Incidence, features and management of radionecrosis in melanoma patients treated with cerebral radiotherapy and anti‐PD‐1 antibodies

Abstract

Background

Brain radiotherapy is used in the management of melanoma brain metastases (MBM), and can result in radionecrosis. Anti‐PD‐1 is active in the brain and may increase the risk of radionecrosis when combined with radiotherapy. We studied the incidence, associated factors and management of radionecrosis in longer‐term survivors with MBM treated with this combination.

Methods

Patients with MBM treated with radiotherapy and anti‐PD‐1 who survived greater than 1‐year were identified to determine radionecrosis incidence (cohort A, n=135). Cohort A plus additional radionecrosis cases were examined for factors associated with radionecrosis and management (cohort B, n=148).

Results

From Cohort A, 17% developed radionecrosis, with a cumulative incidence at 2‐years of 18%. Using Cohort B, multivariable analysis confirmed an association between radionecrosis and elevated lactate dehydrogenase (p=0.0496) and prior treatment with ipilimumab (p=0.0319). Radionecrosis was diagnosed based on MRI (100%), symptoms (69%) and pathology (56%). Treatment included corticosteroids, bevacizumab, and neurosurgery.

Conclusions

Radionecrosis is a significant toxicity in longer‐term melanoma survivors with MBM treated with anti‐PD‐1 and radiotherapy. Identification of those at risk of radionecrosis who may avoid radiotherapy is required.

Significance

Many patients with melanoma brain metastases receive radiotherapy and anti‐PD‐1 therapy, and this study demonstrates that approximately one fifth of those who survive beyond one year develop radionecrosis, which causes symptoms that can be difficult to manage. Recent data demonstrate high activity of anti‐PD‐1‐based therapy in patients with brain metastases, such that some patients may be spared radiotherapy and the risk of radionecrosis.

This article is protected by copyright. All rights reserved.

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Diagnosis and Management of CMV Colitis

Abstract

Purpose of Review

Cytomegalovirus (CMV) colitis is a relatively common end-organ infectious complication in immunocompromised hosts which negatively affects clinical outcomes. This paper presents the contemporary approaches to the diagnosis and management of CMV colitis and discusses some of the controversies of this condition, focusing on methods of diagnosis.

Recent Findings

While certain risk factors for CMV colitis are well recognized, the clinical as well as endoscopic features of this condition are nonspecific. Rapid diagnosis and management are usually needed, especially in critically ill patients, which necessitate invasive diagnostic procedures. Hematoxylin and eosin staining of colonic mucosal tissue may show the typical viral inclusions associated with CMV colitis that are highly specific for this condition. However, the staining has low sensitivity compared to immunohistochemistry, which is considered the gold standard for diagnosis of CMV colitis. Tissue polymerase chain reaction (PCR) is highly sensitive for diagnosis, but is controversial for many reasons, detailed in this paper.

Summary

A high index of suspicion is needed, and once diagnosis is made, treatment should be highly considered to improve the outcome of these severely ill patients. Noninvasive diagnostic tests will be available in the future and will hopefully improve the diagnosis and care of patients with CMV colitis.

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Lymphoepithelial cyst of the pancreas: A case report and summary of imaging features of pancreatic cysts.

Lymphoepithelial cyst of the pancreas: A case report and summary of imaging features of pancreatic cysts.

Int J Surg Case Rep. 2019 Jan 30;55:192-195

Authors: Namba Y, Oshita A, Nishisaka T, Namba M, Sasaki T, Matsugu Y, Itamoto T

Abstract
INTRODUCTION: A lymphoepithelial cyst (LEC) of the pancreas is a benign and rare lesion that is difficult to diagnose preoperatively based on imaging studies.
PRESENTATION OF CASE: We report a case of a 49-year-old man who presented with weight loss and diarrhea. The serum carcinoembryonic antigen and carbohydrate antigen 19-9 levels were slightly elevated to 6.7 ng/mL (reference value <5.0 ng/mL) and 45 U/mL (reference value <37 U/mL), respectively. Computed tomography showed a large cystic mass with internal septa in the pancreatic tail. The cystic wall and the septa showed enhancement while the cystic contents remained unenhanced. Magnetic resonance imaging (MRI) demonstrated a multiple-ball-like lesion with low signal intensity on T1-weighted image and high signal intensity on T2-weighted image. Diffusion-weighted MRI showed high signal intensity in the central and iso-signal intensity in the peripheral portions of the cystic lesion. The cystic wall and septa showed high signal intensity, and the cystic contents showed low signal intensity on an enhanced MRI. Endoscopic ultrasonography showed a cyst with multiple high-echoic lesions in the pancreatic tail. A mucinous cystic neoplasm and branch duct intraductal papillary mucinous neoplasm were considered among the differential diagnoses, and we performed distal pancreatectomy with concomitant splenectomy and lymphadenectomy for both diagnostic and therapeutic purposes. Histopathological findings revealed that the cystic wall was lined by stratified squamous epithelium, and several lymphoid follicles and a few sebaceous glands were observed within the cystic wall without hair follicles, leading to the final diagnosis of an LEC.
CONCLUSION: We report a rare case of a pancreatic LEC, which was difficult to be diagnosed and summarize the imaging features of pancreatic cysts to differentiate from the malignancy preoperatively.

PMID: 30763861 [PubMed - as supplied by publisher]

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Authors' Reply: Routine Pathology and Postoperative Follow-Up are not Cost-Effective in Cholecystectomy for Benign Gallbladder Disease.

Related Articles

Authors' Reply: Routine Pathology and Postoperative Follow-Up are not Cost-Effective in Cholecystectomy for Benign Gallbladder Disease.

World J Surg. 2019 Feb 13;:

Authors: Olthof PB, Metman MME, Roos D, Dekker JWT

Abstract

PMID: 30761405 [PubMed - as supplied by publisher]

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Synthesis and antibiotic activity of novel acylated phloroglucinol compounds against methicillin-resistant Staphylococcus aureus

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Synthesis of the ABCDG ring skeleton of communesin F based on carboborylation of 1,3-diene and Bi(OTf)3-catalyzed cyclizations

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Total Synthesis of trans-Resorcylide via Macrocyclic Stille Carbonylation

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Lactacystin: first-in-class proteasome inhibitor still excelling and an exemplar for future antibiotic research

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Design and fabrication of novel thiourea coordination compounds as potent inhibitors of bacterial growth

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In vitro activities of antimicrobial peptides and ceragenins against Legionella pneumophila

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Barcoding reveals complex clonal behavior in patient-derived xenografts of metastatic triple negative breast cancer

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Disulfide-mediated conversion of 8-mer bowl-like protein architecture into three different nanocages

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Stress-induced inactivation of the Staphylococcus aureus purine biosynthesis repressor leads to hypervirulence

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Resolution limit of image analysis algorithms

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A functional subset of CD8+ T cells during chronic exhaustion is defined by SIRPα expression

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Mutation of a single residue promotes gating of vertebrate and invertebrate two-pore domain potassium channels

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Amine-responsive cellulose-based ratiometric fluorescent materials for real-time and visual detection of shrimp and crab freshness

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Single gametophyte sequencing reveals that crossover events differ between sexes in maize

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Displacement of Simulated Flabby Tissue by Different Tray Designs and Impression Materials

Abstract

Purpose

To compare the effect of 3 tray designs and 3 commonly used impression materials on the displacement of flabby tissue during maxillary edentulous impression by superimposition of 3D digital models.

Materials and Methods

Fifteen maxillary edentulous casts with simulated flabby tissue were fabricated by modifying a standard maxillary edentulous acrylic resin cast. Three types of impression trays were fabricated: trays with conventional relief, trays with additional relief, and trays with an open window. Three impression materials were tested: light‐body polysulfide, light‐body vinylpolysiloxane, and zinc oxide eugenol paste. For the analysis of tissue displacement during impression making, the test and control stone casts were scanned using a 3D laser scanner, and the 3D digital models were superimposed using metrology software. Statistical analyses were performed with an α = 0.05.

Results

Negative deviations were recorded at the areas of the alveolar crest, posterior part of flabby tissue, and middle of the palate. On the other hand, a positive deviation was recorded at the area of the anterior part of flabby tissue. A significant difference in the displacement of flabby tissue was found when using different tray designs (P < 0.0001). The tray with the open window showed significantly low tissue displacement at the flabby tissue region. Depending on sites, the amount of flabby tissue displacement showed different significances by the different impression materials used (anterior part: P < 0.0001; alveolar crest: P = 0.097; posterior part: P < 0.0001). Conventionally relieved trays showed significantly higher values of displacement at the anterior part of flabby tissue (P < 0.0001), while trays with open windows showed similar values of displacement at all measuring points, and no significant differences among different impression materials was found (P = 0.104).

Conclusions

There were significant differences in the displacement of flabby tissue with different tray designs. Especially, with displacement occurring at the anterior and posterior parts of flabby tissue. Tray designs should be considered in order to make proper impressions when flabby tissue is present.

