bluuebunny/crossref_metadata_2025 huggingface dataset:
The Clinicopathological Aspects of Primary Presacral Neuroendocrine Neoplasms
Authors: Yang Guoqing , Dhall Deepti , Yu Run , Tuli Richard , Amersi Farin F. , Friedman Marc L. , Nissen Nicholas N. , Hendifar Andrew E.
Published: December 2017

Objectives

Presacral neuroendocrine neoplasms (NENs) are rare entities that are found at the presacral space. We report our experience in the diagnosis, management, and outcomes of primary presacral NENs.

Methods

This was an institutional review board–approved retrospective review of medical records and surgical pathology specimens of patients with a diagnosis of NENs at Cedars-Sinai Medical Center between January 2000 and April 2016.

Results

Ten patients were identified. The median age at presentation was 38 years (range, 20–77 years), and 8 were women. One patient presented with carcinoid-like symptoms, 2 were diagnosed incidentally, and 7 presented with symptoms related to mass effect. The median size of the tumor was 7.0 cm (range, 3–12 cm). On pathologic review, 3 of 10 were low-grade and well-differentiated, 5 of 10 were intermediate-grade and well-differentiated, 2 of 10 were grade 3 and classified as high-grade and poorly differentiated neuroendocrine tumors. Seven cases were metastatic on presentation with lymph node, liver, lung, or skeletal metastasis. Seven of 8 cases were detectable using Octreoscan. Eight patients were treated with a somatostatin analog and 5 patients were treated surgically.

Conclusions

Presacral NENs are clinically similar to gastroenteropancreatic tumors. Octreoscan imaging and somatostatin analog therapies were frequently applied. Further biologic characterization of this rare subtype is needed.
Comparison of Various Scoring Systems and Biochemical Markers in Predicting the Outcome in Acute Pancreatitis
Authors: Vasudevan Sreejith , Goswami Pooja , Sonika Ujjwal , Thakur Bhaskar , Sreenivas Vishnubhatla , Saraya Anoop
Published: December 2017

Objective

Early risk assessment is important in acute pancreatitis (AP). The primary objective of this study was to compare various scores and biochemical markers done on the day of admission in predicting the outcome.

Methods

Demographic, clinical, and laboratory data of patients presenting within 2 weeks of onset were collected. Various scores were calculated and biochemical markers were measured on the day of admission. Optimum cutoffs were identified through receiver operating curve analysis. Multivariate analysis was used to identify predictors of outcome.

Results

Of 343 patients included, 202 (59%) were male; mean (SD) age was 38.7 (15.5) years. Acute pancreatitis was severe in 170 (49.6%) patients. Twenty-eight percent of the patients developed infected pancreatic necrosis and 18% died. An Acute Physiology and Chronic Health Evaluation (APACHE II) score of at least 7, bedside index for severity of AP (BISAP) of at least 2, systemic inflammatory response syndrome score of at least 3, and C-reactive protein of at least 82 ng/mL predicted severity. Predictors of infected pancreatic necrosis were as follows: PANC 3 score of at least 1, BISAP score of at least 2, and Marshall score of at least 2, whereas C-reactive protein of greater than 98, BISAP score of at least 2, APACHE score of at least 10, and a blood urea nitrogen of at least 17 predicted mortality.

Conclusions

Both BISAP and APACHE II are comparable in predicting outcome, but BISAP predicted all 3 outcomes with the same cutoff and hence is a robust scoring system.
The Insulin Receptor Is Colocalized With the TRPV1 Nociceptive Ion Channel and Neuropeptides in Pancreatic Spinal and Vagal Primary Sensory Neurons
Authors: Lázár Bence András , Jancsó Gábor , Oszlács Orsolya , Nagy István , Sántha Péter
Published: December 2017

Objectives

Recent observations demonstrated the expression of the insulin receptor (InsR) and its functional interaction with the transient receptor potential vanilloid type 1 receptor (TRPV1) in sensory ganglion neurons. Because sensory nerves are implicated in pancreatic inflammatory processes, we studied the colocalization of the InsR with TRPV1 and proinflammatory neuropeptides in spinal and vagal pancreatic afferent neurons.

Methods

Immunohistochemistry and quantitative morphometry were used to analyze the expression of TRPV1, InsR, substance P (SP), and calcitonin gene-related peptide (CGRP) in retrogradely labeled pancreatic dorsal root ganglion (DRG) and nodose ganglion (NG) neurons.

Results

The proportions of retrogradely labeled pancreatic TRPV1-, InsR-, SP-, and CGRP-immunoreactive neurons amounted to 68%, 48%, 33%, and 54% in DRGs and 64%, 49%, 40%, and 25% in the NGs. Of the labeled DRG and NG neurons, 23% and 35% showed both TRPV1 and InsR immunoreactivity. Colocalization of the InsR with SP or CGRP was demonstrated in 14% and 28% of pancreatic DRG and 24% and 8% of pancreatic NG neurons.

Conclusions

The present findings provide morphological basis for possible functional interactions among the nociceptive ion channel TRPV1, the InsR, and the proinflammatory neuropeptides SP and CGRP expressed by pancreatic DRG and NG neurons.
Corticosteroids for Preventing Caustic Esophageal Strictures
Authors: Katibe Raji , Abdelgadir Ibtihal , McGrogan Paraic , Akobeng Anthony K.
Published: December 2017

Objectives:

Caustic ingestion can have a complicated clinical course. Corticosteroids are widely used but there is uncertainty about its role in preventing esophageal stricture formation following caustic ingestion. This systematic review and meta‐analysis assessed the available clinical evidence regarding the efficacy and safety of corticosteroids for preventing esophageal strictures following caustic injury.

