Associations among two vitamin D receptor (VDR) gene polymorphisms (ApaI and TaqI) in acne vulgaris: A pilot susceptibility study

Journal of Cosmetic Dermatology, EarlyView.

A Transgenic MMTV-Flippase Mouse Line for Molecular Engineering in Mammary Gland and Breast Cancer Mouse Models

Abstract

Genetically engineered mouse models have become an indispensable tool for breast cancer research. Combination of multiple site-specific recombination systems such as Cre/loxP and Flippase (Flp)/Frt allows for engineering of sophisticated, multi-layered conditional mouse models. Here, we report the generation and characterization of a novel transgenic mouse line expressing a mouse codon-optimized Flp under the control of the mouse mammary tumor virus (MMTV) promoter. These mice show robust Flp-mediated recombination in luminal mammary gland and breast cancer cells but no Flp activity in non-mammary tissues, with the exception of limited activity in salivary glands. These mice provide a unique tool for studying mammary gland biology and carcinogenesis in mice.

Clinical Trials for Ductal Carcinoma In Situ of the Breast

Abstract

Ductal carcinoma in situ (DCIS) of the breast is a non-obligatory precursor to invasive breast carcinoma, with a variable natural history and biological potential for progression to invasive disease. Over the past 30 years, clinical trials have applied the therapeutic principles used for invasive carcinoma to treat DCIS (surgery, with or without breast radiotherapy, and post-operative endocrine therapy), with excellent survival outcomes, and in-breast recurrence rates that range from 0.5 to 1% annually. However, half of such recurrences are again in-situ lesions, and intensive therapy is likely not necessary for all patients. Current clinical research is focused on a better characterization of the potential of individual lesions to progress to invasive disease, and to identify women who would do well with lesser treatment. Three ongoing trials in the United States and Europe randomize women to active surveillance (with or without endocrine therapy) versus usual treatment with surgery and radiotherapy. The use of pre-operative endocrine therapy has been evaluated in a recently completed trial of letrozole use in postmenopausal women with DCIS; and in on-going trials of tamoxifen, used either orally, or as a 4-hydroxytamoxifen gel formulation for application to the breast skin. This review summaries the major past and current clinical trials of DCIS, and the likely trajectories of DCIS management in the near future.

Intratumoral Heterogeneity in Ductal Carcinoma In Situ: Chaos and Consequence

Abstract

Ductal carcinoma in situ (DCIS) is a non-invasive proliferative growth in the breast that serves as a non-obligate precursor to invasive ductal carcinoma. The widespread adoption of screening mammography has led to a steep increase in the detection of DCIS, which now comprises approximately 20% of new breast cancer diagnoses in the United States. Interestingly, the intratumoral heterogeneity (ITH) that has been observed in invasive breast cancers may have been established early in tumorigenesis, given the vast and varied ITH that has been detected in DCIS. This review will discuss the intratumoral heterogeneity of DCIS, focusing on the phenotypic and genomic heterogeneity of tumor cells, as well as the compositional heterogeneity of the tumor microenvironment. In addition, we will assess the spatial heterogeneity that is now being appreciated in these lesions, and summarize new approaches to evaluate heterogeneity of tumor and stromal cells in the context of their spatial organization. Importantly, we will discuss how a growing understanding of ITH has led to a more holistic appreciation of the complex biology of DCIS, specifically its evolution and natural history. Finally, we will consider ways in which our knowledge of DCIS ITH might be translated in the future to guide clinical care for DCIS patients.

Gap Junctions and Wnt Signaling in the Mammary Gland: a Cross-Talk?

Abstract

Connexins (Cxs), the building blocks of gap junctions (GJs), exhibit spatiotemporal patterns of expression and regulate the development and differentiation of the mammary gland, acting via channel-dependent and channel-independent mechanisms. Impaired Cx expression and localization are reported in breast cancer, suggesting a tumor suppressive role for Cxs. The signaling events that mediate the role of GJs in the development and tumorigenesis of the mammary gland remain poorly identified. The Wnt pathways, encompassing the canonical or the Wnt/β-catenin pathway and the noncanonical β-catenin-independent pathway, also play important roles in those processes. Indeed, aberrant Wnt signaling is associated with breast cancer. Despite the coincident roles of Cxs and Wnt pathways, the cross-talk in the breast tissue is poorly defined, although this is reported in a number of other tissues. Our previous studies revealed a channel-independent role for Cx43 in inducing differentiation or suppressing tumorigenesis of mammary epithelial cells by acting as a negative regulator of the Wnt/β-catenin pathway. Here, we provide a brief overview of mammary gland development, with emphasis on the role of Cxs in development and tumorigenesis of this tissue. We also discuss the role of Wnt signaling in similar contexts, and review the literature illustrating interplay between Cxs and Wnt pathways.

Oxytocin Induces Mammary Epithelium Disruption and Could Stimulate Epithelial Cell Exfoliation

Abstract

Mammary epithelial cells (MEC) are exfoliated from the epithelium into milk, influencing the number of MEC present in the udder. This process is associated with epithelium integrity. The release of oxytocin (OT) induced by milking causes myoepithelial cell contraction, which, in turn, may stimulate MEC exfoliation through mechanical forces. To investigate the role of OT in MEC exfoliation, we inhibited or induced myoepithelial cell contraction by injecting the OT receptor antagonist atosiban (Ato) or a supraphysiological dose of OT, respectively. Eight cows were assigned to 2 treatments during 2 milkings according to a crossover experimental design: Control+OT (cows were first milked to collect standard milk and then received 5 IU of OT to collect residual milk through a second milking) and Ato + OT (cows were injected with Ato (50 μg/kg of body weight) and milked to collect cisternal milk, then received 5 IU of OT to collect alveolar milk through a second milking). Milk MEC were purified to determine their concentration and number in milk. Mammary epithelium integrity was assessed by measuring the kinetics of plasma lactose concentration. Inhibiting myoepithelial cell contraction by Ato injection decreased the number of exfoliated MEC in milk. In contrast, OT injection increased the concentration of MEC in the residual milk and the number of MEC in the alveolar milk. Ato injection reduced plasma lactose concentration, whereas, in both treatments, OT injections increased it. Our results suggested that myoepithelial cell contraction caused by OT could stimulate MEC exfoliation into milk and was associated with epithelium disruption.

cIAP2 Is an Independent Signaling and Survival Factor during Mammary Lactational Involution and Tumorigenesis

Abstract

Cellular inhibitor of apoptosis proteins-1 and -2 (cIAP1/2) are integral to regulation of apoptosis and signaling by the tumor necrosis factor (TNF) and related family of receptors. The expression of cIAP2 in tissues is typically low and considered functionally redundant with cIAP1, however cIAP2 can be activated by a variety of cellular stresses. Members of the TNFR family and their ligands have essential roles in mammary gland biology. We have found that cIAP2^−/− virgin mammary glands have reduced ductal branching and delayed lobuloalveogenesis in early pregnancy. Post-lactational involution involves two phases where the first phase is reversible and is mediated, in part, by TNFR family ligands. In cIAP2−/− mice mammary glands appeared engorged at mid-lactation accompanied by enhanced autophagic flux and decreased cIAP1 protein expression. Severely stretched myoepithelium was associated with BIM-EL expression and other indicators of anoikis. Within 24 h after forced or natural weaning, cIAP2^−/− glands had nearly completed involution. The TNF-related weak inducer of apoptosis (Tweak) which results in degradation of cIAP1 through its receptor, Fn14, began to increase in late lactation and was significantly increased in cIAP2^−/− relative to WT mice by 12 h post weaning accompanied by decreased cIAP1 protein expression. Carcinogen/progesterone-induced mammary tumorigenesis was significantly delayed in cIAP2^−/− mice and tumors contained high numbers of apoptotic cells. We conclude that cIAP2 has a critical role in the mammary gland wherein it prevents rapid involution induced by milk stasis-induced stress associated with Tweak activation and contributes to the survival of mammary tumor cells.

Can Bovine Leukemia Virus Be Related to Human Breast Cancer? A Review of the Evidence

Abstract

The incidence of breast cancer is continuously increasing worldwide, as influenced by many factors that act synergistically. In the last decade there was an increasing interest in the possible viral etiology of human breast cancer. Since then, many viruses have been associated with this disease (murine mammary tumor virus, MMTV; Epstein-Barr virus, EBV; and human papillomavirus, HPV). Recently, BLV has been identified in human breast cancers giving rise to the hypothesis that it could be one of the causative agents of this condition. BLV is a retrovirus distributed worldwide that affects cattle, causing lymphosarcoma in a small proportion of infected animals. Because of its similarity with human retroviruses like HTLV and HIV, BLV was assumed to also be involved in tumor emergence. Based on this assumption, studies were focused on the possible role of BLV in human breast cancer development. We present a compilation of the current knowledge on the subject and some prospective analysis that is required to fully end this controversy.

Attenuation of Mammary Gland Dysplasia and Feeding Difficulties in Tabby Mice by Fetal Therapy

Abstract

Hypohidrotic ectodermal dysplasias (HED) are hereditary differentiation disorders of multiple ectodermal structures including the mammary gland. The X-linked form of HED (XLHED) is caused by a lack of the secreted signaling molecule ectodysplasin A1 (EDA1) which is encoded by the gene EDA and belongs to the tumor necrosis factor (TNF) superfamily. Although male patients (hemizygous) are usually more severely affected by XLHED, heterozygous female carriers of an EDA mutation may also suffer from a variety of symptoms, in particular from abnormal development of their breasts. In Tabby mice, a well-studied animal model of XLHED, EDA1 is absent. We investigated the effects of prenatal administration of Fc-EDA, a recombinant EDA1 replacement protein, on mammary gland development in female Tabby mice. Intra-amniotic delivery of Fc-EDA to fetal animals resulted later in improved breastfeeding and thus promoted the growth of their offspring. In detail, such treatment led to a normalization of the nipple shape (protrusion, tapering) that facilitated sucking. Mammary glands of treated female Tabby mice also showed internal changes, including enhanced branching morphogenesis and ductal elongation. Our findings indicate that EDA receptor stimulation during development has a stable impact on later stages of mammary gland differentiation, including lactation, but also show that intra-amniotic administration of an EDA1 replacement protein to fetal Tabby mice partially corrects the mammary gland phenotype in female adult animals.

Breaking through to the Other Side: Microenvironment Contributions to DCIS Initiation and Progression

Abstract

Refinements in early detection, surgical and radiation therapy, and hormone receptor-targeted treatments have improved the survival rates for breast cancer patients. However, the ability to reliably identify which non-invasive lesions and localized tumors have the ability to progress and/or metastasize remains a major unmet need in the field. The current diagnostic and therapeutic strategies focus on intrinsic alterations within carcinoma cells that are closely associated with proliferation. However, substantial accumulating evidence has indicated that permissive changes in the stromal tissues surrounding the carcinoma play an integral role in breast cancer tumor initiation and progression. Numerous studies have suggested that the stromal environment surrounding ductal carcinoma in situ (DCIS) lesions actively contributes to enhancing tumor cell invasion and immune escape. This review will describe the current state of knowledge regarding the mechanisms through which the microenvironment interacts with DCIS lesions focusing on recent studies that describe the contributions of myoepithelial cells, fibroblasts and immune cells to invasion and subsequent progression. These mechanisms will be considered in the context of developing biomarkers for identifying lesions that will progress to invasive carcinoma and/or developing approaches for therapeutic intervention.