This article is protected by copyright. All rights reserved

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American Board of Prosthodontics: Annual Report

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Issue Information ‐ Editorial Board

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Meetings of Interest

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Geostatistical estimation of surface soil carbon stock in Mt. Wakakusa grassland of Japan

Abstract

Although nation-wide assessments on the grassland soil carbon storage have been conducted in Japan, the uncertainty of the estimation accuracy remains with its local variability. In the present study, using geostatistical approach, we assessed the spatial variability and distribution pattern of organic carbon (OC) and estimated its total stock in the surface soils (0–5 cm) over Mt. Wakakusa grassland (30.2 ha) of Central Japan. The exploratory statistics indicated that the surface soils had 1.88 ± 0.28 kg C m⁻² of soil OC density on average (n = 147) with a moderate variability (CV = 18.8%), while the geostatistical analysis unveiled that its semivariogram was well fitted by a spherical model (R² = 0.93, RSS = 1.15E⁻⁰⁵) and had a strong spatial dependency (nugget–sill ratio = 0.31). Based on these results, we constructed an interpolated map and estimated total OC stock to 552 Mg C in the surface soil of Mt. Wakakusa grassland.

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Dynamics of an old evergreen coppice in southwestern Japan with special focus on a typical coppice species ( Castanopsis cuspidata ) and a climax species ( Distylium racemosum )

Abstract

We investigated stand dynamics of an abandoned evergreen coppice (c.a. 100 years old) over the course of 21 years in south Kyushu, Japan. The study stand showed a change in species composition from being dominated by Castanopsis cuspidata to Distylium racemosum, that is, from a typical coppice species to a typical climax species of the region. However, the relative dominance of Castanopsis spp. appeared to remain very high in the study stand compared to that in the Aya Research Site, a typical old-growth forest in the region, due to abundant C. cuspidata canopy trees of coppice origin. This suggests that the species composition of the study stand remained distinct from that of climax forests in the region. On the other hand, D. racemosum did not show a significant change in diameter at breast height (DBH) class frequency distribution from 1996 to 2017, probably due to the slow growth of this species. However, generalized linear models (GLMs) were used to identify the factors affecting better DBH growth of this species in the gap, indicating the potential for further development of the population structure when small trees are released from suppression of canopy trees. This suggests, inversely, that the development of the D. racemosum population was heavily suppressed by abundant C. cuspidata canopy trees of coppice origin that survived to the age of nearly 100 years. Further, large typhoons are suggested to cause severe canopy disturbances that remove canopy trees of C. cuspidata, which might be important for promoting further forest succession, even for a nearly 100-year-old evergreen old coppice.

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Carbon mineralization characteristics of compost made from pruning material

Abstract

To investigate carbon (C) mineralization characteristics of compost made from pruning material (PM), C mineralization parameters were evaluated, including mineralizable C (C₀), apparent activation energy (E_a), and the rate constant of mineralization (k). These properties were also examined in conventional composts made from dung (D), fallen leaves (L), and bark (B). No significant differences among the plant composts (L, B and PM) were observed for E_a. Notably, the values of the respective indicators were significantly greater in PM, L and B than in D. The C₀ of PM was significantly greater than that of the other composts. Conversely, the k-value for PM was significantly smaller than that for the other composts. These results indicate that PM supplies a substantial amount of mineralizable C that persists for a long time after the PM has been mixed with soil.

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Engineering the effector specificity of regulatory proteins for the in vitro detection of biomarkers and pesticide residues

Abstract

Transcriptional regulatory proteins (TRPs)-based whole-cell biosensors are promising owing to their specificity and sensitivity, but their applications are currently limited. Herein, TRPs were adapted for the extracellular detection of a disease biomarker, uric acid, and a typical pesticide residue, carbaryl. A mutant regulatory protein that specifically recognizes carbaryl as its non-natural effector and activates transcription upon carbaryl binding was developed by engineering the regulatory protein TtgR from Pseudomonas putida. The TtgR mutant responsive to carbaryl and a regulatory protein responsive to uric acid were used for in vitro detection, based on their allosteric binding of operator DNA and inducer molecules. Based on the quantitative polymerase chain reactions (qPCRs) output, the minimum detectable concentration was between 1 nM–1 μM and 1–10 nM for uric acid and carbaryl, respectively. Our results demonstrated that engineering the effector specificity of regulatory proteins is a potential technique for generating molecular recognition elements for not only in vivo but also in vitro applications.

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Enantioselective N‐Heterocyclic Carbene Catalysis that Exploits Imine Umpolung

Poles apart: Imine umpolung is an underdeveloped area of enantioselective catalysis. N‐Heterocyclic carbenes (NHCs) were used to catalyze an enantioselective aza‐Stetter reaction. In contrast to acyl umpolung with NHCs, this reaction requires highly nucleophilic catalysts. The reaction is highly enantioselective (all ≥96:4 er) and accepts various imines and 3‐methylenechroman‐2‐ones.

Abstract

The catalytic umpolung of imines remains an underdeveloped approach to reaction discovery. Herein we report an enantioselective aza‐Stetter reaction that proceeds via imine umpolung using N‐heterocyclic carbene catalysis. The reaction proceeds with high levels of enantioselectivity (all ≥96:4 er) and good generality (21 examples). Mechanistic studies are reported and are consistent with turnover‐limiting addition of the NHC to the imine.

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Catalytic Asymmetric Synthesis of α‐Arylpyrrolidines and Benzo‐fused Nitrogen Heterocycles

An enantioselective copper‐catalyzed intramolecular hydroamination reaction can be used jointly with the Suzuki–Miyaura cross‐coupling to yield a diverse array of α‐arylpyrrolidine scaffolds that contain pharmaceutically relevant heteroarenes with excellent enantiomeric purity under mild conditions. Furthermore, this intramolecular hydroamination strategy is applicable to the asymmetric syntheses of six‐ to nine‐membered benzo‐fused nitrogen heterocycles.

Abstract

Herein, we report a practical two‐step synthetic route to α‐arylpyrrolidines through Suzuki–Miyaura cross‐coupling and enantioselective copper‐catalyzed intramolecular hydroamination reactions. The excellent stereoselectivity and broad scope for the transformation of substrates with pharmaceutically relevant heteroarenes render this method a practical and versatile approach for pyrrolidine synthesis. Additionally, this intramolecular hydroamination strategy facilitates the asymmetric synthesis of tetrahydroisoquinolines and medium‐ring dibenzo‐fused nitrogen heterocycles.

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The chiral trimer and a metastable chiral dimer of achiral hexafluoroisopropanol: A multi‐messenger study

1,1,1,3,3,3‐hexafluoro‐propan‐2‐ol aggregates preferentially into an achiral dimer of achiral monomers, but the trimer is found to prefer three metastable chiral monomer units arranged into a strained OH‐O hydrogen‐bonded ring which is reinforced by secondary CH‐FC interactions. This is shown by a combination of infrared, microwave and Raman spectroscopy in supersonic jet expansions and supported by high level quantum chemical calculations. It involves an activation of the monomers by >15 kJ mol‐1, clearly driven by the much stronger hydrogen bond interaction available to the gauche and even more to the cis monomer units.

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Merging Photochemistry with Electrochemistry: Functional Group Tolerant Electrochemical Amination of sp³ C–H Bonds

Direct amination of sp³ C–H bonds is of broad interest in the realm of C–H functionalization because of the prevalence of nitrogen heterocycles and amines in pharmaceuticals and natural products. Here, we report a combined electrochemical/photochemical method for dehydrogenative C(sp³)–H/N–H coupling that exhibits good reactivity with both sp² and sp³ N–H bonds. The results show how use of iodide as an electrochemical mediator, in combination with light‐induced cleavage of intermediate N–I bonds, enables the electrochemical process to proceed at low electrode potentials. This approach significantly improves the functional‐group compatibility of electrochemical C–H amination, for example, tolerating electron‐rich aromatic groups that undergo deleterious side reactions in the presence of high electrode potentials.

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A multifunctional peptide‐conjugated AIEgen for efficient and sequential targeted gene delivery into the nucleus

Gene therapy has immense potential as a therapeutic approach to serious diseases. However, efficient delivery and real‐time tracking of gene therapeutic agents haven't been solved well for successfully gene‐based therapeutics. Here we present a versatile gene delivery strategy to efficient and visualized deliver therapeutic gene into the targeted nucleus. We develop an integrin‐targeted, cell‐permeable and nucleocytoplasmic trafficking peptide‐conjugated AIEgen named TDNCP for efficient and sequential targeted delivery of antisense single‐stranded DNA oligonucleotide (ASO) and tracking the delivery process into the nucleus. Compared with TDNCP/siRNA‐NPs (siRNA functioned mainly in cytoplasm), TDNCP/ASO‐NPs (ASO functioned mainly in nucleus) exhibit better interference effect, which further testifies that TDNCP is a nucleus targeting vector. Moreover, TDNCP/ASO‐NPs show the favorable tumor suppressive effect in vivo, which demonstrates the multifunctional peptide‐conjugated AIEgen for sequential targeted gene delivery and realizes efficient gene interference therapy.