Methods:

We assessed randomized controlled trials (RCTs) that compared corticosteroids versus no corticosteroids in the prevention of esophageal stricture formation following caustic ingestion. We searched the following databases from inception to March 2017: PubMed, Embase, and the Cochrane Central Register of Controlled Trials. Two reviewers retrieved eligible articles, assessed risk of bias, and performed data extraction. The main outcome measure was the prevention of esophageal stricture formation.

Results:

The search identified 763 citations. Three RCTs involving 244 participants met the inclusion criteria. There was no benefit of corticosteroids in the prevention of esophageal strictures following the ingestion of caustic materials (risk ratio [RR] = 0.63, 95% CI = 0.29–1.37).

Conclusions:

The available evidence does not support the use of corticosteroids for the prevention of esophageal strictures following caustic ingestion. The overall quality of the evidence is limited because of methodological weaknesses and small sample sizes in the primary studies.
Hydrolyzed Formula With Reduced Protein Content Supports Adequate Growth
Authors: Ahrens Birgit , Hellmuth Christian , Haiden Nadja , Olbertz Dirk , Hamelmann Eckard , Vusurovic Milica , Fleddermann Manja , Roehle Robert , Knoll Anette , Koletzko Berthold , Wahn Ulrich , Beyer Kirsten
Published: December 2017

Objective:

A high protein content of nonhydrolyzed infant formula exceeding metabolic requirements can induce rapid weight gain and obesity. Hydrolyzed formula with too low protein (LP) content may result in inadequate growth. The aim of this study was to investigate noninferiority of partial and extensively hydrolyzed formulas (pHF, eHF) with lower hydrolyzed protein content than conventionally, regularly used formulas, with or without synbiotics for normal growth of healthy term infants.

Methods:

In an European multi‐center, parallel, prospective, controlled, double‐blind trial, 402 formula‐fed infants were randomly assigned to four groups: LP‐formulas (1.9 g protein/100 kcal) as pHF with or without synbiotics, LP‐eHF formula with synbiotics, or regular protein eHF (2.3 g protein/100 kcal). One hundred and one breast‐fed infants served as observational reference group. As primary endpoint, noninferiority of daily weight gain during the first 4 months of life was investigated comparing the LP‐group to a regular protein eHF group.

Results:

A comparison of daily weight gain in infants receiving LPpHF (2.15 g/day CI −0.18 to inf.) with infants receiving regular protein eHF showed noninferior weight gain (−3.5 g/day margin; per protocol [PP] population). Noninferiority was also confirmed for the other tested LP formulas. Likewise, analysis of metabolic parameters and plasma amino acid concentrations demonstrated a safe and balanced nutritional composition. Energetic efficiency for growth (weight) was slightly higher in LPeHF and synbiotics compared with LPpHF and synbiotics.

Conclusions:

All tested hydrolyzed LP formulas allowed normal weight gain without being inferior to regular protein eHF in the first 4 months of life. This trial was registered at clinicaltrials.gov, NCT01143233.
Primary Epithelioid Angiosarcoma of Finger Masquerading as Epithelioid Hemangioma: Report of a Case and Analysis of Mutational Pattern in Epithelioid Hemangiomas and Angiosarcomas by Next-generation Sequencing
Authors: Subramaniam Manish M. , Salleh Nur L. , Wu Bingcheng , Rozario Michelle A. , Lim HueyJin , Puhaindran Mark E. , Soong Richie , Lee Victor K.
Published: December 2017

Aims:

We report an unusual case of epithelioid angiosarcoma (AS) mimicking an epithelioid hemangioma (EH) and analyze mutational patterns in EHs and ASs.

Methods and Results:

A 58-year-old woman presented with a finger lump and metastatic lung nodules. Initial needle biopsies showed an EH, with only focal atypical histologic features. The patient underwent finger amputation and resection of lung nodules. The amputation specimen and lung nodules revealed features of AS. Fluorescence in situ hybridization for FOS and FOSB gene rearrangements were negative in the primary tumor as well as in the lung metastasis. Intrigued by the unique morphologic features of an AS masquerading as an EH, we expanded our study by analyzing mutations in EHs versus ASs using a targeted next-generation sequencing of 50 cancer-related genes. Seven EHs and 6 ASs including the present case were subjected to mutation analysis using the Ion AmpliSeq Cancer Hotspot Panel v2 assay of 50 cancer-related genes. The present case lacked mutation. Novel somatic variants were detected in 2 of 7 EHs and 1 of 6 ASs. Sorting intolerant from tolerant and polymorphism phenotyping analysis revealed benign/tolerated and deleterious variants in both tumor types. Deleterious variants TP53 c.707T>C (p.Tyr236Cys), FLT3 c.1995C>T (p.Met665Ile), and SMO c.1919C>T (p.Thr640Ile) were detected in EH, while AS revealed deleterious variant PTPN11 c.226G>A (p.Glu76Lys).

Conclusions:

We present an epithelioid AS mimicking EH. We report novel somatic variants in EHs and AS. Benign variants may not be associated with development of these tumors. Whereas, deleterious variants, especially PTPN11 c.226G>A, may be linked to tumorigenesis of AS.
Distributions and Behavior of Vital Signs in Critically Ill Children by Admission Diagnosis*
Authors: Eytan Danny , Goodwin Andrew J. , Greer Robert , Guerguerian Anne-Marie , Mazwi Mjaye , Laussen Peter C.
Published: December 2017

Objectives:

Define the distributions of heart rate and intraarterial blood pressure in children at admission to an ICU based on admission diagnosis and examine trends in these physiologic signs over 72 hours from admission (or to discharge if earlier).