Modeling Human Ductal Carcinoma In Situ in the Mouse

Abstract

Breast cancer development is a multi-step process in which genetic and molecular heterogeneity occurs at multiple stages. Ductal carcinoma arises from pre-invasive lesions such as atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS), which progress to invasive and metastatic cancer. The feasibility of obtaining tissue samples from all stages of progression from the same patient is low, and thus molecular studies dissecting the mechanisms that mediate the transition from pre-invasive DCIS to invasive carcinoma have been hampered. In the past 25 years, numerous mouse models have been developed that partly recapitulate the histological and biological properties of early stage lesions. In this review, we discuss in vivo model systems of breast cancer progression from syngeneic mouse models to human xenografts, with particular focus on how accurately these models mimic human disease.

Familiarity and Retronasal Aroma Alter Food Perception

Abstract

Introduction

When participants eat foods, they direct their attention to the particular taste quality that is the target of evaluation and subsequently perceive the intensity of the attended taste quality. We defined the ease with which participants pay attention to a particular taste quality as the "noticeability" of that quality. In our previous study, Japanese participants evaluated noticeability and intensity of five fundamental taste qualities (sweetness, umami, saltiness, sourness, and bitterness) under open- and closed-nostril conditions, using a popular traditional Japanese confection, yokan. The correlation between noticeability and intensity of sweetness was significantly reduced when participants were tested with open nostrils. Therefore, we hypothesized that high familiarity with a food and its olfactory information is necessary to decrease the correlation between these two scales.

Methods

In order to verify this hypothesis, we asked Japanese and German participants, who have different food cultures, to subjectively evaluate yokan, which is familiar to Japanese but unfamiliar to Germans. In a control condition, marshmallows were used which are familiar to all participants. Participants consumed each food under open- and closed-nostril conditions and evaluated the noticeability and intensity of the five fundamental taste qualities.

Results

There were significant differences between the participants' groups as the correlation between noticeability and intensity was reduced significantly only for sweetness of a familiar food under open-nostril condition.

Conclusions

These results support our hypothesis that high familiarity with a food and its olfactory information might be necessary to decrease the correlation between noticeability and intensity of a particular taste quality.

Implications

This finding suggests that perception of a food is influenced by its familiarity and retronasal aroma. These results suggest when a food is unfamiliar, the noticeability and intensity of a particular taste quality are not much altered by the retronasal aroma, but when a food is highly familiar, retronasal aroma serves to decouple noticeability and intensity of a given taste quality.

Crossmodal Associations Between Olfaction and Vision: Color and Shape Visualizations of Odors

Abstract

Introduction

In the present study, we assessed crossmodal associations between odors and both color and shape, with particular interest in the principles beneath these mappings. We hypothesized that visual associations of odors would primarily reflect observable features of a smelling object and thus vary with different source assumptions of the very same smell.

Methods

We asked 30 participants to visualize their odor associations on a drawing tablet, freely deciding on color and shape. Additionally, subjects provided ratings on perceptual and shape-related dimensions as well as a verbal label for each sample.

Results

With respect to color selection, the results confirmed a source-based mapping approach: odors rated as familiar were associated with very particular colors that typically resembled the appearance of their source. For less familiar odors, color selection was rather inconsistent but still then went along with assumed odor objects. Shape ratings changed with odor identifications as well, but considerably less than for color associations. Shape ratings and shape drawings produced very different results. While shape ratings were unlikely rooted in the mental imagery of a shape, drawings frequently displayed concrete objects that depended on odor label.

Conclusions

Results confirm the existence of stable odor–vision correspondences and suggest that language plays a major part in mediating these mappings. The frequently assumed hedonic foundation of crossmodal matchings could not be confirmed for this stimuli set.

Implications

Odor sensations may trigger odor naming spontaneously. Assumptions about an odor's identity, as well as the multisensory knowledge we have acquired on it, affect the visual associations of an odor.

Matrine promotes liver cancer cell apoptosis by inhibiting mitophagy and PINK1/Parkin pathways

Abstract

Matrine is a natural alkaloid isolated from the root and stem of the legume plant Sophora. Its anti-proliferative and pro-apoptotic effects on several types of cancer have been well-documented. However, the role of matrine in regulating mitochondrial homeostasis, particularly mitophagy in liver cancer apoptosis, remains uncertain. The aim of our study was to explore whether matrine promotes liver cancer cell apoptosis by modifying mitophagy. HepG2 cells were used in the study and treated with different doses of matrine. Cell viability and apoptosis were determined by MTT assay, TUNEL staining, western blotting, and LDH release assay. Mitophagy was monitored by immunofluorescence assay and western blotting. Mitochondrial function was assessed by immunofluorescence assay, ELISA, and western blotting. The results of our study indicated that matrine treatment dose-dependently reduced cell viability and increased the apoptotic rate of HepG2 cells. Functional studies demonstrated that matrine treatment induced mitochondrial dysfunction and activated mitochondrial apoptosis by inhibiting protective mitophagy. Re-activation of mitophagy abolished the pro-apoptotic effects of matrine on HepG2 cells. Molecular investigations further confirmed that matrine regulated mitophagy via the PINK1/Parkin pathways. Matrine blocked the PINK1/Parkin pathways and repressed mitophagy, whereas activation of the PINK1/Parkin pathways increased mitophagy activity and promoted HepG2 cell survival in the presence of matrine. Together, our data indicated that matrine promoted HepG2 cell apoptosis through a novel mechanism that acted via inhibiting mitophagy and the PINK1/Parkin pathways. This finding provides new insight into the molecular mechanism of matrine for treating liver cancer and offers a potential target to repress liver cancer progression by modulating mitophagy and the PINK1/Parkin pathways.

Upregulation of HSP60 expression in the postnatal rat cochlea and rats with drug-induced hearing loss

Abstract

Heat shock protein 60 (HSP60) is a highly conserved chaperone molecule that plays important roles in mediating some physiological and pathological functions. However, researchers have not yet determined whether HSP60 is expressed in the mammalian cochlea. This study constitutes the first investigation of the expression of HSP60 in the postnatal rat cochlea. We also examined the expression of HSP60 in rats with drug-induced hearing loss. Auditory thresholds were assessed by monitoring the auditory brainstem response (ABR) prior to and after drug injection. Expression levels of the HSP60 gene (Hsp60) and HSP60 protein in the rat cochlea were detected by quantitative real-time polymerase chain reaction and Western blotting, respectively. The distribution of HSP60 in the rat cochlea was further examined by immunofluorescence staining. We have demonstrated that HSP60 was expressed in the postnatal rat cochlea in an age-dependent and cell-specific manner. In addition, after drug exposure, the average hearing threshold of rats in the experimental group was significantly higher than that in the control group, with increased HSP60 expression level in response to kanamycin and furosemide treatments. HSP60 expression was observed in the supporting cells (SCs) within the organ of Corti in both the uninjured and the injured cochlea, but it was undetectable in the mechanosensory hair cells (HCs) and spiral ganglion neurons. Therefore, our research suggests that HSP60 may play an important role in auditory function.

Palmitic acid induces human osteoblast-like Saos-2 cell apoptosis via endoplasmic reticulum stress and autophagy

Abstract

Palmitic acid (PA) is the most common saturated long-chain fatty acid in food that causes cell apoptosis. However, little is known about the molecular mechanisms of PA toxicity. In this study, we explore the effects of PA on proliferation and apoptosis in human osteoblast-like Saos-2 cells and uncover the signaling pathways involved in the process. Our study showed that endoplasmic reticulum (ER) stress and autophagy are involved in PA-induced Saos-2 cell apoptosis. We found that PA inhibited the viability of Saos-2 cells in a dose- and time-dependent manner. At the same time, PA induced the expression of ER stress marker genes (glucose-regulated protein 78 (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP)), altered autophagy-related gene expression (microtubule-associated protein 1 light chain 3 (LC3), ATG5, p62, and Beclin), promoted apoptosis-related gene expression (Caspase 3 and BAX), and affected autophagic flux. Inhibiting ER stress with 4-PBA diminished the PA-induced cell apoptosis, activated autophagy, and increased the expression of Caspase 3 and BAX. Inhibiting autophagy with 3-MA attenuated the PA and ER stress-induced cell apoptosis and the apoptosis-related gene expression (Caspase 3 and BAX), but seemed to have no obvious effects on ER stress, although the CHOP expression was downregulated. Taken together, our results suggest that PA-induced Saos-2 cell apoptosis is activated via ER stress and autophagy, and the activation of autophagy depends on the ER stress during this process.

Role of the heat shock protein family in bone metabolism

Abstract

Heat shock proteins (HSPs) are a family of proteins produced by cells in response to exposure to stressful conditions. In addition to their role as chaperones, they also play an important role in the cardiovascular, immune, and other systems. Normal bone tissue is maintained by bone metabolism, particularly by the balance between osteoblasts and osteoclasts, which are physiologically regulated by multiple hormones and cytokines. In recent years, studies have reported the vital role of HSPs in bone metabolism. However, the conclusions remain largely controversial, and the exact mechanisms are still unclear, so a review and analyses of previous studies are of importance. This article reviews the current understanding of the roles and effects of HSPs on bone cells (osteoblasts, osteoclasts, and osteocytes), in relation to bone metabolism.

Insights into archaeal chaperone machinery: a network-based approach

Abstract

Molecular chaperones are a diverse group of proteins that ensure proteome integrity by helping the proteins fold correctly and maintain their native state, thus preventing their misfolding and subsequent aggregation. The chaperone machinery of archaeal organisms has been thought to closely resemble that found in humans, at least in terms of constituent players. Very few studies have been ventured into system-level analysis of chaperones and their functioning in archaeal cells. In this study, we attempted such an analysis of chaperone-assisted protein folding in archaeal organisms through network approach using Picrophilus torridus as model system. The study revealed that DnaK protein of Hsp70 system acts as hub in protein-protein interaction network. However, DnaK protein was present only in a subset of archaeal organisms and absent from many archaea, especially members of Crenarchaeota phylum. Therefore, a similar network was created for another archaeal organism, Sulfolobus solfataricus, a member of Crenarchaeota. The chaperone network of S. solfataricus suggested that thermosomes played an integral part of hub proteins in archaeal organisms, where DnaK was absent. We further compared the chaperone network of archaea with that found in eukaryotic systems, by creating a similar network for Homo sapiens. In the human chaperone network, the UBC protein, a part of ubiquitination system, was the most important module, and interestingly, this system is known to be absent in archaeal organisms. Comprehensive comparison of these networks leads to several interesting conclusions regarding similarities and differences within archaeal chaperone machinery in comparison to humans.

Protective effects of zymosan on heat stress-induced immunosuppression and apoptosis in dairy cows and peripheral blood mononuclear cells

Abstract

Dairy cows exposed to heat stress (HS) show decreased performance and immunity, but increased heat shock protein expressions and apoptosis. Zymosan, an extract from yeast cell walls, has been shown to modulate immune responses and defense against oxidative stress. However, few literatures are available about the effects of zymosan on immune responses and other parameters of the dairy cows under HS. Here, both primary peripheral blood mononuclear cell (PBMC) and dairy cow models were established to assess the effects of zymosan on performance, immunity, heat shock protein, and apoptosis-related gene expressions of dairy cows under HS. In vitro study showed that proliferation, IL-2 production, and Bcl-2/Bax-α ratio of cow primary PBMC were reduced, whereas hsp70 mRNA and protein expressions, as well as Annexin V-bing, were increased when PBMCs were exposed to heat. In contrast, zymosan significantly reversed these above changes induced by the HS. In the in vivo study, 40 Holstein dairy cows were randomly selected and assigned into zymosan group (supplemental zymosan; n = 20) and control group (no supplemental zymosan; n = 20). The results showed that zymosan improved significantly the dry matter intake and milk yield, increased IgA, IL-2, and tumor necrosis factor-α (TNF-α) contents in sera, as well as hepatic Bcl-2/Bax-α ratio, but decreased respiration rate and hepatic hsp70 expressions in the dairy cows under HS. Taken together, zymosan could alleviate HS-induced immunosuppression and apoptosis and improve significantly the productive performance and immunity of dairy cows under HS.