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An N‐Heterocyclic Boryloxy Ligand Isoelectronic with N‐Heterocyclic Imines: Access to an Acyclic Dioxysilylene and its Heavier Congeners

New O‐donor ligand: By exploiting the isoelectronic relationship with N‐heterocyclic imines (NHIs), a new class of N‐heterocyclic boryloxy (NHBO) ligand, which is a strong O‐donor, is introduced. The NHBO ligand is used to generate the first acyclic two‐coordinate dioxysilylene and its heavier (Ge, Sn, Pb) congeners, which represent the first complete series of heavier group 14 dioxycarbene analogues.

Abstract

Introduced here is a new type of strongly donating N‐heterocyclic boryloxy (NHBO) ligand, [(HCDippN)₂BO]⁻ (Dipp=2,6‐diisopropylphenyl), which is isoelectronic with the well‐known N‐heterocyclic iminato (NHI) donor class. This 1,3,2‐diazaborole functionalized oxy ligand has been used to stabilize the first acyclic two‐coordinate dioxysilylene and its Ge, Sn, and Pb congeners, thereby presenting the first complete series of heavier group 14 dioxycarbene analogues. All four compounds have been characterized by X‐ray crystallography and density‐functional theory, enabling analysis of periodic trends: the potential for the [(HCDippN)₂BO]⁻ ligand to subtly vary its electronic‐donor capabilities is revealed by snapshots showing the gradual evolution of arene π coordination on going from Si to Pb.

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Use of Isotope Effects to Understand the Present and Past of the Atmosphere and Climate and Track the Origin of Life

Mass‐independent isotope effect is a new type of isotopic chemistry that does not follow the traditional isotope fractionation rule. It has been widely used in understanding the origin and evolutions of our solar system, Earth, Mars, life, and modern Earth's atmospheric and environmental physics and chemistry. This Minireview presents the history and most recent advances on this isotope effect, from quantum level understanding to its application in nature.

Abstract

Stable isotope ratio measurements have been used as a measure of a wide variety of processes, including solar system evolution, geological formational temperatures, tracking of atmospheric gas and aerosol chemical transformation, and is the only means by which past global temperatures may be determined over long time scales. Conventionally, isotope effects derive from differences of isotopically substituted molecules in isotope vibrational energy, bond strength, velocity, gravity, and evaporation/condensation. The variations in isotope ratio, such as ¹⁸O/¹⁶O (δ¹⁸O) and ¹⁷O/¹⁶O (δ¹⁷O) are dependent upon mass differences with δ¹⁷O/δ¹⁸O=0.5, due to the relative mass differences (1 amu vs. 2 amu). Relations that do not follow this are termed mass independent and are the focus of this Minireview. In chemical reactions such as ozone formation, a δ¹⁷O/δ¹⁸O=1 is observed. Physical chemical models capture most parameters but differ in basic approach and are reviewed. The mass independent effect is observed in atmospheric species and used to track their chemistry at the modern and ancient Earth, Mars, and the early solar system (meteorites).

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Site‐Specific Oxidation State Assignments of the Irons in the [4Fe:4S]2+/1+/0 States of the Nitrogenase Fe‐Protein

The nitrogenase iron protein (Fe‐protein) serves as the electron donor for biological nitrogen fixation. Understanding how the Fe‐protein controls electron transfer to the active site is critical in addressing the mechanism of substrate reduction. Structural and spectroscopic techniques, including spatially resolved anomalous dispersion (SpReAD) refinement, were combined to report oxidation assignments for individual irons in the cluster for each overall state.

Abstract

The nitrogenase iron protein (Fe‐protein) contains an unusual [4Fe:4S] iron‐sulphur cluster that is stable in three oxidation states: 2+, 1+, and 0. Here, we use spatially resolved anomalous dispersion (SpReAD) refinement to determine oxidation assignments for the individual irons for each state. Additionally, we report the 1.13‐Å resolution structure for the ADP bound Fe‐protein, the highest resolution Fe‐protein structure presently determined. In the dithionite‐reduced [4Fe:4S]¹⁺ state, our analysis identifies a solvent exposed, delocalized Fe^2.5+ pair and a buried Fe²⁺ pair. We propose that ATP binding by the Fe‐protein promotes an internal redox rearrangement such that the solvent‐exposed Fe pair becomes reduced, thereby facilitating electron transfer to the nitrogenase molybdenum iron‐protein. In the [4Fe:4S]⁰ and [4Fe:4S]²⁺ states, the SpReAD analysis supports oxidation states assignments for all irons in these clusters of Fe²⁺ and valence delocalized Fe^2.5+, respectively.

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Origin of Nitric Oxide Reduction Activity in Flavo–Diiron NO Reductase: Key Roles of Second Coordination Sphere

A second chance: QM/MM spectroscopic and mechanistic modeling reveal that the second coordination sphere effect, originating from a conserved tyrosine residue, can significantly enhance the activity of flavo–diiron NO reductase. This finding helps to decipher the mechanistic origin of the NO reductase activity in flavo–diiron proteins, which also reconciles the external reductant controversy in NO reduction chemistry of iron–nitrosyls.

Abstract

The second coordination sphere constitutes a distinguishing factor in the active site to modulate enzymatic reactivity. To unravel the origin of NO‐to‐N₂O reduction activity of non‐heme diiron enzymes, herein we report a strong second‐coordination‐sphere interaction between a conserved Tyr₁₉₇ and the key iron–nitrosyl intermediate of Tm FDP (flavo–diiron protein), which leads to decreased reaction barriers towards N–N formation and N–O cleavage in NO reduction. This finding supports the direct coupling of diiron dinitrosyl as the N–N formation mode in our QM/MM modeling, and reconciles the mechanistic controversy of external reduction between FDPs and synthetic biomimetics of the iron–nitrosyls. This work highlights the application of QM/MM ⁵⁷Fe Mössbauer modeling in elucidating the structural features of not only first, but also second coordination spheres of the key transient species involved in NO/O₂ activation by non‐heme diiron enzymes.

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­Mn‐Catalyzed Dehydrocyanative Transannulation of Heteroarenes via C‐H Activation: Beyond the Permanent Directing Effects of Pyridines/Pyrimidines

Pyridine/pyrimidine rings are common and effective directing groups for catalytic activation of C‐H bonds. However, they are poorly functionalizable either under in situ or ex situ conditions. Reported in this work is Mn‐catalyzed dehydrocyanative transannulation between three classes of heteroarenes and propargyl carbonates. The pyridyl/pyrimidyl groups in the heteroarenes initially function as a directing group to enable C‐H allenylation; they then undergo intramolecular Diels‐Alder‐retro Diels‐Alder reactions with the allene moiety to afford fused carbo/heterocycles. Three key intermediates at different stages of the reaction have been isolated.

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Is a bent crystal still a single crystal?

The mention of the word 'crystal' invokes images of minerals, gems and rocks, all of which are inevitably solid, hard and durable entities with well‐defined smooth faces and straight edges. With the discovery, in the first half of the 20th century that many molecular crystals are soft and can be deformed similarly to rubber or plastic (L. A. K. Staveley, Annu. Rev. Phys. Chem. 1962, 13, 351‒368), this perception is evolving, and both the common apprehension and formal definition of what a crystal is may require reinterpretation in view of their extraordinary mechanical compliance. The seemingly naïve question posed in the title of this Minireview does not have a simple answer. Here, we discuss the effects on the diffraction signature of elastic and plastic deformation of molecular crystals as primary evidence of the degree of their crystallinity. In most cases, the definition of a crystal holds for both elastically and plastically deformed crystals, and unless there is significant or complete physical separation of the crystal during the deformation, they can safely be considered (deformed) single crystals with high concentration of defects.

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Reusable Nickel Nanoparticles‐catalyzed Reductive Amination for Selective Synthesis of Primary Amines

The preparation of nickel nanoparticles as efficient reductive amination catalysts by pyrolysis of in situ generated Ni‐tartaric acid complex on silica is presented. The resulting stable and reusable Ni‐nanocatalyst enables the synthesis of functionalized and structurally diverse primary benzylic, heterocyclic and aliphatic amines starting from inexpensive and readily available carbonyl compounds and ammonia in presence of molecular hydrogen. Applying this Ni‐based amination protocol, ‐NH2 moiety can be introduced in structurally complex compounds, e.g. steroid derivatives and pharmaceuticals.