Design:

A retrospective analysis of continuously acquired signals.

Setting:

A quaternary and primary referral children’s hospital with a general PICU and cardiac critical care unit.

Patients:

One thousand two hundred eighty-nine patients less than 18 years old were analyzed. Data from individual patient admissions were divided into 19 groups by primary admission diagnosis or surgical procedure.

Interventions:

None.

Measurement and Main Results:

Distributions at admission are dependent on patient age and admission diagnosis (p < 10–6). Heart rate decreases over time, whereas arterial blood pressure is relatively stable, with differences seen in the directions and magnitude of these trends when analyzed by diagnosis group (p < 10–6). Multiple linear regression analysis shows that patient age, diagnosis group, and physiologic vital sign value at admission explain 50–63% of the variation observed for that physiologic signal at 72 hours (or at discharge if earlier) with admission value having the greatest influence. Furthermore, the variance of either heart rate or arterial blood pressure for the individual patient is smaller than the variance measured at the level of the group of patients with the same diagnosis.

Conclusions:

This is the first study reporting distributions of continuously measured physiologic variables and trends in their behavior according to admission diagnosis in critically ill children. Differences detected between and within diagnostic groups may aid in earlier recognition of outliers as well as allowing refinement of patient monitoring strategies.
The CGRP receptor antagonist BIBN4096 inhibits prolonged meningeal afferent activation evoked by brief local K+ stimulation but not cortical spreading depression-induced afferent sensitization
Authors: Zhao Jun , Levy Dan
Published: December 2017

Abstract

Introduction:

Cortical spreading depression (CSD) is believed to promote migraine headache by enhancing the activity and mechanosensitivity of trigeminal intracranial meningeal afferents. One putative mechanism underlying this afferent response involves an acute excitation of meningeal afferents by cortical efflux of K+ and the ensuing antidromic release of proinflammatory sensory neuropeptides, such as calcitonin gene-related peptide (CGRP).

Objectives:

We sought to investigate whether (1) a brief meningeal K+ stimulus leads to CGRP-dependent enhancement of meningeal afferent responses and (2) CSD-induced meningeal afferent activation and sensitization involve CGRP receptor signaling.

Methods:

Extracellular single-unit recording were used to record the activity of meningeal afferents in anesthetized male rats. Stimulations included a brief meningeal application of K+ or induction of CSD in the frontal cortex using pinprick. Cortical spreading depression was documented by recording changes in cerebral blood flow using laser Doppler flowmetery. Calcitonin gene-related peptide receptor activity was inhibited with BIBN4096 (333 μM, i.v.).

Results:

Meningeal K+ stimulation acutely activated 86% of the afferents tested and also promoted in ∼65% of the afferents a 3-fold increase in ongoing activity, which was delayed by 23.3 ± 4.1 minutes and lasted for 22.2 ± 5.6 minutes. K+ stimulation did not promote mechanical sensitization. Pretreatment with BIBN4096 suppressed the K+-induced delayed afferent activation, reduced CSD-evoked cortical hyperemia, but had no effect on the enhanced activation or mechanical sensitization of meningeal afferents following CSD.

Conclusion:

While CGRP-mediated activation of meningeal afferents evoked by cortical efflux of K+ could promote headache, acute activation of CGRP receptors may not play a key role in mediating CSD-evoked headache.
18F-FDG PET/CT Findings of Mesenchymal Chondrosarcoma of the Orbit
Authors: Tsuchiya Mitsuteru , Masui Takayuki , Otsuki Yoshiro , Sakahara Harumi
Published: December 2017

Mesenchymal chondrosarcoma of the orbit is an extremely rare and aggressive tumor. We report image findings of 18F-fluorodeoxyglucose (FDG) positron emission/computed tomography (PET/CT) in 2 cases, one primary case and one recurrent case. The 18F-FDG PET/CT images revealed high uptake with an SUVmax of 6.7 and 11.7, respectively. In both cases, the HEY1-CoA2 gene fusion was positive. The high uptake of 18F-FDG in mesenchymal chondrosarcoma of the orbit well suggests the malignancy of this tumor.
Isolated Multinodular Soft-Tissue Rosai-Dorfman Disease on FDG PET/CT
Authors: Pucar Darko , Laskin William B. , Saperstein Lawrence
Published: December 2017

Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) is a rare systemic histiocytic disorder of unknown etiology characterized by the accumulation of enlarged non-Langerhans histiocytes within lymph nodes and extranodal sites. The histiocytes display characteristic emperipolesis (nondestructive engulfment of inflammatory cells) and are CD68 and S100 positive and CD1a negative. Although extranodal disease frequently occurs with nodal involvement, isolated extranodal disease is uncommon. We report a case of isolated localized subcutaneous multinodular disease on FDG PET/CT. We also include a companion classic Rosai-Dorfman case with extensive nodal involvement and a characteristic benign clinical course with spontaneous improvement.
Epstein-Barr Virus–Associated Hemophagocytic Lymphohistiocytosis Mimicking Lymphoma on FDG PET/CT
Authors: Pan Qingqing , Luo Yaping , Wu Huanwen , Ma Yanru , Li Fang
Published: December 2017