Differential correlations between changes to glutathione redox state, protein ubiquitination, and stress-inducible HSPA chaperone expression after different types of oxidative stress

Abstract

In primary bovine fibroblasts with an hspa1b/luciferase transgene, we examined the intensity of heat-shock response (HSR) following four types of oxidative stress or heat stress (HS), and its putative relationship with changes to different cell parameters, including reactive oxygen species (ROS), the redox status of the key molecules glutathione (GSH), NADP(H) NAD(H), and the post-translational protein modifications carbonylation, S-glutathionylation, and ubiquitination. We determined the sub-lethal condition generating the maximal luciferase activity and inducible HSPA protein level for treatments with hydrogen peroxide (H₂O₂), UVA-induced oxygen photo-activation, the superoxide-generating agent menadione (MN), and diamide (DA), an electrophilic and sulfhydryl reagent. The level of HSR induced by oxidative stress was the highest after DA and MN, followed by UVA and H₂O₂ treatments, and was not correlated to the level of ROS production nor to the extent of protein S-glutathionylation or carbonylation observed immediately after stress. We found a correlation following oxidative treatments between HSR and the level of GSH/GSSG immediately after stress, and the increase in protein ubiquitination during the recovery period. Conversely, HS treatment, which led to the highest HSR level, did not generate ROS nor modified or depended on GSH redox state. Furthermore, the level of protein ubiquitination was maximum immediately after HS and lower than after MN and DA treatments thereafter. In these cells, heat-induced HSR was therefore clearly different from oxidative stress-induced HSR, in which conversely early redox changes of the major cellular thiol predicted the level of HSR and polyubiquinated proteins.

Does water stress promote the proteome-wide adjustment of intrinsically disordered proteins in plants?

Abstract

Plant response to water stress involves the activation of mechanisms expected to help them cope with water scarcity. Among these mechanisms, proteome-wide adjustment is well known. This includes actions to save energy, protect cellular and molecular components, and maintain vital functions of the cell. Intrinsically disordered proteins, which are proteins without a rigid three-dimensional structure, are seen as emerging multifunctional cellular components of proteomes. They are highly abundant in eukaryotic proteomes, and numerous functions for these proteins have been proposed. Here, we discuss several reasons why the collection of intrinsically disordered proteins in a proteome (disordome) could be subjected to an active regulation during conditions of water scarcity in plants. We also discuss the potential misinterpretations of disordome content estimations made so far due to bias-prone data and the need for reliable analysis based on experimental data in order to acknowledge the plasticity nature of the disordome.

Identification of differentially expressed microRNAs in Sahiwal ( Bos indicus) breed of cattle during thermal stress

Abstract

microRNAs (miRNAs) are a class of small non-coding RNAs that play key roles in post transcriptional gene regulation that influence various fundamental cellular processes, including the cellular responses during environmental stresses. However, perusal of literatures revealed few reports on the differential expression of miRNA during thermal stress in Indian native (Bos indicus) cattle breeds. The present investigation aimed to identify differentially expressed miRNAs during thermal stress in Sahiwal (Bos indicus) dairy cattle breed of India, adapted with tropical climate over a long period of time. Stress responses of the animals were characterized by determining various physiological as well as biochemical parameters and differential expression profile of major heat shock protein genes. Ion Torrent deep sequencing and CLC-genomic analysis identified a set of differentially expressed miRNAs during summer and winter seasons. Most of the identified differentially expressed miRNAs were found to target heat shock responsive genes especially members of heat shock protein (HSP) family. Real-time quantification-based analysis of selected miRNAs revealed that bta-mir-1248, bta-mir-2332, bta-mir-2478, and bta-mir-1839 were significantly (p < 0.01) over expressed while bta-mir-16a, bta-let-7b, bta-mir-142, and bta-mir-425 were significantly (p < 0.01) under expressed during summer in comparison to winter. The present study enlists differentially expressed miRNAs at different environmental temperatures in Sahiwal (Bos indicus) that may be importance for further understanding the role of miRNAs on thermo-regulatory mechanisms.

Garlic ( Allium sativum ) exhibits a cardioprotective effect in experimental chronic renal failure rat model by reducing oxidative stress and controlling cardiac Na + /K + -ATPase activity and Ca 2+ levels

Abstract

Gentamicin (GNT)-induced nephrotoxicity culminates into renal failure with a possible cardiovascular impact. Garlic extract (GE) is a cardiovascular protectant with limited mechanistic data. Therefore, we assessed the disturbance in specific cardiac parameters and the potential protective effect of GE supplementation against them in a rat model of GNT-induced chronic renal failure (CRF). Adult male rats (n = 24) were randomly assigned into four groups (n = 6 each): normal controls (CON), garlic extract controls (GE; 250 mg kg⁻¹, orally), GNT-induced CRF (GNT; 100 mg kg⁻¹, i.p.), and GNT + GE (GNT and GE in the same previous doses) groups. GNT and GE were given daily for 3 weeks. Animals co-treated with GNT and GE exhibited improved renal functions, body weight (BW), and heart weight (HW)/BW ratio; declined blood pressure; lowered plasma levels of lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), and total peroxides (TP); and elevated total antioxidant capacity (TAC) levels. Moreover, the heart tissue contained raised levels of TAC and Na⁺/K⁺-ATPase activity and lowered levels of TP and Ca²⁺. Findings provide evidence that administration of GE in experimental CRF model helped protect the heart through reducing oxidative stress and controlling cardiac Na⁺/K⁺-ATPase activity and Ca²⁺ levels.

Heat stress-induced renal damage in poultry and the protective effects of HSP60 and HSP47

Abstract

The present study investigates the effects of heat stress on the kidney in broilers, based on previous findings which showed that heat stress caused cardiac damage in broilers. Further, the possible renoprotective role of aspirin and the heat shock proteins HSP60 and HSP47 was also investigated. The enzyme levels of urea and uric acid, which are indicators of renal damage, and lactate dehydrogenase, an indicator of oxidative damage, were measured in chickens that were only exposed to heat stress, chickens that were pretreated with aspirin before heat stress, and chickens that were only treated with aspirin. Further, histological examination of renal tissue from the three groups was also performed. Finally, expression of HSP60 and HSP47 was also examined. In the heat stress group, the enzyme measurements were indicative of renal dysfunction and oxidative damage, and the histological findings were indicative of renal ischemia and damage. Aspirin seemed to have a protective effect against the renal damage caused by the stress, based on the enzyme measurements and histopathological findings in the aspirin-treated group. The findings also indicate that aspirin may induce HSP60 and HSP47 expression in renal cells. Finally, the expression patterns of HSP60 and HSP47 indicated that they may play a renoprotective role, as their expression was higher in the aspirin-treated groups. In conclusion, the present findings show that heat stress causes renal damage in poultry and that aspirin may play a protective role against this damage via pathways that involve HSP60 and HSP47.

Physiological resilience of a temperate soft coral to ocean warming and acidification

Abstract

Atmospheric concentration of carbon dioxide (CO₂) is increasing at an unprecedented rate and subsequently leading to ocean acidification. Concomitantly, ocean warming is intensifying, leading to serious and predictable biological impairments over marine biota. Reef-building corals have proven to be very vulnerable to climate change, but little is known about the resilience of non-reef-building species. In this study, we investigated the effects of ocean warming and acidification on the antioxidant enzyme activity (CAT—catalase, and GST—glutathione S-transferase), lipid peroxidation (using malondialdehyde, MDA—levels as a biomarker) and heat shock response (HSP70/HSC70 content) of the octocoral Veretillum cynomorium. After 60 days of acclimation, no mortalities were registered in all treatments. Moreover, CAT and GST activities, as well as MDA levels, did not change significantly under warming and/or acidification. Heat shock response was significantly enhanced under warming, but high CO₂ did not have a significant effect. Contrasting to many of their tropical coral-reef relatives, our findings suggest that temperate shallow-living octocorals may be able to physiologically withstand future conditions of increased temperature and acidification.

Characterizing functional differences in sea anemone Hsp70 isoforms using budding yeast

Abstract

Marine organisms experience abiotic stressors such as fluctuations in temperature, UV radiation, salinity, and oxygen concentration. Heat shock proteins (HSPs) assist in the response of cells to these stressors by refolding and maintaining the activity of damaged proteins. The well-conserved Hsp70 chaperone family is essential for cell viability as well as the response to stress. Organisms possess a variety of Hsp70 isoforms that differ slightly in amino acid sequence, yet very little is known about their functional relevance. In this study, we undertook analysis of three principal Hsp70 isoforms NvHsp70A, B, and D from the starlet sea anemone Nematostella vectensis. The functionality of Hsp70 isoforms in the starlet sea anemone was assessed through transcriptional analysis and by heterologous expression in budding yeast Saccharomyces cerevisiae. Interestingly, these isoforms were found to not only differ in expression under stress but also appear to have functional differences in their ability to mediate the cellular stress program. These results contribute to an understanding of Hsp70 isoform specificity, their shared and unique roles in response to acute and chronic environmental stress, and the potential basis of local adaptation in populations of N. vectensis.

Elevated expression of DJ-1 (encoded by the human PARK7 gene) protects neuronal cells from sevoflurane-induced neurotoxicity

Abstract

Sevoflurane, an inhaled ether general anesthetic agent, exerts a variety of neurotoxic effects, including oxidative stress, mitochondrial dysfunction, and neuronal apoptosis. However, the underlying molecular mechanisms remain to be elucidated. DJ-1 is a protein that exerts neuroprotective effects against different kinds of stress through multiple pathways. This study aimed to investigate the neuroprotective effects of DJ-1 against sevoflurane-induced neurotoxicity. Here, we found that sevoflurane treatment significantly increased DJ-1 expression in human neuroblastoma M17 cells in a dose-dependent manner at both the mRNA and protein levels. Interestingly, we found that overexpression of wild-type (WT) DJ-1 prevented sevoflurane-induced generation of reactive oxygen species (ROS) and nitric oxide (NO), deletion of reduced GSH, reduction of adenosine triphosphate (ATP), and mitochondrial membrane potential. Interestingly, we found that WT DJ-1 could inhibit sevoflurane-induced apoptosis by modulating the mitochondrial pathway. However, its "loss of function" mutation DJ-1(L166P) exacerbated sevoflurane-induced neurotoxicity in M17 cells. Our findings suggest that WT DJ-1 protects neuronal cells against sevoflurane-induced neurotoxicity.