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Chemical and Ribosomal Synthesis of Topologically Controlled Bicyclic and Tricyclic Peptide Scaffolds Primed by Selenoether Formation

Bicyclic and tricyclic peptides have emerged as promising candidates for the development of protein binders and new therapeutics. However, convenient and efficient strategies that can generate topologically controlled bicyclic and tricyclic peptide scaffolds from fully‐unprotected peptides are still much in demand, particularly for those amenable to the design of biosynthetic libraries. In this work, we report a reliable chemical and ribosomal synthesis of topologically controlled bicyclic and tricyclic peptide scaffolds. Our strategy involves the combination of selenoether cyclization followed by disulfide or thioether cyclization, yielding desirable bicyclic and tricyclic peptides. This work thus lays the foundation for developing peptide libraries with controlled topology of multicyclic scaffolds for in vitro display techniques.

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Reversible Hydrogen Uptake/Release over a Sodium Phenoxide–Cyclohexanolate Pair

Hydrogen uptake and release in arene–cycloalkane pairs is an attractive strategy for hydrogen storage but is hampered by the large enthalpy change associated with dehydrogenation. In their Communication (DOI: 10.1002/anie.201810945), P. Chen, T. He, A. Wu, and co‐workers describe how reversible hydrogen storage under moderate conditions is possible with a sodiated phenoxide–cyclohexanolate pair.

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ADUC Prizes 2019/Ignaz L. Lieben Award for Nuno Maulide

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Ryo Yoshida

"The most important future application of my research is artificial life. The secret of being a successful scientist is having a sense of beauty …" Find out more about Ryo Yoshida in his Author Profile.

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Multi‐Light‐Responsive Quantum Dot Sensitized Hybrid Micromotors with Dual‐Mode Propulsion

The multi‐light‐controlled propulsion and on‐the‐fly chemical acceleration capabilities of micromotors based on Pt, Pd, and MnO₂ catalysts is described by Prof. A. Escarpa, Dr. B. Jurado, and R. M. Hormigos in their Communication (DOI: 10.1002/anie.201811050). The built‐in accelerating optical system allows for the control of the velocity over the entire UV/Vis light spectrum for future on‐demand operation, motion‐based sensing, and beyond.

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Covalently Grafting Cobalt Porphyrin onto Carbon Nanotubes for Efficient CO2 Electroreduction

Highly dispersed: The covalent attachment of cobalt porphyrin onto carbon nanotubes is achieved by a substitution reaction at the metal center. This leads to large improvements in the efficiency of electrochemical CO₂ reduction compared to systems where the compounds are physically mixed.

Abstract

Molecular complexes with inexpensive transition‐metal centers have drawn extensive attention, as they show a high selectivity in the electrochemical conversion of CO₂ to CO. In this work, we propose a new strategy to covalently graft cobalt porphyrin onto the surface of a carbon nanotube by a substitution reaction at the metal center. Material characterization and electrochemical studies reveal that the porphyrin molecules are well dispersed at a high loading of 10 wt. %. As a result, the turnover frequency for CO formation is improved by a factor of three compared to traditional physically‐mixed catalysts with the same cobalt content. This leads to an outstanding overall current density of 25.1 mA cm⁻² and a Faradaic efficiency of 98.3 % at 490 mV overpotential with excellent long‐term stability. This work provides an effective pathway for the improvement of the performance of electrocatalysts that could inspire rational design of molecular catalysts in the future.

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Angiosarcoma of the Liver: Clinicopathologic Features and Morphologic Patterns

Angiosarcoma is a rare malignant neoplasm of the liver. The various morphologic patterns seen with angiosarcomas of the liver have not been systematically studied and their recognition remains a major diagnostic challenge. In order to provide more comprehensive data on the morphologic patterns, angiosarcomas that had been diagnosed between 1996 and 2016 at a large medical referral center were reviewed. The major growth patterns were classified as sinusoidal (non–mass forming) versus mass forming. The mass-forming cases were further subdivided into epithelioid, spindled, or vasoformative. The study identified 21 patients with primary hepatic angiosarcoma: 13 men and 8 women. The ages ranged from 26 to 89 years. Seventeen angiosarcomas were mass-forming tumors, of which 9 showed predominantly vasoformative growth. Most of these vasoformative cases (6/9) were composed of small vessels, 2 cases had slit-like vascular spaces, and one case showed a mixture of small and large vessels. There were 7 mass-forming angiosarcomas without vasoformation: 3 had an epithelioid morphology and 4 were composed primarily of spindled cells. The final mass-forming tumor showed a mixture of vasoformative and nonvasoformative areas. Four of 21 cases were non–mass forming and showed either diffuse sinusoidal infiltration (N=2) or prominent peliotic changes (N=2). Finally, 3 uncommon patterns were identified. One case showed nodules of spindle cells arranged in prominent whorls in a background of loose connective tissue with abundant inflammation. A second case arose in the setting of the Blue Rubber Bleb Nevus Syndrome and showed numerous tumor nodules with an architectural pattern that resembled infantile hemangioma, some with areas of atypia consistent with malignant transformation to angiosarcoma. The third unusual pattern showed multiple nodules of thin walled large caliber vascular proliferations, some of which showed atypia that reached the level of angiosarcoma. The results from this study indicate that the majority of hepatic angiosarcomas are mass forming (two third of cases), a pattern that is recognizable on H&E when vasoformative, but can mimic carcinoma or undifferentatied sarcomas when nonvasoformative (one third of cases). The sinusoidal patterns are particularly challenging and are frequently missed on initial review. Finally, we describe several unsual patterns of angiosarcoma. Awareness of these classic and rare morphologic patterns can help make the diagnosis of angiosarcoma. Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Michael S. Torbenson, MD, Department of Pathology and Laboratory Medicine, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905 (e-mail: torbenson.michael@mayo.edu). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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UV Signature Mutations Reclassify Salivary High-grade Neuroendocrine Carcinomas as Occult Metastatic Cutaneous Merkel Cell Carcinomas

Salivary high-grade neuroendocrine carcinomas (NECs) are rare, occur predominantly in the parotid gland, and are difficult to differentiate from metastatic cutaneous Merkel cell carcinomas (MCCs), which have overlapping morphologic, immunophenotypic, and molecular profiles. Oncogenic Merkel cell polyomavirus (MCPyV), found in 70% to 80% of MCCs, has also been reported in a few salivary NECs, but this is controversial. A promising biomarker to distinguish the 2 tumor types are UV signature mutations. UV signature mutations indicate a sun damage-induced mechanism of pathogenesis and recently have been found to be highly prevalent in MCPyV-negative MCCs but would be inconsistent with salivary origin. Here, we examine UV signature mutations as a molecular marker to distinguish primary salivary high-grade NEC from MCC. Whole exome DNA sequencing was performed on matched tumor-normal tissue from 4 MCPyV-negative high-grade salivary NECs with no other primary source identified, as well as 3 melanomas and 3 lung NECs as positive and negative controls, respectively. UV signature mutations were found in all salivary NECs, when defined as ≥60% of total mutations being C-to-T transitions at dipyrimidine sites, and when compared with known human cancer-related mutational signatures. The presence of UV signature mutations in salivary high-grade NECs strongly favors these to be occult metastatic MCCs. True salivary primary NECs are likely exceedingly rare. When a high-grade NEC is encountered in the salivary gland, the presence of UV signature mutations or MCPyV may be useful to exclude occult unknown primary MCC. Conflicts of Interest and Sources of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Rebecca D. Chernock, MD, Department of Pathology, Washington University School of Medicine, 660 South Euclid, Campus Box 8118, St. Louis, MO 63110 (e-mail: rchernock@wustl.edu). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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Small and Isolated Immunohistochemistry-positive Cells in Melanoma Sentinel Lymph Nodes are Associated With Disease-specific and Recurrence-free Survival Comparable to that of Sentinel Lymph Nodes Negative for Melanoma

Although immunohistochemistry (IHC) has improved our ability to detect melanoma metastases in sentinel lymph nodes (SLN), the American Joint Committee on Cancer (AJCC) does not provide a lower threshold for determining if a SLN is positive for metastasis. Existing literature suggests that even a small aggregate or an enlarged, abnormal cell detectable by IHC can be associated with an adverse outcome. In our experience, however, some SLNs contain small solitary cells the size of neighboring lymphocytes demonstrable only by IHC. We sought to determine their clinical significance. A total of 821 patients underwent a SLN biopsy at our institution over a 12-year period. In all, 639 (77.8%) were SLN-negative, 125 (15.2%) were SLN-positive, and 57 (6.9%) had rare IHC-positive cells of undetermined clinical significance with no disease progression over a mean 59-month follow-up. Kaplan-Meier method with pair-wise comparisons revealed no significant difference in disease-specific survival and recurrence-free survival between SLN-negative and rare IHC-positive groups. There were significant differences in survival and recurrence between patients in the rare IHC-positive group and those with melanoma metastases, including those with solitary melanoma cells and those with tumor burdens ≤0.2 mm. While the lower diagnostic threshold for metastatic melanoma on IHC-stained sections needs to be studied further, our data suggest that rare IHC-positive cells lacking cytomorphologic features of overt malignancy are equivocal for melanoma and could impart a similar prognosis as patients with no evidence of SLN involvement. R.E.L. and D.T.B. contributed equally to this paper. The data presented in this manuscript was in part generated through CGAT in the Department of Pathology and Laboratory Medicine of the Geisel School of Medicine at Dartmouth, the Dartmouth-Hitchcock Medical Center and the Norris Cotton Cancer Center (NCI Cancer Support Grant #5P30CA023108-37). The content is solely the responsibility of the author(s) and does not necessarily represent the official views of the NIH. This study received approval by our Institutional Review Board. Conflicts of Interest and Source of Funding: Research reported in this publication was also supported by the Dartmouth Clinical and Translational Science Institute, under award number UL1TR001086 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Shaofeng Yan, MD, PhD, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756 (e-mail: shaofeng.yan@hitchcock.org). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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Intraductal Oncocytic Papillary Neoplasms: Clinical-Pathologic Characterization of 24 Cases, With An Emphasis on Associated Invasive Carcinomas