A 15-year-old boy with fever, pancytopenia, and hepatosplenomegaly was diagnosed as hemophagocytic lymphohistiocytosis (HLH). 18F-FDG PET/CT showed hypermetabolic foci in the liver, spleen, and bone marrow, as well as multiple FDG-avid lymph nodes, which were highly suggestive of lymphoma. Specimens from splenectomy depicted a large number of macrophages/histiocytes with hemophagocytosis of erythrocytes, without evidence of malignancy. Considering increased Epstein-Barr virus (EBV) DNA in peripheral blood and positive staining for EBV-encoded RNA in the spleen, EBV-associated HLH was confirmed. This case indicates that FDG-avid foci in the liver, spleen, and bone marrow may also be seen in EBV-associated HLH.
The Americleft Project: Comparison of Ratings Using Two-Dimensional Versus Three-Dimensional Images for Evaluation of Nasolabial Appearance in Patients With Unilateral Cleft Lip and Palate
Authors: Jones Christine M. , Roth Benjamin , Mercado Ana M. , Russell Kathy A. , Daskalogiannakis John , Samson Thomas D. , Hathaway Ronald R. , Smith Andrea , Mackay Donald R. , Long Ross E.
Published: December 2017

This study was conducted to determine if nasolabial appearance is rated with comparable results and reliability on 3-dimensional stereophotogrammetric facial images versus standard clinical photographs (2-dimensional). Twenty-seven consecutively treated patients with repaired complete unilateral cleft lip and palate were selected. Six trained and calibrated raters assessed cropped 2- and 3-dimensional facial images. Nasolabial profile, nasolabial frontal, and vermillion border esthetics were rated with the 5-point scale described by Asher-McDade using the modified Q-sort method. Cropped 3-dimensional images were available for viewing by each rater, allowing for complete rotational control for viewing the images from all aspects. Two- and three-dimensional ratings were done separately and repeated the next day.

Interrater reliability scores were good for 2-dimensional (κ = 0.607–0.710) and fair to good for 3-dimensional imaging (κ = 0.374–0.769). Intrarater reliability was good to very good for 2-dimensional (κ = 0.749–0.836) and moderate to good for 3-dimensional imaging (κ = 0.554–0.855). Bland–Altman analysis showed satisfactory agreement of 2- and 3-dimensional scores for nasolabial profile and nasolabial frontal, but more systematic error occurred in the assessment of vermillion border.

Although 3-dimensional images may be perceived as more representative of a direct clinical facial evaluation, their use for subjective rating of nasolabial aesthetics was not more reliable than 2-dimensional images in this study. Conventional 2-dimensional images provide acceptable reliability while being readily accessible for most cleft palate centers.
Predicting Intestinal Adaptation in Pediatric Intestinal Failure
Authors: Belza Christina , Fitzgerald Kevin , de Silva Nicole , Avitzur Yaron , Steinberg Karen , Courtney-Martin Glenda , Wales Paul W.
Published: December 2017

Objective:

The primary goal in intestinal failure (IF) is adaptation and enteral autonomy (EA). Our goals were to determine the proportion of patients treated for IF by an established intestinal rehabilitation program who achieved EA and to assess the predictors of EA.

Background:

There have been considerable advancements in the management of IF over the last 15 years, children with short bowel syndrome with a reduction in mortality. Several studies have discussed variables that may influence the ability to attain EA; however, majority were written when mortality rates were considerably higher compared with the current contemporary experience.

Methods:

A retrospective analysis of infants <12 months with short bowel syndrome referred between 2006 and 2013 (n = 120). Data was collected on IF-related factors and nutritional intake. The cohort was stratified based on achievement of EA. Statistical testing completed using t test, Chi Square, and Cox Proportional Hazards regression (P < 0.05).

Results:

EA was achieved in 84 (70.0%) patients. Patients who remained parenteral nutrition dependent were more likely to have volvulus (1.2 vs 22.2%, P < 0.001), shorter percent residual small bowel (29.4 vs 68.6%; P < 0.0001) and colon length (64.6 vs 86.0%; P = 0.001), and no ileocecal valve (61.1 vs 29.8%; P = 0.05). Mortality was also decreased in those who achieved EA (4 vs 22%; P = 0.004). Percent residual small bowel (HR = 1.03; 95% CI 1.02–1.03) and colon (HR = 1.01; 95% CI 1.00–1.02) length were positively associated with EA, while number of septic episodes was negatively associated (HR = 0.95; 95% CI 0.91–0.99).

Conclusion:

Seventy percent of infants with IF achieved EA. Residual small and large bowel length were the most important predictors of EA and septic events had a negative impact.
Benchmarking Complications Associated with Esophagectomy
Authors: Low Donald E. , Kuppusamy Madhan Kumar , Alderson Derek , Cecconello Ivan , Chang Andrew C. , Darling Gail , Davies Andrew , D’Journo Xavier Benoit , Gisbertz Suzanne S. , Griffin S. Michael , Hardwick Richard , Hoelscher Arnulf , Hofstetter Wayne , Jobe Blair , Kitagawa Yuko , Law Simon , Mariette Christophe , Maynard Nick , Morse Christopher R. , Nafteux Philippe , Pera Manuel , Pramesh C. S. , Puig Sonia , Reynolds John V. , Schroeder Wolfgang , Smithers Mark , Wijnhoven B. P. L.
Published: December 2017

Objective:

Utilizing a standardized dataset with specific definitions to prospectively collect international data to provide a benchmark for complications and outcomes associated with esophagectomy.