Topical heat shock protein 70 prevents imiquimod-induced psoriasis-like inflammation in mice

Abstract

Psoriasis is a chronic inflammatory skin disease with systemic manifestations and potential genetic etiology. The newest treatments utilize antibodies against one of several cytokines known to underlie the inflammatory signaling molecules that produce the skin and systemic symptoms. However, these agents must be regularly injected, and they may compromise the normal responses of the immune system. Furthermore, they do not address the causes of the abnormal immunoregulatory responses of the disease because the etiology is not yet completely understood. In this short-term treatment study, the potential anti-inflammatory activity of an alfalfa-derived Hsp70-containing skin cream (aHsp70) was tested on imiquimod (IMQ)-induced psoriasis-like lesions in wild-type mice. Treatment of the mice with the aHsp70 skin cream simultaneously with the imiquimod application mitigated the induction of psoriatic-like lesions and correlated with altered expression of various skin cytokines.

Association between circulating levels of heat-shock protein 27 and aggressive periodontitis

Abstract

Heat-shock protein (Hsp) 27 is a major intracellular molecular chaperone and controller of intracellular responses to inflammatory signals. In the extracellular space, recombinant Hsp27 has been described to exert anti-inflammatory activities. The aim of this study was to assess the association between circulating levels of Hsp27 and different types of periodontitis. Pro- and anti-inflammatory cytokines and the stress proteins Hsp27 and Hsp60 with proposed anti- and pro-inflammatory properties, respectively, were measured by two-site ELISA in the serum of patients with aggressive periodontitis (AgP, n = 30), chronic periodontitis (CP, n = 29) and periodontally healthy controls (H, n = 28). Furthermore, Hsp27 and Hsp60 levels were also measured longitudinally in 12 AgP patients at 6 time points up to 3 months after treatment. AgP patients had lower levels of Hsp27 compared to CP patients and healthy subjects (adjusted one-way ANOVA, p < 0.001, followed by post hoc Tukey HSD comparisons), while no differences in levels of Hsp60 or cytokines between the three groups were detected. In CP patients and H subjects, the systemic Hsp27 levels correlated with Hsp60 (r = 0.43, p < 0.001; r = 0.59, p < 0.001, respectively) and with pro-inflammatory cytokines TNF-α (r = 0.48, p < 0.001; r = 0.55, p < 0.001, respectively) and IL-6 (r = 0.44, p < 0.01). However, no such correlations were detected in AgP cases. No consistent temporal patterns of changes of Hsp27 concentration were detected across AgP patients following periodontal treatment. This study provides the first evidence that Hsp27 may be differentially expressed and regulated in AgP patients as compared with CP patients and healthy individuals.

Drug-induced keratin 9 interaction with Hsp70 in bladder cancer cells

Abstract

A pull-down experiment (co-immunoprecipitation) was performed on a T24 human bladder cancer cell lysate treated with the Hsp inhibitor VER155008 using an Hsp70 antibody attached to Dynabeads. Keratin 9, a cytoskeleton intermediate filament protein, was identified by LC MS/MS analysis. This novel finding was confirmed by Western blotting, RT-PCR, and immunocytochemistry. Other members of the keratin family of proteins have been shown to be involved in cancer progression, most recently identified to be associated with cell invasion and metastasis. The specific role of keratin 9 expression in these cells is yet to be determined.

Rosmarinic acid and siRNA combined therapy represses Hsp27 (HSPB1) expression and induces apoptosis in human glioma cells

Abstract

High expression of Hsp27 in glioma cells has been closely associated with tumor cell proliferation and apoptosis inhibition. The aim of the present study was to asses the effects of rosmarinic acid (RA) on Hsp27 expression and apoptosis in non-transfected and transfected human U-87 MG cells. The effect of rosmarinic acid was compared to quercetin, which is known to be a good Hsp27 inhibitor. In order to block the expression of Hsp27 gene (HSPB1), transfection with specific siRNAs was performed. Western blotting technique was used to assess the Hsp27 expression, and caspase-3 colorimetric activity assay was performed to determine apoptosis induction. According to the results, it was found that RA and quercetin effectively silenced Hsp27 and both agents induced apoptosis by activating the caspase-3 pathway. Eighty and 215 μM RA decreased the level of Hsp27 by 28.8 and 46.7% and induced apoptosis by 30 and 54%, respectively. For the first time, we reported that rosmarinic acid has the ability to trigger caspase-3 induced apoptosis in human glioma cells. As a result of siRNA transfection, the Hsp27 gene was silenced by ~ 50% but did not cause a statistically significant change in caspase-3 activation. It was also observed that apoptosis was induced at a higher level as a result of Hsp27 siRNA and subsequent quercetin or RA treatment. siRNA transfection and 215 μM RA treatment suppressed Hsp27 expression level by 90.5% and increased caspase-3 activity by 58%. Herein, we demonstrated that RA administered with siRNA seems to be a potent combination for glioblastoma therapy.

Hyperhidrose – Ätiopathogenese, Diagnostik, Klinik und Therapie

Zusammenfassung

Die Hyperhidrose tritt meist als primäre, selten als sekundäre symptomatische Hyperhidrose auf. Die primäre Hyperhidrose wird als komplexe neuropathische Dysregulation mit genetischer Disposition verstanden, die ein pathologisches Schwitzverhalten mit vermehrter Schweißsekretion über mindestens 6 Monate bedingt und mindestens 4 der folgenden Diagnosekriterien erfüllt: Betroffenheit der Axillae und/oder der Handinnenflächen und/oder der Fußsohlen und/oder des Stirnbereiches, symmetrisches Auftreten, kein nächtliches Schwitzen, Häufigkeit des Auftretens mindestens wöchentlich, Beginn der Erkrankung vor dem 25. Lebensjahr, positive Familienanamnese sowie Beeinträchtigung der täglichen Aktivitäten. Zur Therapie der primären Hyperhidrose werden v. a. topisch Aluminiumsalze und Anticholinergika, Leitungswasseriontophorese sowie intrakutan Botulinumtoxin angewendet. In der systemischen Therapie kommen ebenfalls verschiedene Anticholinergika zum Einsatz. Meist als Ultima-Ratio-Therapie werden chirurgische Verfahren angewendet. Außerdem sind Verfahren zur Thermolyse entwickelt worden.

„Schuppenflechte“ oder „Psoriasis“?

Versorgungsforschung in der Dermatologie 2018 – Kraft des Faktischen

Zusammenfassung

In der in Deutschland praktizierten Dermatologie ist Versorgungsforschung eine etablierte und hoch differenzierte Disziplin. In vielen universitären dermatologischen Einrichtungen und niedergelassenen Praxen werden Studien zu Vorgängen der gesundheitlichen Versorgung bei Hautkrankheiten durchgeführt. Unter dem Dach der Deutschen Dermatologischen Gesellschaft und des Berufsverbandes der Deutschen Dermatologen wird ein wesentlicher Teil der Studien und Projekte des Competenzzentrums Versorgungsforschung in der Dermatologie (CVderm) als bundesweites Referenzzentrum getragen. Wichtige Projekte sind Implementierung von Patientenregistern, Umsetzung nationaler Versorgungsstudien, Forschung mit Sekundärdaten sowie Durchführung methodischer Studien zur Weiterentwicklung wissenschaftlicher Fragestellungen. Wichtige Ergebnisse sind die nationalen Versorgungskonferenzen für Psoriasis, Hautkrebs, Wunden und Neurodermitis, die regionalen Versorgungsnetze sowie Projekte und Kooperationen mit Krankenkassen, Selbstverwaltung und öffentlichen Trägern. Im Interesse der verbesserten Patientenversorgung werden wichtige Faktoren der Versorgung laufend verbessert. Zukünftige dermatologische Versorgungsforschung wird in noch effizienterer Weise zur besseren Versorgungsplanung und -lenkung beitragen. Patientenregister werden den Transfer von Innovationen in die Versorgung erleichtern und dazu beitragen, dass neue Therapieverfahren angewendet werden können. Register unterstützen auch die Optimierung der Therapieansätze, die inzwischen beispielsweise bei Psoriasis wegen der Fülle an zur Verfügung stehenden Arzneimitteln nicht mehr allein auf der Basis klinischer Studien durchgeführt werden kann. Im Zeitalter der digitalen Medizin kommt der Versorgungsforschung eine noch wichtigere Funktion zu.

Verminderte berufliche Leistungsfähigkeit und Lebensqualität bei Patienten mit moderater bis schwerer Neurodermitis

Zusammenfassung

Hintergrund

Klinische Register tragen zur Evidenzbasierung der Gesundheitsversorgung und zur Umsetzung von Forschungsergebnissen in die Praxis bei. TREATgermany schließt Erwachsene mit moderater bis schwerer Neurodermitis („atopic dermatitis" [AD]) mit prospektiver Beobachtung über mindestens 2 Jahre ein. Der Beitrag zeigt erste Ergebnisse zum Zusammenhang von krankheitsbezogener Lebensqualität und Leistungseinschränkungen im Beruf.

Material und Methoden

Dokumentiert werden objektive und subjektive Outcomes mit validierten Messinstrumenten: klinischer Schweregrad (EASI [Eczema Area and Severity Index], oSCORAD [objective-SCORing Atopic Dermatitis]), Lebensqualität (DLQI [Dermatology Life Quality Index]), Symptome (POEM [Patient-oriented Eczema Measure]), globaler Schweregrad (Investigator Global Assessment [IGA]/Patient Global Assessment [PGA]), Patientenzufriedenheit und berufsbezogene Leistungseinschränkungen (WLQ [Work Limitation Questionnaire]) inklusive Präsentismus (Produktivitätsverlust bei der Arbeit) sowie der Therapieverlauf. Von 06/2016 bis 12/2017 wurden 241 Patienten (Alter 43 ± 15 Jahre; 38,6 % Frauen) in deutschlandweit 19 Zentren eingeschlossen, 69 % waren berufstätig.

Ergebnisse

Erwerbstätige hatten DLQI- und WLQ-Mittelwerte von 10,6 ± 6,9 Punkten bzw. 17,7 ± 18,1 %. Der mittlere Präsentismus betrug 9,2 %. Mit r = 0,39 und 0,33 korrelierten die WLQ- und Präsentismus-Scores signifikant mit dem DLQI (p < 0,001). Eine geringere Lebensqualität war am stärksten mit körperlichen und allgemeinen Leistungseinschränkungen im Beruf assoziiert. Regressionsmodelle zeigten einen Zuwachs von Limitationen bei der Bewältigung von Arbeitsanforderungen um 1,7 % und des Präsentismus um 0,5 % mit der Zunahme des DLQI um 1 Punkt.

Diskussion

Eine moderate bis schwere AD hat negative wirtschaftliche Auswirkungen mit einem mittleren Produktivitätsverlust der Patienten von fast 10 %. Weitere Analysen sollten den Einfluss innovativer Behandlungsmethoden auf Lebensqualität und Arbeitsproduktivität in den Fokus rücken.

Druckdolenter, subkutaner Tumor an der Handinnenfläche

Es brennt uns wieder auf den Nägeln

Panorama Dermatologische Praxis

Schmerzhafte rezidivierende Ulzerationen am Bein

Tinea faciei durch Nannizzia persicolor

Zusammenfassung

Wir berichten über eine Tinea faciei durch Nannizzia (N.) persicolor. Der 4‑jährige Junge hatte sich vermutlich an einem Meerschweinchen infiziert. Gesicherte Infektionen durch N. persicolor sind in Deutschland sehr selten. Möglicherweise wird dieser zoo- und geophile Dermatophyt aber aufgrund seiner Ähnlichkeit mit Trichophyton (T.) mentagrophytes auch nur selten erkannt. Die diagnostischen Merkmale von N. persicolor und seine Unterscheidung von T. mentagrophytes werden deshalb dargestellt. Insbesondere bei Kontakt zu Nagetieren sollte auch an N. persicolor gedacht werden.