Background: Intraductal oncocytic papillary neoplasm (IOPN) of the pancreas is a rare tumor. Recent molecular data indicate that it is distinct from other intraductal neoplasms; however, its clinicopathologic characteristics, especially the frequency/significance of an invasive carcinoma component, and biologic behavior remain to be fully defined. Design: Clinicopathologic characteristics and survival of 24 IOPNs were analyzed. By definition, all tumors exhibited intraductal growth and oncocytic morphology. Results: The female:male ratio was 1.7, and mean age was 59. In 44% of the patients, the IOPN was discovered incidentally; however, the working diagnosis was "ductal adenocarcinoma" in 42%. Fourteen IOPNs occurred in the head of the pancreas. The median tumor size was 4.5 cm. The tumors often grew along adjacent benign ducts, mimicking invasion, but only 29% exhibited unequivocal invasive carcinoma, mostly in the form of microscopic foci (pT1a=4, pT1b=1, pT2=2), and only 6% had lymph node metastasis. Invasive carcinoma was predominantly composed of small tubular units lined by oncocytic cells, or individual oncocytic cells infiltrating the periductal stroma. Follow-up information was available for 18 patients (median=6.8 y). No patients died from the disease, and the overall 10-year survival was 94%. Patients with invasive carcinoma trended toward a lower 5-year recurrence-free survival than those with noninvasive IOPNs (66% vs. 93%, P=0.066), but overall survival was not impacted by the presence of invasion (P=0.38). Conclusions: IOPN is a distinct tumor type in the pancreas. Despite its morphologic complexity and often extensive pagetoid spread to adjacent ducts, conventional invasive carcinoma is seen in only 29% and usually as microscopic foci. Thus, it is not surprising that IOPN exhibits indolent behavior even when invasion is present. This study was presented in part at the 105th annual meeting of the United States and Canadian Academy of Pathology in Seattle, WA, in March 2016. Present address: Tao Wang, MD, MSc, Department of Pathology, Queen's University, Kingston, ON, Canada. Conflicts of Interest and Source of Funding: Supported in part by the Cancer Center Support Grant (CCSG)/Core Grant/P30 CA008748 and by the Melamed Family Foundation. The remaining authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Olca Basturk, MD, Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065 (e-mail: basturko@mskcc.org). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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SOX11-negative Mantle Cell Lymphoma: Clinicopathologic and Prognostic Features of 75 Patients

Studies have suggested that SOX11 expression has prognostic implications in patients with mantle cell lymphoma (MCL), but the data are controversial. In this study, we describe the clinicopathologic and prognostic features of 75 patients with SOX11-negative MCL. Compared with patients with SOX11-positive MCL, SOX11-negative MCL patients more frequently had leukemic non-nodal disease (21% vs. 4%, P=0.0001). SOX11-negative MCLs more often showed classic morphology (83% vs. 65%, P=0.005), were more often positive for CD23 (39% vs. 22%, P=0.02) and CD200 (60% vs. 9%, P=0.0001), and had a lower proliferation index (Ki67 23% vs. 33%, P=0.04). Overall survival (OS) was not significantly different between patients with SOX11-negative versus SOX11-positive MCL (P=0.63). High Ki67 index and blastoid/pleomorphic morphology were associated with shorter OS in both SOX11-negative (P

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Mechanism of action of 4‐substituted phenols to induce vitiligo and anti‐melanoma immunity

Summary

Monobenzone is a 4‐substituted phenol that can induce vitiligo and antimelanoma immunity. We investigated the influence of the chemical structure on the biological activity of a series of structurally‐related 4‐substituted phenols. All phenols inhibited cellular melanin synthesis, and eight of ten phenols inhibited tyrosinase activity, using the MBTH assay. These phenols also induced glutathione (GSH) depletion, indicative of quinone formation and protein thiol binding, which can increase the immunogenicity of melanosomal proteins. Specific T cell activation was found upon stimulation with phenol‐exposed pigmented cells, which also reacted with unexposed cells. In contrast, 4‐tertbutylphenol induced immune activation was not restricted to pigment cells, analogous to contact sensitization. We conclude that 4‐substituted phenols can induce specific T cell responses against melanocytes and melanoma cells, also acting at distant, unexposed body sites, and may confer a risk of chemical vitiligo. Conversely, these phenols may be applicable to induce specific antimelanoma immunity.

This article is protected by copyright. All rights reserved.

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Fluorescence‐Advanced Videodermatoscopy: A promising and potential technique for the in vivo evaluation of vitiligo

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Effect of Source-Detector Distance on the Measurement of Hemoglobin Using Near-Infrared Spectroscopy in Breast Cancer

Technology in Cancer Research &Treatment, Volume 18, Issue , January 2019.


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Nitric oxide mediates aluminum-induced citrate secretion through regulating the metabolism and transport of citrate in soybean roots

Abstract

Aims

Citrate secretion is a kind of typical strategy for plant against aluminum (Al) toxicity. However, the signaling process in Al-activated citrate secretion needs to be clarified.

Methods

Physiological and biochemical methods as well as gene expression analysis were employed to examine the regulatory roles of nitric oxide (NO) in Al-activated citrate secretion in soybean roots.

Results

Application of NO donor alleviated root growth inhibition and decreased Al content in Al-treated root apices. Al-induced NO production and citrate secretion were further elevated by NO donor, but inhibited by NO scavenger. Inhibition of citrate synthase (CS) or plasma membrane (PM) H⁺-ATPase activity significantly decreased Al-induced secretion of citrate, but inhibition of aconitase (ACO) activity enhanced citrate secretion under Al stress. Furthermore, NO mediated Al-stimulated CS and PM H⁺-ATPase activities, but decreased ACO activity under Al stress. Further investigation showed that NO modulated Al-activated transcriptional expression of CS and PM H⁺-ATPase as well as GmMATE. Overexpression of GmMATE in soybean hairy roots caused an enhanced Al-induced citrate efflux and Al resistance.

Conclusions

Our findings suggest that NO-dependent up-regulation of citrate synthesis and activation of PM H⁺-ATPase-coupled MATE transporter co-transport system participates in Al-activated citrate exudation, thus conferring plant resistance to Al toxicity.

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Pyromellitic dianhydride (PMDA) may cause occupational asthma

Introduction

Anhydrides are widely used as cross-linking agents in epoxy resins and alkyd production, for example, as coatings and adhesives in plastic products. Sensitisation to several anhydrides is known to cause occupational asthma. There are indications that the lesser known pyromellitic dianhydride (PMDA) can cause irritative respiratory symptoms and possibly asthma. We report three cases of workers from a plastic foil manufacturing plant, who developed asthma when exposed to PMDA during specific inhalation challenge (SIC).

Methods

SIC was performed over 2 days according to recommendations of European Respiratory Society. Lactose powder was used in control challenges and a mixture of 10% PMDA and 90% lactose powder in active challenges.

Results

All cases experienced a delayed decrease in forced expiratory flow in 1 s (FEV₁) 4–12 hours after active challenge. FEV₁ decreased by 19%, 15% and 16%, respectively. After 21 hours, FEV₁ decreased by 24% in one worker.

Discussion

Respiratory symptoms after working hours may represent delayed work-related asthma. During SIC, the three patients developed lower respiratory symptoms and a delayed decrease in FEV₁ which suggest sensitisation. The mechanism of anhydride-related asthma is not well understood. Anhydrides are known irritants and hence an irritative response cannot be excluded. The company improved ventilation and enforced the use of respiratory protection equipment, and finally phased out PMDA. Occupational workplace risk identification may help to identify exposures. SIC can contribute to improving working conditions, by identifying and confirming asthmogens in the environment.

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Early detection of lung cancer in a population at high risk due to occupation and smoking

Objective

The US National Comprehensive Cancer Network (NCCN) recommends two pathways for eligibility for Early Lung Cancer Detection (ELCD) programmes. Option 2 includes individuals with occupational exposures to lung carcinogens, in combination with a lesser requirement on smoking. Our objective was to determine if this algorithm resulted in a similar prevalence of lung cancer as has been found using smoking risk alone, and if so to present an approach for lung cancer screening in high-risk worker populations.