Summary of Background Data:

Outcome reporting in oncologic surgery has suffered from the lack of a standardized system for reporting operative results particularly complications. This is particularly the case for esophagectomy affecting the accuracy and relevance of international outcome assessments, clinical trial results, and quality improvement projects.

Methods:

The Esophageal Complications Consensus Group (ECCG) involving 24 high-volume esophageal surgical centers in 14 countries developed a standardized platform for recording complications and quality measures associated with esophagectomy. Using a secure online database (ESODATA.org), ECCG centers prospectively recorded data on all resections according to the ECCG platform from these centers over a 2-year period.

Results:

Between January 2015 and December 2016, 2704 resections were entered into the database. All demographic and follow-up data fields were 100% complete. The majority of operations were for cancer (95.6%) and typically located in the distal esophagus (56.2%). Some 1192 patients received neoadjuvant chemoradiation (46.1%) and 763 neoadjuvant chemotherapy (29.5%). Surgical approach involved open procedures in 52.1% and minimally invasive operations in 47.9%. Chest anastomoses were done most commonly (60.7%) and R0 resections were accomplished in 93.4% of patients. The overall incidence of complications was 59% with the most common individual complications being pneumonia (14.6%) and atrial dysrhythmia (14.5%). Anastomotic leak, conduit necrosis, chyle leaks, recurrent nerve injury occurred in 11.4%, 1.3%, 4.7%, and 4.2% of cases, respectively. Clavien-Dindo complications ≥ IIIb occurred in 17.2% of patients. Readmissions occurred in 11.2% of cases and 30- and 90-day mortality was 2.4% and 4.5%, respectively.

Conclusion:

Standardized methods provide contemporary international benchmarks for reporting outcomes after esophagectomy.
PD-L1 Expression, Tumor-infiltrating Lymphocytes, and Clinical Outcome in Patients With Surgically Resected Esophageal Cancer
Authors: Yagi Taisuke , Baba Yoshifumi , Ishimoto Takatsugu , Iwatsuki Masaaki , Miyamoto Yuji , Yoshida Naoya , Watanabe Masayuki , Baba Hideo
Published: December 2017

Objectives:

To examine the prognostic impact of the programmed death ligand 1 (PD-L1) expression, tumor-infiltrating lymphocyte (TIL) status, and their combination in esophageal cancer.

Summary Background Data:

PD-L1 has garnered much attention for its roles in tumor immunology and as an immune-based therapeutic target. To ensure a response to PD-L1 checkpoint inhibitor, a new framework based on PD-L1 expression and the presence or absence of TILs is required.

Methods:

Using a nonbiased database of 305 curatively resected esophageal cancers, we evaluated PD-L1 expression and TIL status (cluster of differentiation 8 (CD8) expression) by immunohistochemical analysis. The Cox proportional hazard model was used to compute the hazard ratio (HR) for mortality.

Results:

Compared with PD-L1 negative cases (n=252), PD-L1 positive cases (n = 53) showed significantly worse overall survival [log-rank P = 0.016; HR: 1.71; 95% confidence interval: 1.08–2.61; P = 0.024; multivariate HR: 1.69; 95% confidence interval: 1.05–2.67; P = 0.033]. TIL positivity was significantly correlated with longer overall survival (log-rank P < 0.0001) and high CD8 expression (P < 0.0001). A stratification based on PD-L1 expression and TIL status was also significantly associated with overall survival (log rank P < 0.0001).

Conclusions:

PD-L1 expression was associated with an unfavorable clinical outcome in esophageal cancer, supporting its role as a prognostic biomarker. In addition, the combination with TIL status enabled further classification patients according to clinical outcome. PD-L1 expression and TIL status may serve as predictive tissue biomarkers and can be used for patient selection in clinical trials of drugs targeting the PD-1/PD-L1 pathways.
Thirst in heart failure: what do we know so far?
Authors: Allida Sabine M. , Hayward Christopher S. , Newton Phillip J.
Published: December 2017

Purpose of review

Thirst is a common and burdensome symptom of heart failure, which impacts adversely on quality of life. To date, there is limited research on the prevalence of thirst, the factors associated with thirst and interventions to help manage thirst in heart failure. This review summarizes key empirical research developments of thirst.

Recent findings

Recent research shows that the heart failure syndrome, medications, self-care practice such as fluid restriction and anxiety contributes greatly to increased thirst in patients with heart failure. In addition, predictors such as being younger, male patient, with high symptom burden and serum urea is also associated with thirst. There are no intervention studies to manage thirst, only reports of various strategies recommended to heart failure patients in clinical practice.

Despite the burden of thirst in heart failure patients, strategies to relieve thirst remains insufficiently addressed in literature. Further research to improve the understanding of the severity of thirst and its relationship to possible factors associated with thirst is required in order to develop future interventions to either prevent or alleviate troublesome thirst in patients with heart failure.
Palliative care needs assessment in chronic heart failure
Authors: Janssen Daisy J.A. , Johnson Miriam J. , Spruit Martijn A.
Published: December 2017

Purpose of review

The unmet palliative care needs of patients with chronic heart failure (CHF) are well known. Palliative care needs assessment is paramount for timely provision of palliative care. The present review provides an overview of palliative care needs assessment in patients with CHF: the role of prognostic tools, the role of the surprise question, and the role of palliative care needs assessment tools.

Recent findings

Multiple prognostic tools are available, but offer little guidance for individual patients. The surprise question is a simple tool to create awareness about a limited prognosis, but the reliability in CHF seems less than in oncology and further identification and assessment of palliative care needs is required. Several tools are available to identify palliative care needs. Data about the ability of these tools to facilitate timely initiation of palliative care in CHF are lacking.

