNSCC). We report the Cleveland Clinic experience with this patient population.
http://ift.tt/2Itc2NS
Primary (Chemo)Radiation Therapy Versus Surgery Followed by Adjuvant (Chemo)Radiation Therapy in Stage IVA (TNM 7th edition) Squamous Cell Carcinoma of the Tonsil
To compare the treatment outcome and toxicity between patients with stage IVA (TNM 7th edition) squamous cell carcinoma of the tonsil treated with either primary (chemo)radiation therapy or surgery followed by adjuvant (chemo)radiation therapy.
http://ift.tt/2pevVzi
In Reply to Hamstra
To the Editor: We appreciate the thoughtful letter by Dr Hamstra regarding our recent study "Value of elective radiation oncology rotations: how many is too many?" (1, 2). Anecdotal discussions with medical students at our institution support our report that many are pursuing multiple radiation oncology electives. This is often at the expense of other highly relevant opportunities in fields, such as, medical oncology, surgical oncology, radiology, otolaryngology, and nuclear medicine. We advise our medical students, as we do our residents, that we want them to become comprehensive physicians and oncologists.
http://ift.tt/2pcYSeU
WEE1 Kinase Inhibition Reverses DNA Damage Checkpoint Activation to Sensitize Oral Cancer Cells to Immunotherapy
Most head and neck cancers harbor genomically altered TP53, resulting in dependence on G2/M DNA damage checkpoint activation for cell cycle control. Here, we describe G2/M DNA damage checkpoint activation as a tumor cell intrinsic mechanism of resistance to cytotoxic T-lymphocyte (CTL) killing.
http://ift.tt/2InIQI2
A Dosimetric Comparison of Split-Field IMRT, Whole-Field IMRT, and Volumetric Modulated Arc Therapy for Patients With Early-Stage Tonsillar Cancer
Three of the most widely used techniques in the treatment of head and neck malignancies include split-field intensity-modulated radiation therapy (SF-IMRT) in which the low neck is treated with a single anterior-posterior beam matched above the glottis, whole-field IMRT (WF-IMRT) where the entire target volume is treated with a single IMRT plan using a static beam arrangement, and volumetric modulated arc therapy (VMAT). We have recently demonstrated that comparable laryngeal sparing in the setting of bilateral neck radiation can be achieved using all three techniques for the treatment of advanced oropharyngeal cancers.
http://ift.tt/2pcSPqU
Treatment Intensification for HPV-Unrelated Head and Neck Squamous Cell Carcinoma With Nab-Paclitaxel-Based Chemotherapy followed by Cisplatin and Radiation Therapy
In human papillomavirus (HPV)-unrelated head and neck squamous cell carcinoma (HNSCC), locoregional relapse (LRR) is the most common cause of treatment failure. Following cisplatin and radiation therapy (CisRT), the LRR rate at two years is 25%-35% (RTOG 0129, 0522, 91-11). We present our experience of treatment intensification for HPV-unrelated HNSCC with nab-paclitaxel-based chemotherapy followed by CisRT.
http://ift.tt/2peFrmc
Prognostic Factors Associated With Progression-Free Survival in Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma Treated With Induction Chemotherapy Followed By Chemoradiation Therapy
Chemoradiation therapy (CRT) is the standard of care for locally advanced head and neck squamous cell carcinoma (LAHNSCC). Induction chemotherapy (IC) with TPF (taxane, CDDP, FU) has shown benefit compared to PF (CDDP, FU), but its use is controversial. Response to IC may be associated with further response to CRT. We hypothesized that response to IC is an independent prognostic factor associated with PFS. Objective: to analyze the PFS of patients with LAHNSCC (larynx[L], hypopharynx[HP], oropharynx[OP], oral cavity[OC]), treated with IC followed by CRT, according to response to IC and CRT.
http://ift.tt/2Ip8hcc
TPF Induction Chemotherapy Prior to Chemoradiation for Locally Advanced Nasopharyngeal Carcinoma
Platinum-based chemoradiation (CRT) with or without adjuvant chemotherapy is considered standard treatment for locally advanced nasopharyngeal carcinoma (LA NPC). Recently, a large randomized trial reported overall survival benefit with TPF induction chemotherapy (IC) prior to CRT compared to CRT alone. We have used TPF IC prior to CRT selectively in patients (pts) with symptomatic LA NPC and report our outcomes with this approach.
http://ift.tt/2pevEwg
Treatment of Postoperative Chyle Fistulas With Octreotide: A Systematic Review
To systematically summarize and compare published data on the safety and efficacy of somatostatin or octreotide for the treatment of postsurgical chyle fistulas, with special attention paid to head and neck surgery.
http://ift.tt/2pevvJe
Posterior reversible encephalopathy syndrome (PRES) attributed to mycophenolate mofetil during the management of SLE: a case report and review.
| Related Articles |
Posterior reversible encephalopathy syndrome (PRES) attributed to mycophenolate mofetil during the management of SLE: a case report and review.
Am J Clin Exp Immunol. 2018;7(1):1-7
Authors: Zhang L, Xu J
Abstract
Posterior reversible encephalopathy syndrome (PRES) is a rare clinical entity associated with systemic lupus erythematosus which characterized by seizure, headache, and altered mental status. The pathophysiology involves subcortical vasogenic edema secondary to hypertension and endothelial damage. PRES is reversible with withdrawal of the offending agent, strict blood pressure control, and treating the underlying disease. We report present here a patient with lupus nephritis who developed PRES following mycophenolate administration.
PMID: 29531864 [PubMed]
http://ift.tt/2FQQImW
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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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