Methods

We enrolled 1260 former workers meeting NCCN criteria, with modifications to account for occupational exposures in an ELCD programme.

Results

At baseline, 1.6% had a lung cancer diagnosed, a rate similar to the National Lung Cancer Screening Trial (NLST). Among NLST participants, 59% were current smokers at the time of baseline scan or had quit smoking fewer than 15 years prior to baseline; all had a minimum of 30 pack-years of smoking. Among our population, only 24.5% were current smokers and 40.1% of our participants had smoked fewer than 30 pack-years; only 43.5% would meet entry criteria for the NLST. The most likely explanation for the high prevalence of screen-detected lung cancers in the face of a reduced risk from smoking is the addition of occupational risk factors for lung cancer.

Conclusion

Occupational exposures to lung carcinogens should be incorporated into criteria used for ELCD programmes, using the algorithm developed by NCCN or with an individualised risk assessment; current risk assessment tools can be modified to incorporate occupational risk.

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Work-unit organisational changes and subsequent prescriptions for psychotropic medication: a longitudinal study among public healthcare employees

Objectives

We examined exposure to different types of organisational changes at work as risk factors for subsequent prescription for psychotropic medication among employees.

Methods

The study population included 15 038 public healthcare employees nested within 1284 work units in the Capital Region of Denmark. Multilevel mixed-effects parametric survival models were developed to examine time to prescription for psychotropic medications (anxiolytics/hypnotics/sedatives/antidepressants) during the 12-month interval following exposure to organisational changes relative to no change from January to December 2013. Data on work-unit level organisational changes (including mergers, split-ups, relocation, change in management, employee lay-offs and budget cuts) were collected from work-unit managers (59% response).

Results

Any organisational change versus no change was associated with a higher risk of psychotropic prescription (HR: 1.14, 95% CI: 1.02 to 1.26), especially change in management (HR: 1.23, 95% CI: 1.07 to 1.41). Splitting the 12-month follow-up period into two halves yielded particularly high rates of psychotropic prescription in the latter half of the follow-up, for example, any change (HR: 1.25, 95% CI: 1.11 to 1.41), change in management (HR: 1.42, 95% CI: 1.22 to 1.65), mergers (HR: 1.26, 95% CI: 1.06 to 1.50), employee lay-off (HR: 1.23, 95% CI: 1.03 to 1.46) and budget cuts (HR: 1.13, 95% CI: 1.00 to 1.41). The associations did not vary by sex.

Conclusions

Organisational changes in the workplace, especially change in management, may be associated with increased risk of psychotropic prescription among employees regardless of sex.

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Urinary 2,5-dicholorophenol and 2,4-dichlorophenol concentrations and prevalent disease among adults in the National Health and Nutrition Examination Survey (NHANES)

Objective

To test cross-sectional associations between urinary concentrations of 2,5-dichlorophenol (2,5-DCP) and 2,4-dichlorophenol (2,4-DCP) with the prevalence of cardiovascular disease (CVD), cancer, lung disease, thyroid problems and liver conditions.

Methods

Logistic regression was used to evaluate associations of urinary concentrations of 2,5-DCP and 2,4-DCP with prevalence of various medical conditions among 3617 National Health and Nutrition Examination Survey participants from 2007–2008 and 2009–2010. ORs and 95% CIs for each disease were estimated. All regression models were adjusted for urinary creatinine.

Results

We observed a monotonically increasing association between quartiles of 2,5-DCP and prevalence of CVD. After adjustment for sociodemographic and lifestyle characteristics, participants with the highest versus lowest quartile of urinary 2,5-DCP had an OR=1.84 (95% CI 1.26 to 2.70) (p linear trend=0.006). The association was similar with further adjustment for established clinical CVD risk factors. Higher 2,5-DCP was also associated with prevalence of all cancers combined (OR_{Q4 vs Q1}=1.50 (95% CI 1.00 to 2.26); p trend=0.05) and, in exploratory analyses, with gynaecological cancers (OR_{Q4 vs Q1}=4.15 (95% CI 1.51 to 11.40; p trend=0.01)). No associations were detected between 2,5-DCP and lung diseases, thyroid problems or liver conditions, nor between 2,4-DCP and prevalent disease.

Conclusion

In this nationally representative study, higher urinary 2,5-DCP concentrations were associated with greater prevalence of CVD and all cancers combined. Further examination may be warranted to assess whether chronic exposure to 2,5-DCP is associated with incidence of adverse health outcomes.

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ECG conduction disturbances and ryanodine receptor expression levels in occupational lead exposure workers

Objectives

A significant number of researches have evidenced that occupational lead (Pb) exposure increased risks of cardiovascular disease. However, evidences about the potential effects of Pb on the cardiac conduction system are sparse and inconclusive. Besides, ryanodine receptors (RyRs) induced dysfunction of cardiac excitation contraction coupling which is considered to be one of the mechanisms in cardiovascular diseases. Therefore, we examined the association between occupational Pb exposure and ECG conduction abnormalities, as well as RyRs in Pb-induced ECG abnormalities.

Methods

We investigated 529 Pb smelter workers, and measured blood lead (BPb), zinc protoporphyrin (ZPP), ECG outcomes and RyR expression levels. Based on BPb levels, the workers were divided into three groups: the BPb not elevated group, the BPb elevated group and the Pb poisoning group. Descriptive and multivariable analyses were performed.

Results

Compared with the BPb not elevated group, the Pb poisoning group had a higher incidence of high QRS voltage, and a lower level of RyR1 gene expression (p<0.05). Further unconditional multivariable logistic regression analyses showed that high QRS voltage was positively related to BPb (OR=1.045, 95% CI 1.014 to 1.078) and inversely associated with RyR1 expression (OR=0.042, 95% CI 0.002 to 0.980) after adjusting for potential confounders. In addition, multiple linear regression analyses showed that the QTc interval was positively associated with ZPP (β=0.299, 95% CI 0.130 to 0.468) after adjusting for potential confounders.

Conclusions

Our study provided evidences that occupational exposure to Pb may be associated with worse ECG outcomes (high QRS voltage), which might be related to decreased levels of RyR1.

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Functional variant of the carboxypeptidase M (CPM) gene may affect silica-related pneumoconiosis susceptibility by its expression: a multistage case-control study

Objectives

In a genome-wide association study, we discovered chromosome 12q15 (defined as rs73329476) as a silica-related pneumoconiosis susceptibility region. However, the causal variants in this region have not yet been reported.

Methods

We systematically screened eight potentially functional single-neucleotide polymorphism (SNPs) in the genes near rs73329476 (carboxypeptidase M (CPM) and cleavage and polyadenylation specific factor 6 (CPSF6)) in a case–control study including 177 cases with silicosis and 204 healthy controls, matched to cases with years of silica dust exposure. We evaluated the associations between these eight SNPs and the development of silicosis. Luciferase reporter gene assays were performed to test the effects of selected SNP on the activity of CPM in the promoter. In addition, a two-stage case–control study was performed to investigate the expression differences of the two genes in peripheral blood leucocytes from a total of 64 cases with silicosis and 64 healthy controls with similar years of silica dust exposure as the cases.

Results

We found a strong association between the mutant rs12812500 G allele and the susceptibility of silicosis (OR=1.45, 95% CI 1.03 to 2.04, p=0.034), while luciferase reporter gene assays indicated that the mutant G allele of rs12812500 is strongly associated with increased luciferase levels compared with the wild-type C allele (p<0.01). Moreover, the mRNA (peripheral blood leucocytes) expression of the CPM gene was significantly higher in subjects with silicosis compared with healthy controls.

Conclusions

The rs12812500 variant of the CPM gene may increase silicosis susceptibility by affecting the expression of CPM, which may contribute to silicosis susceptibility with biological plausibility.

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Cancer mortality in an international cohort of reinforced plastics workers exposed to styrene: a reanalysis

Objective

To investigate the carcinogenicity of styrene by reanalysing data from a previous international cohort study of workers in the reinforced plastics industry.

Methods

Mortality from cancers of prior interest was analysed with more detailed consideration of exposure–response relations and an updated classification of leukaemias and lymphomas in data from a previous international cohort study of 37 021 reinforced plastics workers exposed to airborne styrene.

Results

Increased mortality from non-Hodgkin's lymphoma (NHL) was associated with the mean level of exposure to styrene in air (relative risk (RR) 2.31, 95% CI 1.29 to 4.12 per 100 ppm), but not with cumulative styrene exposure. Similar associations with mean exposure were observed for the oesophagus (RR 2.44, 95% CI 1.11 to 5.36 per 100 ppm) and pancreas (RR 1.89, 95% CI 1.17 to 3.09). Oesophageal cancer mortality was also associated with cumulative styrene exposure lagged 20 years (RR 1.16, 95% CI 1.03 to 1.31). No other cancer, including lung cancer, was associated with any indicator of styrene exposure.