Cocktails für die Mundschleimhaut – was ist sinnvoll und was nicht?

Nachruf auf Herrn Prof. Dr. med. Dr. h.c. mult. Otto Braun-Falco

Neue Erkenntnisse zur Psychodermatologie bei Psoriasis

Eingewachsene Zehennägel – Optionen für die tägliche Praxis

Zusammenfassung

Der eingewachsene Zehennagel ist ein häufiges, schmerzhaftes und entzündliches Erkrankungsbild v. a., aber nicht ausschließlich des jugendlichen Patienten. Zahlreiche konservative Behandlungsmethoden stehen zur Verfügung. Meist steht jedoch am Ende einer Leidenskette die operative Therapie. Zur operativen Behandlung wird immer noch die als obsolet einzustufende, sog. Emmert-Plastik eingesetzt. Als schonende Alternative kommt zunehmend die selektive Behandlung des lateralen Matrixhorns durch Resektion oder Phenolkaustik zum Einsatz. Letztere Verfahren bieten zahlreiche Vorteile mit geringem postoperativem Schmerz und schnellerer Wiedererlangung der normalen Lebensqualität.

Kollisionstumoren in der Dermatoskopie

Früherkennung von berufsspezifischen Hauterkrankungen bei Kanalarbeitern

Zusammenfassung

Hintergrund

Hautkrankheiten betreffen 30–70 % der Weltbevölkerung mit seit Jahren kontinuierlich steigenden Inzidenzen von Hautkrebs. Zielgerichtete Präventionsstrategien inklusive frühestmöglicher Detektion von Hauterkrankungen sind daher von entscheidender Bedeutung.

Ziel der Arbeit

Es erfolgte die Untersuchung von Kanalarbeitern auf Hautkrankheiten unter Berücksichtigung ihrer berufsspezifischen Anforderungen.

Methodik

Im Rahmen eines Gesundheitstages erhoben 2 Dermatologen bei Beschäftigten der Münchner Stadtentwässerung standardisierte Ganzkörperinspektionen der Haut. Zusätzlich beantworteten alle Teilnehmer einen Fragebogen zum Risiko- und Präventionsverhalten in Bezug auf Hautkrebs und andere Hauterkrankungen.

Ergebnisse

Von 81 Beschäftigten (79 Männer, 2 Frauen, durchschnittliches Alter 45,7 ± 9,5 Jahre) litten 25 Personen (30,9 %) unter behandlungsbedürftigen Dermatosen: Die häufigsten Diagnosen waren Onychomykosen und Tinea pedis (16,1 %). Daneben wurde bei einem Beschäftigten ein Basalzellkarzinom und bei 2 weiteren wurden aktinische Keratosen gefunden; 43,5 % (30 von 81) aller Teilnehmer gaben an, früher bereits ein Hautkrebsscreening in Anspruch genommen zu haben.

Schlussfolgerung

Zur Früherkennung von berufsspezifischen Hautkrankheiten können gerade betrieblich organisierte Screeninguntersuchungen während der Arbeitszeit eine hocheffektive Maßnahme darstellen, da diese dank einer niedrigen Schwelle meist sehr hohe Teilnehmerzahlen erreichen. So legen die Ergebnisse der vorliegenden Studie den Verdacht nahe, dass Kanalarbeiter aufgrund ihrer beruflichen Exposition gehäuft an Fußpilz erkranken.

Bullosis diabeticorum

Zusammenfassung

Wir berichten über 2 Patienten mit Diabetes mellitus, bei denen sich an den Fingern oder Zehen bis zu 2 cm durchmessende Blasen entwickelten, die nach Ausschluss der zu diskutierenden Differenzialdiagnosen als Bullosis diabeticorum (BD) eingeordnet werden konnten. Die BD ist eine seltene Blasenbildung, die bei Menschen mit Diabetes hauptsächlich palmoplantar beobachtet wird. Das klinische Bild ist gekennzeichnet durch bis zu 10 cm durchmessende, prallelastisch gefüllte Blasen mit klarem bis hämorrhagischem Inhalt. Die Abheilung erfolgt narbenlos, seltener unter Hinterlassung postinflammatorischer Pigmentierung oder zarter Narben. Histopathologisch finden sich sowohl intra- als auch subepidermale Spaltbildungen bei weitgehend fehlendem entzündlichen Infiltrat. Die Ätiopathogenese der BD ist nicht geklärt.

Onychomykose: Konzepte für die Praxis

Zusammenfassung

Hintergrund

Die Onychomykose ist die häufigste infektiöse Nagelerkrankung, wobei die Fallzahlen stetig ansteigen. Eine Nagelpilzinfektion hat keine Selbstheilungstendenz, sondern muss immer therapiert werden. Das Krankheitsbild gehört deshalb zur Kernkompetenz des Dermatologen.

Schlussfolgerung

Eine wichtige Voraussetzung zur erfolgreichen Behandlung ist eine korrekte Diagnose, basierend auf der sorgfältigen Anamnese, der Klinik sowie dem mikroskopischen und kulturellen Erregernachweis. Außerdem kommt hier der Dermatoskopie und der histologischen Untersuchung eine wichtige Bedeutung zu. Der beigefügte Algorithmus verknüpft anschaulich Diagnostik und Therapie bei Verdacht auf Onychomykose.

Schnitzler-Syndrom

Zusammenfassung

Das Schnitzler-Syndrom ist eine sehr seltene, erworbene Systemerkrankung, die viele Gemeinsamkeiten mit den hereditären autoinflammatorischen Syndromen aufweist. Das Exanthem und eine monoklonale Gammopathie mit IgM sind die Charakteristika der Erkrankung. Zu den klinischen Hauptmerkmalen gehören Fieber, urtikarielles Exanthem, Muskel‑, Knochen- und/oder Gelenkschmerzen und eine Lymphadenopathie. Etwa 15–20 % der Patienten mit Schnitzler-Syndrom entwickeln eine lymphoproliferative Erkrankung, und selten kann es zum Auftreten einer AA-Amyloidose kommen, wenn die Erkrankung nicht behandelt wird. Eine Aktivierung des angeborenen Immunsystems, speziell des Interleukin(IL)-1β, ist zentral in der Pathogenese der Erkrankung. Folgerichtig kann bei 80 % der Patienten eine komplette Kontrolle der Krankheitssymptome durch Behandlung mit dem IL-1-Rezeptorantagonisten Anakinra erreicht werden.

Logical fallacies and invasion biology

Abstract

Leading invasion biologists sometimes dismiss critics and criticisms of their field by invoking "the straw man" fallacy. Critics of invasion biology are also labelled as a small group of "naysayers" or "contrarians", who are sometimes engaging in "science denialism". Such unfortunate labels can be seen as a way to possibly suppress legitimate debates and dismiss or minimize reasonable concerns about some aspects of invasion biology, including the uncertainties about the geographic origins and complex environmental impacts of species, and the control programs against species perceived as "invasive". In assessing the quality of the debate in this area, we examine the validity of the use of various strategies, including the "straw man" concept, and explore a range of potential logical fallacies present in some recent prominent discussions about invasion biology and so-called "invasive" species. The goal is to add some clarity to the concepts involved, point out some problematic issues, and improve the quality of the debates as the discussions move forward.

De-extinction and the conception of species

Abstract

Developments in genetic engineering may soon allow biologists to clone organisms from extinct species. The process, dubbed "de-extinction," has been publicized as a means to bring extinct species back to life. For theorists and philosophers of biology, the process also suggests a thought experiment for the ongoing "species problem": given a species concept, would a clone be classified in the extinct species? Previous analyses have answered this question in the context of specific de-extinction technologies or particular species concepts. The thought experiment is given more comprehensive treatment here. Given the products of three de-extinction technologies, twenty-two species concepts are "tested" to see which are consistent with the idea that species may be resurrected. The ensuing discussion considers whether or not de-extinction is a conceptually coherent research program and, if so, whether or not its development may contribute to a resolution of the species problem. Ultimately, theorists must face a choice: they may revise their commitments to species concepts (if those concepts are inconsistent with de-extinction) or they may recognize de-extinction as a means to make progress in the species problem.

Evolutionary models and the normative significance of stability

Abstract

Many have expected that understanding the evolution of norms should, in some way, bear on our first-order normative outlook: How norms evolve should shape which norms we accept. But recent philosophy has not done much to shore up this expectation. Most existing discussions of evolution and norms either jump headlong into the is/ought gap or else target meta-ethical issues, such as the objectivity of norms. My aim in this paper is to sketch a different way in which evolutionary considerations can feed into normative thinking—focusing on stability. I will discuss two (related) forms of argument that utilize information about social stability drawn from evolutionary models, and employs it to assess claims in political philosophy. One such argument treats stability as feature of social states that may be taken into account alongside other features. The other uses stability as a constraint on the realization of social ideals, via a version of the ought-implies-can maxim. These forms of argument are not new; indeed they have a history going back at least to early modern philosophy. But their marriage with evolutionary information is relatively recent, has a significantly novel character, and has received little attention in recent moral and political philosophy.

Universal common ancestry, LUCA, and the Tree of Life: three distinct hypotheses about the evolution of life

Abstract

Common ancestry is a central feature of the theory of evolution, yet it is not clear what "common ancestry" actually means; nor is it clear how it is related to other terms such as "the Tree of Life" and "the last universal common ancestor". I argue these terms describe three distinct hypotheses ordered in a logical way: that there is a Tree of Life is a claim about the pattern of evolutionary history, that there is a last universal common ancestor is an ontological claim about the existence of an entity of a specific kind, and that there is universal common ancestry is a claim about a causal pattern in the history of life. With these generalizations in mind, I argue that the existence of a Tree of Life entails a last universal common ancestor, which would entail universal common ancestry, but neither of the converse entailments hold. This allows us to make sense of the debates surrounding the Tree, as well as our lack of knowledge about the last universal common ancestor, while still maintaining the uncontroversial truth of universal common ancestry.

Not null enough: pseudo-null hypotheses in community ecology and comparative psychology

Abstract

We evaluate a common reasoning strategy used in community ecology and comparative psychology for selecting between competing hypotheses. This strategy labels one hypothesis as a "null" on the grounds of its simplicity and epistemically privileges it as accepted until rejected. We argue that this strategy is unjustified. The asymmetrical treatment of statistical null hypotheses is justified through the experimental and mathematical contexts in which they are used, but these contexts are missing in the case of the "pseudo-null hypotheses" found in our case studies. Moreover, statistical nulls are often not epistemically privileged in practice over their alternatives because failing to reject the null is usually a negative result about the alternative, experimental hypothesis. Scientists should eschew the appeal to pseudo-nulls. It is a rhetorical strategy that glosses over a commitment to valuing simplicity over other epistemic virtues in the name of good scientific and statistical methodology.