Several tools are available aiming to facilitate timely introduction of palliative care. Focus on identification of needs rather than prognosis appears to be more fitting for people with CHF. Future studies are needed to explore whether and to what extent these tools can help in addressing palliative care needs in CHF in a timely manner.
Caregiver anticipatory grief: phenomenology, assessment and clinical interventions
Authors: Coelho Alexandra , de Brito Maja , Barbosa António
Published: December 2017

Purpose of review

This review aims to synthesize recent findings on anticipatory grief in caregivers, referring to its phenomenology, assessment and clinical interventions.

Recent findings

Recent literature illustrates the wide scope of the current use of the term anticipatory grief, reflecting caregivers’ experiences in different end-of-life trajectories. The anticipation of death is the distinctive aspect of anticipatory grief in the predeath grief continuum, encompassing several progressive losses, past and future. Recently developed assessment instruments capture key aspects of this experience, such as separation anxiety, anticipation of death and future absence of the person, denial and relational losses. Recent findings on prevalence of clinically significant predeath symptoms in caregivers range from 12.5 to 38.5%. Beyond personal and relational factors, difficult circumstances of end-of-life care significantly interfere in adjustment to anticipatory grief. Useful therapeutic interventions were identified, such as validation of grief feelings, increased coping and self-care, anticipation of future losses and reframing roles. However, rigorous interventional studies are needed to create guidelines and the manualization of specific therapeutic approaches to caregiver anticipatory grief.

Findings suggest that anticipatory grief dynamics in different end-of-life trajectories should be recognized and adequately assessed. Clinical interventions considered useful to support anticipatory grief caregivers are presented, but further research is needed to verify effectiveness.
Heat shock proteins and cancer: intracellular chaperones or extracellular signalling ligands?
Authors: Calderwood Stuart K.
Published: December 2017

Heat shock proteins (HSPs) are found at elevated concentrations in tumour cells, and this increase reflects the proteotoxic stress experienced by the cells due to expanding levels of the mutated oncoproteins that drive tumorigenesis. The protection of oncogenic proteins by HSPs offers a window of vulnerability in tumour metabolism that has been exploited using Hsp90-targeting drugs. Such compounds have been shown to cause inhibition and degradation of a wide range of proteins essential for oncogenesis. Recently, Hsp90 has also been shown to be secreted by tumour cells and to interact in autocrine or paracrine manners with the surfaces of adjacent cells, leading to increased growth and metastasis. Future studies will address a number of key questions associated with these findings, including the relative importance of intracellular versus extracellular HSPs in tumorigenesis, as well as overcoming potential problems with normal tissue toxicity associated with Hsp90 drugs. Targeting individual members of HSP families and inactivating extracellular HSPs may be desirable future approaches that offer increased selectivity in targeting HSPs in cancer.

This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.
Membrane heat shock protein 70: a theranostic target for cancer therapy
Authors: Shevtsov Maxim , Huile Gao , Multhoff Gabriele
Published: December 2017

Members of the 70 kDa stress protein family are found in nearly all subcellular compartments of nucleated cells where they fulfil a number of chaperoning functions. Heat shock protein 70 (HSP70), also termed HSPA1A, the major stress-inducible member of this family is overexpressed in a large variety of different tumour types. Apart from its intracellular localization, a tumour-selective HSP70 membrane expression has been determined. A membrane HSP70–positive tumour phenotype is associated with aggressiveness and therapy resistance, but also serves as a recognition structure for targeted therapies. Furthermore, membrane-bound and extracellularly residing HSP70 derived from tumour cells play pivotal roles in eliciting anti-tumour immune responses. Herein, we want to shed light on the multiplicity of different activities of HSP70, depending on its intracellular, membrane and extracellular localization with the goal to use membrane HSP70 as a target for novel therapies including nanoparticle-based approaches for the treatment of cancer.

This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.
Immune tolerance therapies for autoimmune diseases based on heat shock protein T-cell epitopes
Authors: van Eden Willem
Published: December 2017

Experimental models of autoimmune diseases have revealed the disease protective role of heat shock proteins (HSPs). Both the administration of exogenous extracellular, mostly recombinant, HSP and the experimental co-induction of endogenous intracellular HSP in models have been shown to lead to production of disease protective regulatory T cells (Tregs). Similar to HSP taken up from extracellular bodily fluids, due to stress-related autophagy upregulated HSP also from intracellular sources is a major provider for the major histocompatibility class II (MHCII) ligandome; therefore, both extracellular and intracellular HSP can be prominent targets of Treg. The development of therapeutic peptide vaccines for the restoration of immune tolerance in inflammatory diseases is an area of intensive research. In this area, HSPs are a target for tolerance-inducing T-cell therapy, because of their wide expression in inflamed tissues. In humans, in whom the actual disease trigger is frequently unknown, HSP peptides offer chances for tolerance-promoting interventions through induction of HSP-specific Treg. Recently, we have shown the ability of a bacterial HSP70-derived peptide, HSP70-B29, to induce HSP-specific Tregs that suppressed arthritis by cross-recognition of their mammalian HSP70 homologues, abundantly present in the MHCII ligandome of stressed mouse and human antigen-presenting cells in inflamed tissues.