Conclusion

This reanalysis does not substantially change the conclusions of the original study with respect to NHL or lung cancer but new evidence concerning cancers of the oesophagus and pancreas merits further investigation.

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Multiorgan accelerated silicosis misdiagnosed as sarcoidosis in two workers exposed to quartz conglomerate dust

Introduction

Clusters of silicosis cases have been reported in the fabrication of quartz conglomerate, a new high-silica-content artificial stone for kitchen and bathroom benchtops (countertops).

Aim

We describe two cases of accelerated-type silicosis with hepatic granulomas arising in workers exposed to artificial quartz conglomerates.

Methods

A confident diagnosis of multiorgan silicosis was based on high level of respirable silica in the workplace, typical radiological alterations in chest high-resolution CT, histological findings in the lung and liver, and detection of silica crystals in both tissues by phase-contrast polarising light microscopy and scanning electron microscopy and energy dispersive spectroscopy.

Results

The development of the disease <10 years after the first exposure is consistent with an accelerated-type of silicosis. Compared with other studies related to quartz conglomerate exposure, we determined that the levels of airborne crystalline silica during activity in the finishing area were between 0.260 and 0.744 mg/m³, that is, much higher than the threshold limit value according to American Conference of Governmental Industrial Hygienists (0.025 mg/m³). Moreover, liver granulomas were associated with accumulation of crystalline silica particles in the hepatic tissue.

Conclusions

Quartz conglomerate fabrication is a potentially dangerous occupation. General practitioners and physicians should have awareness of this newly described occupational hazard. Accurate occupational history is critical in avoiding misdiagnosis, as silicosis caused by inhalation of dust from artificial quartz conglomerates may exhibit atypical presentation. These features seem to be related to the extremely high level of silica exposure and, possibly, to an increased toxicity of the dust generated in this process.

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Night work and sick leave during pregnancy: a national register-based within-worker cohort study

Objective

The aim of our study was to investigate the acute effect of night work during pregnancy on the risk of calling in sick the following day using register-based information and the workers as their own controls.

Methods

Using the payroll-based national Danish Working Hour Database, including all public hospital employees in Denmark, we identified 9799 pregnant women with ≥1 day shift and ≥1 night shift and ≥1 day of sick leave during the first 32 pregnancy weeks from January 2007 to December 2013. We performed fixed effects logistic regression, that is, within-worker comparisons, of the risk of sick leave of any duration starting within 24 hours after night shifts of different length versus day shifts.

Results

Most of the participants were nurses (64%) or physicians (16%). We found an increased relative risk of sick leave following night shifts compared with day shifts during all pregnancy trimesters. The risk was highest for night shifts lasting >12 hours (OR 1.37, 95% CI 1.15 to 1.63 for nurses; OR 1.87, 95% CI 1.69 to 2.08 for physicians) and among women aged >35 years (OR 1.42, 95% CI 1.24 to 1.63).

Conclusion

Among Danish public hospital employees night shifts during pregnancy, especially shifts longer than 12 hours, increased the risk of calling in sick the following day independent of personal factors and time-invariant confounders in all pregnancy trimesters.

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Cemented versus uncemented femoral component total hip arthroplasty in elderly patients with primary osteoporosis: retrospective analysis with 5-year follow-up

Journal of International Medical Research, Ahead of Print.


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Idiopathic cervical spinal subdural haematoma: a case report and literature review

Journal of International Medical Research, Ahead of Print.


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Erratic movement disorders disclosing Graves’ disease and paralleling thyroid function but not autoantibody levels

Journal of International Medical Research, Ahead of Print.


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Bilateral cerebral infarction associated with severe arteriosclerosis in the A1 segment: a case report

Journal of International Medical Research, Ahead of Print.


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Delivering mobile eye care to underserved communities while providing training in ophthalmology to medical students: experience of the Guerrilla Eye Service

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A phase 2 randomized, double-masked, placebo-controlled study of novel nonsystemic kinase inhibitor TOP1630 for the treatment of dry eye disease

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Zika Virus-Associated Aseptic Meningitis and Guillain–Barre Syndrome in a Traveler Returning from Latin America: a Case Report and Mini-Review

Abstract

ZIKV-associated Guillain–Barré syndrome presents with an accelerated clinical course compared to classic post-infectious Guillain–Barré syndrome. Clinicians should anticipate and screen patients with ZIKV infection for neurologic complications bearing in mind that these may manifest during the acute viremic phase or during early convalescence.

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Recent Innovations in Diagnosis and Treatment of Pediatric Tuberculosis

Abstract

Purpose of Review

Tuberculosis is leading cause of global morbidity and mortality and a significant proportion of the burden of disease occurs in children. In the past 5 years, a number of innovations have improved the diagnosis and treatment for children with both latent tuberculosis infection and active disease.

Recent Findings

This review discusses three key areas of innovation. First, we assess utilization and performance of interferon-gamma release assays (IGRAs) in different clinical and epidemiologic scenarios. Recent literature has demonstrated good performance of IGRAs for diagnosis of latent tuberculosis infection, particularly in low-incidence settings such as TB control programs in North America. For high-incidence populations, or when testing is done for possible active TB disease, IGRA performance has some important limitations, but IGRA sensitivity when measured against culture proven disease may be better than earlier studies suggested. The second area of innovation is in increased uptake of nucleic acid amplification (NAA) tests and broader application in non-sputum samples for both pediatric pulmonary and extrapulmonary tuberculosis. Finally, recent studies have provided solid evidence in support of shorter treatment courses for pediatric latent tuberculosis infection, such as 12 weeks of weekly isoniazid and rifapentine or 4 months daily rifampin, that improve compliance and may reduce resources required for TB control.

Summary

Many recent innovations in pediatric tuberculosis relate to an improved understanding of how to optimally use existing tests and treatments. Until diagnostic tests and interventions such as vaccination are developed that can dramatically alter the paradigm of pediatric TB management and control, it is important for stakeholders to have a nuanced understanding of tools currently available.

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Gravitational-wave observatory LIGO set to double its detecting power

Gravitational-wave observatory LIGO set to double its detecting power

Gravitational-wave observatory LIGO set to double its detecting power, Published online: 15 February 2019; doi:10.1038/d41586-019-00573-4

A planned $35-million upgrade could enable LIGO to spot one black-hole merger per day by the mid-2020s.

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[ASAP] Direct Quantification of Rapid and Efficient Single-Stroke Actuation by a Martensitic Transition in a Thermosalient Crystal

Journal of the American Chemical Society

DOI: 10.1021/jacs.8b12752

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Gravitational-wave observatory LIGO set to double its detecting power

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Microarray and Bioinformatics

The data generated through the microarray technology are gathered and saved in a computer with the help of an image scanner. As these data are found in large amounts, it is difficult even for statistical experts to perform the analysis using traditional methods. The problem has turned to be a highly important one to get addressed, especially challenges arising due to the quality and standardization of the data produced by this technology. Thus, bioinformatics tools are invented. Bioinforma...

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First Fabric to Automatically Regulate Temperature

The material created regulates the amount of heat automatically as it passes through. "This is the first technology that allows us to dynamically gate infrared radiation," explains YuHuang Wang, a professor of chemistry and biochemistry and the study's corresponding author. If conditions are warm and moist, the fabric allows infrared radiation (heat) to pass through. If conditions become cooler and drier, fabric reduces escaping heat. "The human body is a perfect radiator. It gives off hea...

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Heartburn (Acid Reflux) Triggers

In general, heartburn may be caused by food, exercise, medications, position, and some anatomical variations. Thus, each individual must find out what triggers the sensation in his or her own case. Food Eating large meals is a sure trigger for heartburn in many patients. This is especially so if the meal is fatty and is taken very shortly before going to bed. After a large meal, the stomach is filled with food and acidic gastric juice, which may overflow through the lower esophageal sp...

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Exercising with Sciatica

How does pain occur in sciatica? The sciatic nerves are the largest nerves in the body, passing down from their origin in the lumbar spine to the buttocks, down each leg at the back, to the end of the big toes. The pain in sciatica occurs, when the sciatic nerves or any of their several roots are pinched or irritated. The pain may therefore occur anywhere along its path, in the lower part of the back, the buttocks, the leg, calf or foot. The type of pain may also vary from dull aching pai...

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A New Way to Detect Any Human Virus

Now, scientists in the lab of Pardis Sabeti at there Broad Institute have created a way to design molecular baits that can grab viral particles. The new tool, called CATCH, will enable researchers to study viruses that are only present at low levels in clinical samples. The work has been reported in Nature Biotechnology. Sabeti discussess how we monitor and respond to infectious disease outbreaks in the video."As genomic sequencing becomes a critical part of disease surveillance, tools like C...