Lamarckism and epigenetic inheritance: a clarification

Abstract

Since the 1990s, the terms "Lamarckism" and "Lamarckian" have seen a significant resurgence in biological publications. The discovery of new molecular mechanisms (DNA methylation, histone modifications, RNA interference, etc.) have been interpreted as evidence supporting the reality and efficiency of the inheritance of acquired characters, and thus the revival of Lamarckism. The present paper aims at giving a critical evaluation of such interpretations. I argue that two types of arguments allow to draw a clear distinction between the genuine Lamarckian concept of inheritance of acquired characters and transgenerational epigenetic inheritance. The first concerns the explanandum of the processes under consideration: molecular mechanisms of transgenerational epigenetic inheritance are understood as evolved products of natural selection. This means that the kind of inheritance of acquired characters they might be responsible for is an obligatory emergent feature of evolution, whereas traditional Lamarckisms conceived the inheritance of acquired characters as a property inherent in living matter itself. The second argument concerns the explanans of the inheritance of acquired characters: in light of current knowledge, epigenetic mechanisms are not able to drive adaptive evolution by themselves. Emergent Lamarckian phenomena would be possible if and only if individual epigenetic variation allowed the inheritance of acquired characters to be a factor of unlimited change. This implies specific requirements for epigenetic variation, which I explicitly define and expand upon. I then show that given current knowledge, these requirements are not empirically grounded.

Correction to: Holobionts and the ecology of organisms: Multi-species communities or integrated individuals?

In the original publication, the acknowledgment was published incorrectly. The correct version is given below.

Dress for Success: a Review of Dressings and Wound Care in Hidradenitis Suppurativa

Abstract

Purpose of Review

Hidradenitis suppurativa is characterized by lesions and draining sinus tracts in intimate locations. Although often overlooked, the selection of an effective, comfortable dressing can dramatically improve patients' lives. We aimed to review dressings based on management of post-surgical and non-surgical wound dressings. We reviewed the characteristics and types of dressings used in patients with hidradenitis suppurativa and addressed recommendations for dressing post-surgical and non-surgical wounds.

Recent Findings

Available studies on dressings are few in number with small sample sizes. There were no studies comparing the efficacy of dressings in hidradenitis suppurativa patients. The types of dressings include superabsorbent/absorbent dressings, foam dressings, hydrofiber dressings, alginate dressings, silicone adherent dressings, non-adherent dressings, hydrocolloid dressings, silver-impregnated dressings, iodine-impregnated dressings, and honey-impregnated dressings, and platelet-rich plasma gel and hyaluronic acid scaffold dressings. Providers should consider the "TIME" acronym when assessing post-surgical and non-surgical wounds to select the appropriate dressing.

Summary

As an important component of wound healing, large, randomized controlled trials that compare dressing options for the management of wounds in hidradenitis suppurativa patients are needed.

Skin Barrier Function and Atopic Dermatitis

Abstract

Purpose of Review

The purpose of this review was to highlight the importance of the skin barrier in the development of atopic dermatitis (AD).

Recent Findings

Skin barrier function relies on the stratum corneum (SC) and tight junction. These components are deranged in the AD epidermis. Deficiency in filaggrin gives rise to abnormal epidermal integrity. The intercellular lipid composition, ratio, and organization are found to be disturbed. Keratinocyte shedding from the SC is also impaired. Tight junction proteins are reduced and result in sweat leakage into the skin surface.

Summary

Strategies to enhance skin barrier strength will alleviate AD symptoms and may prevent the disease.

Complementary and Alternative Methods for Treatment of Acne Vulgaris: a Systematic Review

Abstract

Purpose of Review

To review the current literature regarding complementary and alternative treatment options for acne vulgaris.

Recent Findings

Acne vulgaris is an increasingly prevalent disease worldwide. While conventional methods of treatment are still primarily used to treat acne, complementary and alternative methods of treatment are becoming utilized in conjunction or in place of prescription medications.

Summary

Studies have shown comparable benefit of Complementary and Alternative Medicine (CAM) therapies to conventional treatment. Oral green tea extract was a moderately effective treatment of inflammatory acne without significant side effects. Nicotinamide oral and topical preparations demonstrated efficacy in the treatment of moderate inflammatory acne without significant side effects. Oral zinc gluconate was not as effective as oral minocycline in the treatment of inflammatory acne. CAM therapy has relatively few reported side effects for acne vulgaris, and is mildly effective in treatment of inflammatory and comedonal acne. More studies are needed for further comparison of CAM modalities with each other as well as with conventional treatment.

Heterogeneity analysis of 18 F-FDG PET imaging in oncology: clinical indications and perspectives

Abstract

Purpose

To evaluate the performances and perspectives of heterogeneity analysis of FDG PET imaging in oncology.

Methods

We performed a review of the literature using PubMed/Medline and Google scholar, with multiple research keywords for each organ accompanying the terms ''radiomics'', ''texture'', ''heterogeneity'', ''FDG'', ''PET'' and ''PET/CT''. The review considers shape, histogram and textural analysis of FDG PET. The references of the retrieved articles were also considered to identify additional articles. The search was limited to English language. Preoperative workup exploration, preclinical and animal studies were not included in the review. A total of 128 original articles were considered for the review.

Results

Many publications have explored the use of radiomics for multiple cancer sites, especially lung, head and neck, oesophageal and breast cancers. The results show variable levels of correlation with pathological characteristics and prediction of tumoral staging. Although initial results are promising, few studies have explored PET radiomics for delineating the radiotherapy target volume. Studies have predominantly investigated the prognostic value of radiomics for identifying failure of tumour response to treatment, high risk of recurrence and high mortality. Results are for the most part encouraging although rarely properly validated. The studies also exhibit a great methodological diversity for extracting and analysing features extraction, as various statistical approaches have been used, with the increasing help of machine learning tools.

Conclusion

PET radiomics show their potential to non-invasively improve tumoral characterisation and identification of aggressive pattern complementary to other omics. To be implemented in clinic, these promising results nevertheless need further validation, which must go through a standardisation of their extraction conditions. Machine learning, especially deep learning, could allow the empowerment of the selection of features and the creation of powerful prognostic models including clinical, pathological and iconographic parameters.

18 F-FCH and 90 Y PET/CT data for the early evaluation of HCC radioembolisation

Abstract

In the recent years, there has been a growing interest in the use of ⁹⁰Y-microspheres for regional HCC therapy with the therapy response assessment as a crucial point. Because morphologic imaging performance is limited in this set, functional metabolic imaging method, which can early and reliably distinguish between therapy responders and non-responders, is highly needed. The purpose of this pictorial essay was to demonstrate the potential value of ¹⁸F-fluoro-choline positron emission tomography (¹⁸F-FCH-PET)/CT in detecting and early-therapy monitoring of HCC patients who underwent to TARE, by showing exemplary HCC patients who underwent ¹⁸F-FCH-PET/CT as part of their routine clinical work-up in our institution. In addition, we aimed to illustrate that the mapping of the ⁹⁰Y-microspheres distribution provided by ⁹⁰Y-PET/CT may anticipate information about treatment response.

Post-operative radioiodine therapy (RaIT) as adjuvant therapy in low–intermediate risk differentiated thyroid cancer

Abstract

Aim

For many years, thyroid surgery and radioiodine therapy for thyroid remnant ablation (i.e. post-operative RaIT) have been the first-line therapeutic approaches in differentiated thyroid carcinoma (DTC). In the latest American Thyroid Association Guidelines (ATA), post-operative RaIT is not indicated in low-risk DTC, while no clear indication is postulated regarding low- to intermediate-risk patients, even if it is discouraged in most of them. The European Association of Nuclear Medicine did not endorse ATA guidelines since the role of nuclear medicine was marginalized in patients affected by low- or low- to intermediate-risk cancers. The present review evaluates the adjuvant role of post-operative RaIT in low and low- to intermediate-risk DTC patients.

Materials and methods

The terms radioiodine adjuvant therapy, radioiodine adjuvant treatment, thyroid remnant ablation, radioiodine thyroid remnant ablation, radioiodine therapy and radioiodine treatment were used to search MEDLINE for papers published from January 2008 to May 2018. Among 895 papers, we considered 8 in which patients underwent post-operative RaIT and the results of post-therapy whole body scans (pT-WBS) were reported.

Results

pT-WBS identified metastases in 282 out of 1622 patients (17.4%). All except 28 metastatic patients were affected by either low- or low- to intermediate-risk DTC. Metastases were confirmed by (targeted)-morphological and/or morphofunctional and/or morphometabolic studies in about 40% of patients.

Conclusion

According to the presented data, slightly less than 20% of low- or low- to intermediate-risk DTC patients showed metastases at pT-WBS. Thus, in our opinion post-operative RaIT should be considered as an adjuvant therapy also in low and low- to intermediate-risk DTC patients.

FDG-PET/CT in venous thromboembolism

Abstract

Purpose

Venous thromboembolism (VTE) is common; deep venous thrombosis (DVT) and pulmonary embolism (PE) are the most common presentations. VTE may arise from anywhere in the entire venous bed and the diagnosis may be difficult. VTE is a dynamic disease, inflammation is key, and ¹⁸F-Fluorodeoxyglucose positron emission tomography/computer tomography (FDG-PET/CT) has been proposed in the evaluation of VTE to detect thrombi in any anatomic location, to differentiate acute from chronic VTE, and to differentiate bland VTE from tumor thrombosis. The aim of this systematic review was to assess if the potential uses of FDG-PET/CT in VTE are described and documented in the literature and to appraise the literature.

Methods

PubMed and Embase databases were searched. Duplicates and papers in other languages than English and Scandinavian were removed. Remaining papers were screened by title and abstract. Eligible papers were assessed in full text.

Results

The master search yielded 3897 hits; 316 papers were eligible for full-text assessment. Ten papers were included: six on diagnostic performance of PET/CT in VTE, and four on the ability of PET/CT to differentiate bland VTE from tumor thrombosis. Three papers were prospective; seven were retrospective.

Conclusion

The available literature is too sparse to draw firm conclusions; however, FDG-PET/CT may have a role in diagnosing early DVT, but not PE, in discriminating acute from chronic VTE, in demonstrating recurrent VTE, and possibly for screening for occult malignancy.

Abstracts of the 13th German Allergy Congress

Placebo effects in allergen immunotherapy: an experts’ opinion

Abstract

Placebo effects are common in medicine. Randomised clinical trials help us to understand their magnitude in different therapies. There are particular problems with placebo effects in allergen immunotherapy (AIT) as it is difficult to blind the active treatment and the endpoints are largely subjective. This may explain why large placebo effects are often found in AIT trials. Patients receiving open label AIT get the benefit of the active and placebo components but it can be difficult to say how much benefit is due to the active component. The use of active placebos has been proposed but brings its own problems (ethical and scientific). An EAACI Task Force has been established to address these issues. Here we review the current literature on the placebo effect in general, with a special focus on AIT trials, and indicate what we believe to be important considerations and unmet needs in AIT trial design.

Positive and negative AIT trials: What makes the difference?

Abstract

Background

Allergen immunotherapy has proven to be efficacious in allergic rhinitis and asthma. However, results from randomised clinical trials may vary substantially. Clinical trials may unexpectedly fail. The purpose of this review is to discuss the possible factors that may contribute to a successful or unsuccessful study.

Methods

Descriptive review exploring the possible causes of negative outcomes in allergen immunotherapy trials.

Results

A series of factors may lead to negative results. Among of these are underpowering of the study, low allergen content in tested extracts, insufficient allergen exposure during monitoring and recruitment of inappropriate patients. In addition, the choice of the primary endpoint may be critical.

Discussion

A clinical trial aims to evaluate the efficacy of an agent. However, studies with potential effective compounds may fail because of methodical issues. Sometimes, they are the cause of discrepancies between successful phase II and unsuccessful phase III trials. To understand more about failure of studies, investigators and editors should be encouraged to publish negative trials.