This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.
Real-time halo correction in phase contrast imaging
Authors: Kandel Mikhail E. , Fanous Michael , Best-Popescu Catherine , Popescu Gabriel
Published: December 2017

As a label-free, nondestructive method, phase contrast is by far the most popular microscopy technique for routine inspection of cell cultures. Yet, features of interest such as extensions near cell bodies are often obscured by a glow, which came to be known as the halo. Advances in modeling image formation have shown that this artifact is due to the limited spatial coherence of the illumination. Yet, the same incoherent illumination is responsible for superior sensitivity to fine details in the phase contrast geometry. Thus, there exists a trade-off between high-detail (incoherent) and low-detail (coherent) imaging systems. In this work, we propose a method to break this dichotomy, by carefully mixing corrected low-frequency and high-frequency data in a way that eliminates the edge effect. Specifically, our technique is able to remove halo artifacts at video rates, requiring no manual interaction ora prioripoint spread function measurements. To validate our approach, we imaged standard spherical beads, sperm cells, tissue slices, and red blood cells. We demonstrate the real-time operation with a time evolution study of adherent neuron cultures whose neurites are revealed by our halo correction. We show that with our novel technique, we can quantify cell growth in large populations, without the need for thresholds and calibration.
A 16S rRNA gene sequencing and analysis protocol for the Illumina MiniSeq platform
Authors: Pichler Monica , Coskun Ömer K. , Ortega Ana Sofia , Conci Nicola , Wörheide Gert , Vargas Sergio , Orsi William D.
Published: December 2017

High-throughput sequencing of the 16S rRNA gene is widely used in microbial ecology, with Illumina platforms being widely used in recent studies. The MiniSeq, Illumina’s latest benchtop sequencer, enables more cost-efficient DNA sequencing relative to larger sequencing platforms (e.g. MiSeq). Here we used a modified custom primer sequencing approach to test the fidelity of the MiniSeq for high-throughput sequencing of the V4 hypervariable region of 16S rRNA genes from complex communities in environmental samples. To this end, we designed an additional sequencing primer that enabled application of a dual-index barcoding method on the MiniSeq. A mock community was sequenced alongside the environmental samples as a quality control benchmark. After careful filtering procedures, we were able to recapture a realistic richness of the mock community, and identify meaningful differences in alpha and beta diversity in the environmental samples. These results show that the MiniSeq can produce similar quantities of high quality V4 reads compared to the MiSeq, yet is a cost-effective option for any laboratory interested in performing high-throughput 16S rRNA gene sequencing.

IMPORTANCE

We modified a custom sequencing approach and used a mock community to test the fidelity of high-throughput sequencing on the Illumina MiniSeq platform. Our results show that the MiniSeq can produce similar quantities of high quality V4 reads compared to the MiSeq. In addition, our protocol increases feasibility for small laboratories to perform their own high-throughput sequencing of the 16S rRNA marker gene.
A myopic perspective on the future of protein diagnostics
Authors: Landegren Ulf , Al-Amin Rasel A. , Björkesten Johan
Published: December 2017

Plasma proteome analyses of the future promise invaluable insights into states of health, not only by measuring proteins whose role it is to ensure blood homeostasis, but increasingly also as a window into the health of practically any tissue in the body via so-called leakage protein biomarkers. Realizing more of this vast potential will require progress along many lines. Here we discuss the main ones, such as optimal selection of target proteins, affinity reagents, immunoassay formats, samples, and applications, with a view from ongoing work in our laboratory.
Suppression of the dihydrolipoamide dehydrogenase gene (dld-1) protects against the toxicity of human amyloid beta inC. elegansmodel of Alzheimer’s disease
Authors: Ahmad Waqar
Published: December 2017

Declines in energy metabolism and associated mitochondrial enzymes are linked to the progression of Alzheimer’s disease (AD). Dihydrolipoamide dehydrogenase (dld) and two of its enzyme complexes namely, pyruvate dehydrogenase and α-ketoglutarate dehydrogenase are associated with AD and have a significant role in energy metabolism. Interestingly,dldgene variants are genetically linked to late-onset AD; and reduced activity of DLD-containing enzyme complexes has been observed in AD patients. To understand how energy metabolism influences AD progression, we suppressed thedld-1gene inC. elegansexpressing the human Aβ peptide.dld-1gene suppression improved many aspects of vitality and function directly affected by Aβ pathology inC. elegans.This includes protection against paralysis, improved fecundity and improved egg hatching rates. Suppression of thedld-1gene restores normal sensitivity to aldicarb, levamisole and serotonin, and improves chemotaxis. Suppression ofdld-1does not decrease levels of the Aβ peptide, but does reduce the formation of toxic Aβ oligomers. The mitochondrial uncoupler, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) acts synergistically with Aβ to overcome the protective effect ofdld-1gene suppression. Another metabolic toxin, phosphine, acted additively with Aβ. Our work supports the hypothesis that lowering energy metabolism may protect against Aβ pathogenicity, but that this may increase susceptibility to other metabolic disturbances.
Collective cell behaviour in mechanosensing of substrate thickness
Authors: Tusan CG , Man YH , Zarkoob H , Johnson DA , Andriotis OG , Thurner PJ , Yang S , Sander EA , Gentleman E , Sengers BG , Evans ND
Published: December 2017