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OMI Portable Medallion from NewMed

Can This Replace an OMI Full Body PEMF Mat? No, the OMI medallion has a much smaller treatment area than the full body body mat, it is designed to be used alongside other PEMF devices to "top up" the therapy rather than be used as your only PEMF device. Magnetize Water The OMI Medallion can be used to magnetize your water. The therapy is activated by holding the sides and device is a handy coaster shape making it the ideal device to add magnetic therapy to your water! The OMI Medallio...

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DeepLabel™ Antibody Staining Kit for Cleared Tissues

Antibody Labeling for Cleared Tissues Clearing methods allow light to penetrate samples for imaging, although the method used can affect tissue permeability to molecular probes. Conventional labeling protocols involve the slow diffusion of probes into thin sample sections, which translates to a time-consuming impracticality when applied to thicker samples. The slow progression of diffusion can also lead to uneven staining, with higher, nonspecific binding on the outside of a thicker sampl...

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NewMed's OMI Mini Mat

Why Buy the OMI Mini Mat? The OMI mat has been specifically designed for both humans and pets. The 60 cm x 40 cm (23" by 15") size makes it an ideal size to be used as a full body mat for pets or as a localized therapy for humans. How It Works The gentle magnetic field produced by the OMI mini mat will induce electrical current inside the body that helps restore the blocked ion flow and stimulates regeneration processes. Same PEMF Therapy for Pets & Humans! The only difference with t...

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Preparing Samples of Cannabis Plant for THC/CBD Analysis

With increasing legalization of cannabis for medicinal and research purposes, demand for accurate and high throughtput analysis of its active ingredients has dramatically risen. Cannabis plant material contains several cannabinoids for which the human brain has evolved receptors. The two most important are the psychoactive THC and the analgesic CBD which has therapeutic uses. The ratio of THC and CBD is crucial for differentiating medicinal versus recreational cannabis. This ratio is importan...

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OMI Pulsepad from NewMed

Why OMI? Easy to use! no training required The product comes with a 3-year warranty and lifetime product support. On the market for over 10 years Includes Pad & Controller For over 15 years OMI have been working to provide drug-free and all natural products that can promote healing and healthy living. The OMI PEMF range is the result of this dedication to providing the highest quality products that accelerate self healing. PEMF therapy has never been so affordable and easy to use. Ove...

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ntered Porous Materials for High Performance Chromatography

This unique material, produced from high-density polyethylene resin using a proprietary process that can be modified, is activated and then formed into filtration media of different void volumes according to the target application. Of special note is the application of BioVyon in chromatography. Used in filter and pipette tips, solid-phase extraction microplates (such as the Porvair Sciences MicroLute™) and cartridges, BioVyon has found a niche with many blue-chip Chromatography supplies ...

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Rapidly Standardise & Scale Your ChIP Workflows

Preparing samples for Chromatin Immunoprecipitation (ChIP) has traditionally been a multi-step, time-consuming, and error-prone workflow. Pairing the bead-free Chromatrap immunoprecipitation system with the Covaris truChIP® and AFA® sample preparation technologies enables investigators to rapidly profile protein-DNA interactions of interest. By combining the two technologies, researchers now have access to a compatible and optimised workflow that increases productivity and allows the user to...

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What is Microbial Forensics?

What are bioweapons? Bioweapons encompass the use of any biological entity for the purpose of damaging the health of other living creatures. Most bioweapons concern the use of microorganisms such as bacteria, fungi, or viruses. Specially designed bioweapons may be engineered to function only in specific environments or to only affect animals or plants with particular features. These specifications are made to ensure that the weapon does not also affect the user. They may be intended to di...

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Purifying Antibodies Using Ion Exchange Chromatography

The stationary phase is made of immobilized ion exchange groups that have the opposite charge as the target component that is to be carried in the mobile phase. Generally, ion exchange experiments are performed in five stages. What is IEC and how is it performed? The first stage of IEC is called equilibration. During this process, the ion exchange stationary phase is equilibrated to ensure that it is operating at the optimized pH and ionic strength conditions to maximize adsorption of the...

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Foods that Reduce Heartburn (Acid Reflux)

It is caused by the upward movement of the acidic gastric contents into the gullet or esophagus, causing irritation of the mucous lining. In addition to the discomfort, the acid may cause a bitter taste in the mouth if it reaches as far as the pharynx. Some foods that intensify or trigger heartburn may not be the same for all individuals. These foods include spices like garlic or raw onions, black pepper, tomatoes, citrus fruit and vinegar. Fatty foods may also trigger heartburn, because ...

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NewMed's OMI PEMF Therapy Ring

Why OMI? Easy to use! no training required The product comes with a 3-year warranty and lifetime product support. On the market for over 10 years Includes Ring & Controller For over 15 years OMI have been working to provide drug-free and all natural products that can promote healing and healthy living. The OMI PEMF range is the result of this dedication to providing the highest quality products that accelerate self healing. PEMF therapy has never been so affordable and easy to use.. 3...

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OMI PEMF Mat from NewMed

Discover the OMI PEMF Range Low intensity, low frequency PEMF therapy has many applications and is now available with the OMI full body mat. Ease of use, affordability and comfort have all been combined to create a full body PEMF mat for home use.. 3 Easy to Use Programs Each program is able to cover a wide variety of applications What's Included? Everything you need for Full Body PEMF therapy is included with the OMI PEMF mat: What's Included? 1 x Full Body Mat 65"x25" (165 c...

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Gentle Efficient Buffer Reagents for Lysing Cells

There are many benefits to using Chromatrap® buffer reagents for lysing cells. These buffers have been formulated to act rapidly, gently and efficiently, ensuring reproducible results with high quality chromatin yields from various sample types. With chromatin being at the heart of Chromatin Immunoprecipitation (ChIP), the extraction and purification of chromatin is a vital starting point for epigenetics research. Chromatrap® Hypotonic Buffer has been widely proven to provide effective d...

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Organo-modification of montmorillonite for enhancing the adsorption efficiency of cobalt radionuclides from aqueous solutions

Abstract

Montmorillonite clay was organically modified with thoron (TH) and was employed as an adsorbent for removal of cobalt(II) radionuclides from aqueous solutions. Batch adsorption experiments, under several operational parameters such as pH, contact time, initial adsorbate concentration, adsorbent dosage, ionic strength, and temperature, were conducted to determine the optimum conditions for efficient removal of cobalt(II) radionuclides. The obtained data showed that almost complete removals were achieved for cobalt(II) at pH values ≥ 3.5 using TH-modified montmorillonite (TMM), while only 63% were obtained by unmodified clay at pH ≥ 5.4. Adsorption kinetic data of cobalt(II) were better fitted by the pseudo-second order kinetic model and its adsorption rate was controlled by film diffusion. Both Langmuir and Freundlich models had the ability to well describe the equilibrium data of cobalt(II) radionuclides at the studied temperatures. The adsorption capacity of TMM (0.85 mmol/g) was found to be not only nine times that of unmodified montmorillonite (0.097 mmol/g), but also higher than those reported in literature using various unmodified and modified clays. Thermodynamic parameters (ΔH°, ΔS°, and ΔG°) were calculated. Among the examined desorbing agents, both Al³⁺ and EDTA were succeeded to desorb most of cobalt(II) radionuclides (desorption % ~ 90%) loaded onto TMM. The results of this study clarified that TMM can be considered as an effective adsorbent for removal of cobalt(II) radionuclides from aqueous solutions.

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[ASAP] KLi(HC3N3O3)·2H2O: Solvent-drop Grinding Method toward the Hydro-isocyanurate Nonlinear Optical Crystal

Journal of the American Chemical Society

DOI: 10.1021/jacs.8b13280

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[ASAP] Zeolitic Intermetallics: LnNiSi (Ln = La–Nd)

Journal of the American Chemical Society

DOI: 10.1021/jacs.8b12784

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[ASAP] Protein Flexibility and Stiffness Enable Efficient Enzymatic Catalysis

Journal of the American Chemical Society

DOI: 10.1021/jacs.8b10836

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[ASAP] Room-Temperature and Selective Triggering of Supramolecular DNA Assembly/Disassembly by Nonionizing Radiation

Journal of the American Chemical Society

DOI: 10.1021/jacs.8b10355

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[ASAP] The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K

Journal of the American Chemical Society

DOI: 10.1021/jacs.8b11027

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[ASAP] Probing the Dynamics of the Imine-Based Pentafoil Knot and Pentameric Circular Helicate Assembly

Journal of the American Chemical Society

DOI: 10.1021/jacs.8b12800

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[ASAP] Electrochemical Fragmentation of Cu2O Nanoparticles Enhancing Selective C–C Coupling from CO2 Reduction Reaction

Journal of the American Chemical Society

DOI: 10.1021/jacs.8b11237

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[ASAP] Anomalous Halogen–Halogen Interaction Assists Radial Chromophoric Assembly

Journal of the American Chemical Society

DOI: 10.1021/jacs.8b13754

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