Comparison of sublingual immunotherapy and oral immunotherapy in peanut allergy

Abstract

The prevalence of food allergy has been increasing over the past few decades at an alarming rate with peanut allergy affecting about 2% of children. Both oral immunotherapy (OIT) and sublingual immunotherapy (SLIT) have shown promise as a treatment option for peanut allergy. Immunotherapy induces desensitization and reduces the risk of reaction during accidental ingestion and may also enable those who are successfully desensitized to include the food allergen in their diet. OIT has been very well studied and has been found to be more efficacious than SLIT with an acceptable safety profile. However, SLIT is associated with fewer side effects. Studies indicate that a combination of SLIT and OIT may together induce a significant increase in challenge thresholds with fewer adverse events. More head-to-head clinical trials that directly compare OIT and SLIT as well as SLIT and OIT combination studies are warranted.

Comparison of 18 F-Choline PET/CT and MRI functional parameters in prostate cancer

Abstract

Aim

¹⁸F-Choline (FCH) uptake parameters are strong indicators of aggressive disease in prostate cancer. Functional parameters derived by magnetic resonance imaging (MRI) are also correlated to aggressive disease. The aim of this work was to evaluate the relationship between metabolic parameters derived by FCH PET/CT and functional parameters derived by MRI.

Materials and methods

Fourteen patients with proven prostate cancer who underwent FCH PET/CT and multiparametric MRI were enrolled. FCH PET/CT consisted in a dual phase: early pelvic list-mode acquisition and late whole-body acquisition. FCH PET/CT and multiparametric MRI examinations were registered and tumoral volume-of-interest were drawn on the largest lesion visualized on the apparent diffusion coefficient (ADC) map and projected onto the different multiparametric MR images and FCH PET/CT images. Concerning the FCH uptake, kinetic parameters were extracted with the best model selected using the Akaike information criterion between the one- and two-tissue compartment models with an imaging-derived plasma input function. Other FCH uptake parameters (early SUVmean and late SUVmean) were extracted. Concerning functional parameters derived by MRI scan, cell density (ADC from diffusion weighting imaging) and vessel permeability (K_trans and V_e using the Tofts pharmakinetic model from dynamic contrast-enhanced imaging) parameters were extracted. Spearman's correlation coefficients were calculated to compare parameters.

Results

The one-tissue compartment model for kinetic analysis of PET images was selected. Concerning correlation analysis between PET parameters, K₁ was highly correlated with early SUVmean (r = 0.83, p < 0.001) and moderately correlated with late SUVmean (r = 0.66, p = 0.010) and early SUVmean was highly correlated with late SUVmean (r = 0.90, p < 0.001). No significant correlation was found between functional MRI parameters. Concerning correlation analysis between PET and functional MRI parameters, K₁ (from FCH PET/CT imaging) was moderately correlated with K_trans (from perfusion MR imaging) (r = 0.55, p = 0.041).

Conclusions

No significant correlation was found between FCH PET/CT and multiparametric MRI metrics except FCH influx which is moderately linked to the vessel permeability in prostate cancer.

The value of different 18 F-FDG PET/CT baseline parameters in risk stratification of stage I surgical NSCLC patients

Abstract

Objective

Administration of postoperative chemotherapy to patients with completely resected stage I NSCLC is still a matter of debate. The aim of the present study was to evaluate the value of different baseline ¹⁸F-FDG PET parameters in identifying surgical stage I NSCLC patients who are at high risk of recurrence, and thus are indicated for further postoperative treatment.

Methods

This is a retrospective study, which included 49 patients (28 males, 21 females) with the median age of 69 years (range 28–84), who had pathologically proven stage I NSCLC. All patients underwent ¹⁸F-FDG PET/CT at baseline followed by complete surgical resection of the tumor (R0). Baseline SUV_max, MTV and TLG were measured. Patients' follow-up records were retrospectively reviewed, and DFS (disease-free survival) was assessed. For each parameter, the most accurate cut-off value for the prediction of recurrence was calculated using the ROC curve analysis and the Youden index. DFS was evaluated for patients above and below the calculated cut-off value using the Kaplan–Meier method and the difference in survival between the two groups was estimated using the log-rank test.

Results

Median observation time of the patients after surgery was 28.7 months (range 3.5–58.8 months). 9 patients developed recurrence. The calculated cut-off values for SUV_max, MTV and TLG were 6, 6.6 and 33.6, respectively. Using these cut-offs, the observed sensitivity for SUV_max, MTV and TLG for prediction of recurrence was 100%, 89% and 89%, respectively, while the observed specificity was 43%, 73% and 65%, respectively. The difference in survival between patients below and above the cut-off value was statistically significant in all three studied parameters. The highest AUC was observed for MTV (AUC = 0.825, p = 0.003), followed by TLG (AUC = 0.789, p = 0.007), and lastly SUV_max (AUC = 0.719, p = 0.041). ROC curve analysis showed that volumetric parameters had better predictive performance than SUV_max as regards recurrence.

Conclusion

PET-derived parameters at baseline were predictive of recurrence in stage I surgical NSCLC patients. Moreover, the metabolic volume of the tumor was the most significant parameter for this purpose among the studied indices.

The significant value of predicting prognosis in patients with colorectal cancer using 18 F-FDG PET metabolic parameters of primary tumors and hematological parameters

Abstract

Objects

The purpose was to evaluate the correlation of the pre-treatment hematological parameters with metabolic parameters of primary tumor in baseline ¹⁸F-FDG PET/CT in patients with colorectal cancer (CRC) and estimate the prognostic value of both.

Methods

We retrospectively investigated 231 patients with CRC who underwent baseline ¹⁸F-FDG PET/CT. Routine blood sampling was tested in the same term. PET parameters in term of hematological parameters and pathological characteristics of primary tumor were compared. Kaplan–Meier survival analysis was performed in the patients without distant metastasis. The differences of disease-free survival between groups were compared by log-rank tests.

Results

Neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) were significantly correlated with all the metabolic parameters including maximum standardized uptake value (SUV_max), metabolic tumor volume (MTV) and tumor lesion glycolysis (TLG). The patients with NLR > 3 had higher MTV (24.82 ± 18.16 vs 19.06 ± 13.30, P = 0.039) and TLG (219.04 ± 186.94 vs 166.45 ± 146.39, P = 0.047) than those whose NLR ≤ 3. NLR in those patients with distant metastasis was significantly higher than those without distant metastasis (P = 0.018) while LMR in those patients with distant metastasis was significantly lower than those without distant metastasis (P = 0.032). Survival analysis showed that those patients with low MTV (P = 0.015), low NLR (P = 0.008) and high LMR (P = 0.027) revealed significant survival benefit.

Conclusions

There was a significant association between the pre-treatment hematological parameters and metabolic parameters of baseline ¹⁸F-FDG PET/CT in the patients with CRC. It might be helpful in those patients with high NLR and low LMR to undergo ¹⁸F-FDG PET/CT to detect distant metastasis and predict prognosis.

Advantages of 99m Tc-3PRGD 2 SPECT over CT in the preoperative assessment of lymph node metastasis in patients with esophageal cancer

Abstract

Background

Our study was designed to compare the diagnostic efficacies of integrated ^99mTc-HYNIC-PEG4-E[PEG4-c(RGDfK)]2 (^99mTc-3PRGD₂) single-photon emission computed tomography (SPECT) images and computed tomography (CT) images in lymph node metastasis in the patients with esophageal cancer.

Methods

From September 2015 and May 2018, 32 patients with histologically proven primary esophageal carcinoma underwent both ^99mTc-3PRGD₂ SPECT and CT scans followed by esophagectomy with lymph node dissection. The results of reviewing ^99mTc-3PRGD₂ SPECT and CT images for the lymph node metastasis were compared in relation with pathologic findings.

Results

During surgery, a total of 168 lymph nodes were dissected in 32 patients, of which 42 node groups in 18 patients were malignant on histologic examination. Preoperative nodal staging was compared with postoperative histopathological staging, The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of ^99mTc-3PRGD₂ SPECT for lymph nodes were 80.95%, 86.51%, 85.12%, 66.67%, and 93.16% on per-node basis, respectively; compared with 59.52%, 73.02%, 69.64%, 42.37%, and 84.40% for CT (p = 0.034, 0.008, 0.005, 0.011, and 0.038, respectively). 70.59% (12/17) false-negative interpretations and 50% (17/34) false-positive interpretations on CT were corrected by ^99mTc-3PRGD₂ SPECT. 37.5% false-negative interpretations on ^99mTc-3PRGD₂ SPECT were corrected by CT. 11.90% (5/42) positive lymph nodes and 13.49% (17/126) negative nodes at pathology were incorrectly diagnosed both by ^99mTc-3PRGD₂ SPECT and CT. The accuracy of ^99mTc-3PRGD₂ SPECT (87.50%, 28/32) was significantly higher than that of CT (62.50, 20/32; p = 0.022) on per-patient basis. ^99mTc-3PRGD₂ SPECT showed significantly higher sensitivity and accuracy in the neck and upper thoracic regions than CT. For nodal staging, ^99mTc-3PRGD₂ SPECT was correct in 78.12% (25/32) of the patients, whereas CT was correct in 53.12% (17/32), p = 0.037.

Conclusion

^99mTc-3PRGD₂ SPECT is more accurate than CT for preoperative assessment of lymph node metastasis in esophageal cancer and may be helpful in determining the therapeutic plan.

Volume-based parameters on FDG PET may predict the proliferative potential of soft-tissue sarcomas

Abstract

Introduction

Soft-tissue sarcomas (STS) are rare types of tumors that have variable levels of tumor differentiation. F-18 fluorodeoxyglucose positron emission tomography (FDG PET) has been established as an useful tool for STS patients, and the metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are reported to be useful in various cancers. We compared the diagnostic value of four PET parameters (maximum standardized uptake value [SUVmax], SUVmean, MTV, and TLG) from two acquisition timings for predicting the expression of the pathological marker of cell proliferation Ki-67, based on pathological investigation.

Materials and methods

In this retrospective study, we investigated 20 patients (59 ± 19 years old, 18–87 years old) with pathologically confirmed STS who underwent FDG PET before surgical intervention. The patients fasted ≥ 6 h before the intravenous injection of FDG. The whole body was scanned twice; at an early phase (61.5 ± 2.6 min) and at a delayed phase (118.0 ± 2.1 min) post-injection. The SUVmax, SUVmean, MTV, and TLG of the primary lesion were measured with a tumor boundary determined by SUV ≥ 2.0. Ki-67 was measured using MIB-1 immunohistochemistry. We used Pearson's correlation coefficient to analyze the relationships between the PET parameters and Ki-67 expressions. The Kaplan–Meier analysis with the log-rank test was performed to compare overall survival between high-group and low-group at each of the four PET parameters and Ki-67 expression.

Results

All four PET parameters at each phase showed significant correlations with Ki-67. Among them, the Pearson's correlation coefficient (r) was largest for TLG (r = 0.76 and 0.77 at the early and delayed phases, respectively), followed by MTV (0.70 and 0.72), SUVmax (r = 0.65 and 0.66), and SUVmean (r = 0.62 and r = 0.64). From early to delayed phases, the SUVmax and SUVmean both increased in all 20 patients, whereas the MTV and TLG increased in 13/20 (65%) and 16/20 (80%) patients, respectively. None of the %increases of the PET parameters were significantly correlated with Ki-67. The overall survival was shorter for high-SUVmax, high-SUVmean, high-TLG, and high-Ki-67 groups than the other groups, although the difference did not reach statistical significance.