Extracellular matrix stiffness has a profound effect on the behaviour of many cell types. Adherent cells apply contractile forces to the material on which they adhere, and sense the resistance of the material to deformation – its stiffness. This is dependent on both the elastic modulus and the thickness of the material, with the corollary that single cells are able to sense underlying stiff materials through soft hydrogel materials at low (<10 µm) thicknesses. Here, we hypothesised that cohesive colonies of cells exert more force and create more hydrogel deformation than single cells, therefore enabling them to mechanosense more deeply into underlying materials than single cells. To test this, we modulated the thickness of soft (1 kPa) elastic ECM-functionalised polyacrylamide hydrogels adhered to glass substrates and allowed colonies of MG63 cells to form on their surfaces. Cell morphology and deformations of fluorescent fiducial-marker labelled hydrogels were quantified by time-lapse fluorescence microscopy imaging. Single cell spreading increased with respect to decreasing hydrogel thickness, with data fitting to an exponential model with half-maximal response at a thickness of 3.2 μm. By quantifying cell area within colonies of defined area, we similarly found that colony-cell spreading increased with decreasing hydrogel thickness but with a greater halfmaximal response at 54 μm. Depth-sensing was dependent on ROCK-mediated cellular μ contractility. Surface hydrogel deformations were significantly greater on thick hydrogels compared to thin hydrogels. In addition, deformations extended greater distances from the periphery of colonies on thick hydrogels compared to thin hydrogels. Our data suggest that by acting collectively, cells mechanosense rigid materials beneath elastic hydrogels at greater depths than individual cells. This raises the possibility that the collective action of cells in colonies or sheets may allow cells to sense structures of differing material properties at comparatively large distances.
Time-resolved analyses of elemental distribution and concentration in living plants: An example using manganese toxicity in cowpea leaves
Authors: Blamey F. Pax C. , Paterson David J. , Walsh Adam , Afshar Nader , McKenna Brigid A. , Cheng Miaomiao , Tang Caixan , Horst Walter J. , Menzies Neal W. , Kopittke Peter M.
Published: December 2017

Knowledge of elemental distribution and concentration within plant tissues is crucial in the understanding of almost every process that occurs within plants. However, analytical limitations have hindered the microscopic determination of changes over time in the location and concentration of nutrients and contaminants in living plant tissues.

We developed a novel method using synchrotron-based micro X-ray fluorescence (μ-XRF) that allows for laterally-resolved, multi-element, kinetic analyses of plant leaf tissues in vivo. To test the utility of this approach, we examined changes in the accumulation of Mn in unifoliate leaves of 7-d-old cowpea (Vigna unguiculata) plants grown for 48 h at 0.2 and 30 μM Mn in solution.

Repeated μ-XRF scanning did not damage leaf tissues demonstrating the validity of the method. Exposure to 30 μM Mn for 48 h increased the initial number of small spots of localized high Mn and their concentration rose from 40 to 670 mg Mn kg-1 fresh mass. Extension of the two-dimensional μ-XRF scans to a three-dimensional geometry provided further assessment of Mn localization and concentration.

This method shows the value of synchrotron-based μ-XRF analyses for time-resolved in vivo analysis of elemental dynamics in plant sciences.
The Brain/MINDS 3D digital marmoset brain atlas
Authors: Woodward Alexander , Hashikawa Tsutomu , Maeda Masahide , Kaneko Takaaki , Hikishima Keigo , Iriki Atsushi , Okano Hideyuki , Yamaguchi Yoko
Published: December 2017

We present a new 3D digital brain atlas of the non-human primate, common marmoset monkey (Callithrix jacchus), with MRI and coregistered Nissl histology data. To the best of our knowledge this is the first comprehensive digital 3D brain atlas of the common marmoset having normalized multi-modal data, cortical and sub-cortical segmentation, and in a common file format (NIfTI). The atlas can be registered to new data, is useful for connectomics, functional studies, simulation and as a reference.

The atlas was based on previously published work but we provide several critical improvements to make this release valuable for researchers. Nissl histology images were processed to remove illumination and shape artifacts and then normalized to the MRI data. Brain region segmentation is provided for both hemispheres. The data is in the NIfTI format making it easy to integrate into neuroscience pipelines, whereas the previous atlas was in an inaccessible file format. We also provide cortical, mid-cortical and white matter boundary segmentations useful for visualization and analysis.
A zinc-finger fusion protein refines Gal4-defined neural circuits
Authors: Raghu Shamprasad Varija , Mohammad Farhan , Yi Chua Jia , Barros Claudia S. , Lam Joanne , Loberas Mavis , Sahani Sadhna , Claridge-Chang Adam
Published: December 2017

The analysis of behavior requires that the underlying neuronal circuits are identified and genetically isolated. In several major model species—most notablyDrosophila, neurogeneticists identify and isolate neural circuits with a binary heterologous expression-control system: Gal4–UASG. One limitation of Gal4–UASG is that expression patterns are often too broad to map circuits precisely. To help refine the range of Gal4 lines, we developed an intersectional genetic AND operator. Interoperable with Gal4, the new system’s key component is a fusion protein in which the DNA-binding domain of Gal4 has been replaced with a zinc finger domain with a different DNA-binding specificity. In combination with its cognate binding site (UASZ) thezinc-finger-replaced Gal4 (‘Zal1’) was functional as a standalone transcription factor. Zal1 transgenes also refined Gal4 expression ranges when combined with UASGZ, a hybrid upstream activation sequence. In this way, combining Gal4 and Zal1 drivers captured restricted cell sets compared with single drivers and improved genetic fidelity. This intersectional genetic AND operation presumably derives from the action of a heterodimeric transcription factor: Gal4-Zal1. Configurations of Zal1–UASZ and Zal1-Gal4-UASGZ are versatile tools for defining, refining, and manipulating targeted neural expression patterns with precision.