Conclusion

The SUVmax, SUVmean, MTV, and TLG acquired at both 1 and 2 h after injection showed significant correlations with Ki-67. Among them, correlation coefficient with Ki-67 expression was highest for TLG, although the best parameter should be determined in a larger population. The delayed-phase FDG PET was equally useful as that of early-phase to predict tumor aggressiveness in STS.

Preliminary feasibility study on differential diagnosis between radiation-induced cerebral necrosis and recurrent brain tumor by means of [ 18 F]fluoro-borono-phenylalanine PET/CT

Abstract

Objectives

A previous study reported that a differential diagnosis between glioblastoma progression and radiation necrosis by 4-borono-2-[¹⁸F]-fluoro-phenylalanine ([¹⁸F]FBPA) PET can be made based on lesion-to-normal ratio of [¹⁸F]FBPA accumulation. Two-dimensional data acquisition mode PET alone system, with in-plane resolution of 7.9 mm and axial resolution of 13.9 mm, was used. In the current study, we aimed to confirm the differential diagnostic capability of [¹⁸F]FBPA PET/CT with higher PET spatial resolution by three-dimensional visual inspection and by measuring mean standardized uptake value (SUVmean), maximum SUV (SUVmax), metabolic tumor volume (MTV), and total lesion (TL) [¹⁸F]FBPA uptake.

Methods

Twelve patients of glioma (9), malignant meningioma (1), hemangiopericytoma (1), and metastatic brain tumor (1) were enrolled. All had preceding radiotherapy. High-resolution three-dimensional data acquisition mode PET/CT with in-plane resolution of 4.07 mm and axial resolution of 5.41 mm was employed for imaging. Images were three-dimensionally analyzed using the PMOD software. SUVmean and SUVmax of lesion and normal brain were measured. Lesion MTV and TL FBPA uptake were calculated. The diagnostic accuracy of [¹⁸F]FBPA PET/CT in detecting recurrence (n = 6) or necrosis (n = 6) was verified by clinical follow-up.

Results

All parameters showed significantly higher values for tumor recurrence than for necrosis. SUVmean in recurrence was 2.95 ± 0.84 vs 1.18 ± 0.24 in necrosis (P = 0.014); SUVmax in recurrence was 4.63 ± 1.23 vs 1.93 ± 0.44 in necrosis (P = 0.014); MTV in recurrence was 44.92 ± 28.93 mL vs 10.66 ± 8.46 mL in necrosis (P = 0.032); and mean TL FBPA uptake in recurrence was 121.01 ± 50.48 g vs 12.36 ± 9.70 g in necrosis (P = 0.0029).

Conclusion

In this preliminary feasibility study, we confirmed the possibility of differentiating tumor recurrence from radiation necrosis in patients with irradiated brain tumors by [¹⁸F]FBPA PET/CT using indices of SUVmean, SUVmax, MTV, and TL ¹⁸FBPA uptake.

Does lung perfusion scintigraphy continue to have a role in the clinical management of patients suspected of pulmonary embolism in the CT pulmonary angiography era?

Abstract

Objective

Acute pulmonary embolism (PE) is a life-threatening disorder with high mortality. A prompt diagnosis and treatment is essential for reducing the mortality rate. The purpose of the study is to evaluate if lung perfusion scintigraphy (LPS) continues to have a role in the clinical management of patients suspected of pulmonary embolism in the CT pulmonary angiography (CTPA) era.

Methods

For this study, 1183 patients who had been subjected to LPS were retrospectively evaluated and classified into the following groups: A (positive LPS), B (negative LPS) and C (indeterminate LPS). Patients were further classified into A1 ('PE likely' and LPS-negative), B1 (PE unlikely and LPS-positive) and C1 (PE likely and indeterminate LPS) by combining the LPS findings and the clinical pretest probability (cpp). Subgroups A1, B1 and C1 underwent additional CTPA.

Results

Groups A, B, and C included 1086/1183, 69/1183 and 28/1183 patients, respectively. The proportion of patients with inconsistent cpp LPS findings who underwent additional CTPA was 106/1183 patients: subgroup A1 (n = 73), B1 (n = 21), and C1 (n = 12). In subgroup A1, CTPA was negative in 61/73, non-diagnostic in 12/73 and positive in 0/73 patients. In subgroup B1, CTPA excluded PE in 2/21, non-diagnostic in 3/21 and positive in 16/21 patients. In group C1, CTPA was negative in 8/12, positive in 2/12 and non-diagnostic in 2/12 patients.

Conclusion

In the CTPA era, LPS continues to have a role in the clinical management of patients suspected of PE.

F-18 fluoride uptake in primary breast cancer

Abstract

Objective

Bone-specific radiotracers are known to accumulate in breast lesions. Tc-99m diphosphonates have been widely studied in differentiating breast lesions. In this retrospective study, we aimed to assess the uptake of the bone-specific PET radiotracer, F-18 fluoride (NaF), in primary breast cancers to determine its sensitivity and to identify any differences in NaF uptake between calcified and non-calcified tumors, histological subtypes, and patients with or without axillary lymphadenopathy.

Methods

NaF positron emission tomography/computed tomography (PET/CT) images of 69 newly diagnosed breast cancer patients were reviewed. F-18 fluoride uptake as maximum standardized uptake value (NaF SUVmax) was measured in the primary tumor, enlarged axillary lymph nodes and contralateral normal/non-tumoral breast tissue. Low-dose CT images were reviewed to locate the primary tumor and grossly assess its calcification and check for ipsilateral axillary lymphadenopathy. Whole body NaF PET/CT images were reviewed to search for bone metastases. Eighteen patients also underwent F-18 fluorodeoxyglucose (FDG) PET/CT study.

Results

The primary breast tumor was clearly seen as focal or diffuse uptake on NaF PET images in 27 of 69 patients (39%) (mean NaF SUVmax: 2.0 ± 1.0). In the rest, there was only mild bilateral diffuse breast uptake. When analyzing images per histological subtype (42 patients, 43 tumors), 14 of 31 invasive ductal carcinomas (IDC) (45%) and 3 of 4 ductal carcinoma in situ (DCIS) were visible on PET. Five invasive lobular carcinomas, 2 invasive mammary carcinomas, and 1 mucinous carcinoma were not visible on PET. Mean NaF SUVmax of contralateral normal/non-tumoral breast tissue was 1.0 ± 0.4. There was no significant difference in mean NaF SUVmax of primary tumor in cases with and without calcification or with and without axillary lymphadenopathy (p 0.892 and 0.957). There was no correlation between NaF SUVmax and FDG SUVmax values of the primary tumors (r 0.072, p 0.797, Pearson correlation).

Conclusion

NaF PET has relatively low sensitivity in detecting breast cancer. However, abnormal breast uptake on NaF PET requires further evaluation. F-18 fluoride uptake in the primary breast tumor does not seem to be correlated with axillary lymphadenopathy (metastasis potential), gross tumor calcification or metabolic activity of the tumor.

Super-early images of brain perfusion SPECT using 123 I-IMP for the assessment of hyperperfusion in stroke patients

Abstract

Objective

With the advancement of reperfusion therapy in stroke patients, assessment of perfusion status after therapy is gaining importance. Hyperperfusion tends to be underestimated by the conventional early imaging of ¹²³I-IMP brain perfusion SPECT. We evaluated the utility of super-early imaging as an adjunct to early imaging for the assessment of postischemic hyperperfusion in stroke patients.

Methods

Sixty-seven patients who underwent ¹²³I-IMP brain perfusion SPECT within 14 days after the onset of cerebral infarction were retrospectively analyzed. Super-early (4–10 min) and early (15–45 min) images were acquired using a dual-headed gamma camera. Postischemic hyperperfusion was visually assessed using the early images alone and then using both the super-early and early images, and the frequency of postischemic hyperperfusion and the confidence level of the judgement were evaluated. For quantitative evaluation of image contrast, the contrast ratios (the count ratios of the hyperperfused to normal areas) were calculated.

Results

The frequency of postischemic hyperperfusion was significantly higher using both the super-early and early images (28/67 patients) than using the early images alone (17/67 patients, p < 0.001). In 56 patients in whom judgement regarding the presence or absence of postischemic hyperperfusion was unchanged, the confidence level was increased in 8 patients using both image sets. The addition of the super-early SPECT images was judged to be useful and marginally useful in 14 and 15 patients, respectively. The contrast ratio was significantly higher on the super-early images (1.48 ± 0.25) than on the early images (1.26 ± 0.18, p < 0.001).

Conclusions

The addition of super-early imaging to the conventional early imaging aids assessment of postischemic hyperperfusion by ¹²³I-IMP brain perfusion SPECT and may contribute to management of stroke patients in the era of reperfusion therapy.

Comparative analysis of surgical processes for image-guided endoscopic sinus surgery

Abstract

Purpose

This study proposes a method to analyze surgical performance by modeling, aligning, and comparing surgical processes. This method is intended to serve as a means to support the enhancement of surgical skills for endoscopic sinus surgeries (ESSs). We focus on surgical navigation systems used in image-guided ESSs and aim to construct a comparative analysis method for surgical processes based on the information about the surgical instruments motion obtained from the navigation system.

Methods

The proposed method consists of the following three parts: quantification of surgical features, modeling of surgical processes, and alignment and comparison of surgical process models (SPMs). First, we defined time-series parameters using the navigation-based surgical data. Second, we created SPMs by applying the defined parameters and the relative positional information of the instruments to the patient's anatomy. Third, we constructed a method to align and compare SPMs based on dynamic time warping with barycenter averaging.

Results

The proposed method was validated on a dataset containing surgical data obtained by an optical tracking system from 14 clinical ESS cases. We evaluated the validity of the comparative analysis by aligning and comparing SPMs between experts and residents. The validation results suggested that the proposed method could achieve proper alignment of the SPMs and clarify the differences in surgical processes between experts and residents.

Conclusion

We developed a method to enable a time-series comparative analysis of surgical processes based on the surgical data from the navigation system. This method can allow surgeons to identify differences between their procedures and reference procedures such as experts' procedures.

FCN-based approach for the automatic segmentation of bone surfaces in ultrasound images

Abstract

Purpose

A new algorithm, based on fully convolutional networks (FCN), is proposed for the automatic localization of the bone interface in ultrasound (US) images. The aim of this paper is to compare and validate this method with (1) a manual segmentation and (2) a state-of-the-art method called confidence in phase symmetry (CPS).

Methods

The dataset used for this study was composed of 1738 US images collected from three volunteers and manually delineated by three experts. The inter- and intra-observer variabilities of this manual delineation were assessed. Images having annotations with an inter-observer variability higher than a confidence threshold were rejected, resulting in 1287 images. Both FCN-based and CPS approaches were studied and compared to the average inter-observer segmentation according to six criteria: recall, precision, F1 score, accuracy, specificity and root-mean-square error (RMSE).

Results

The intra- and inter-observer variabilities were inferior to 1 mm for 90% of manual annotations. The RMSE was 1.32 ± 3.70  mm and 5.00 ± 7.70 mm for, respectively, the FCN-based approach and the CPS algorithm. The mean recall, precision, F1 score, accuracy and specificity were, respectively, 62%, 64%, 57%, 80% and 83% for the FCN-based approach and 66%, 34%, 41%, 52% and 43% for the CPS algorithm.

Conclusion

The FCN-based approach outperforms the CPS algorithm, and the obtained RMSE is similar to the manual segmentation uncertainty.