Repeated mutKRAS ctDNA measurements represent a novel and promising tool for early response prediction and therapy monitoring in advanced pancreatic cancer

Abstract

Background

The presence of mutated KRAS (^mutKRAS ctDNA) in plasma samples has been consistently shown to be a negative prognostic indicator in pancreatic cancer (PC). Only small pilot studies have evaluated the value of serial ^mutKRAS ctDNA-measurements in PC.

Patients and methods

The aim of the present study was to explore the potential of repeated ^mutKRAS ctDNA measurements for response prediction and therapy monitoring in advanced PC patients. We used the BEAMing technology to determine levels of ^mutKRAS ctDNA, CA 19-9, CEA and CYFRA 21-1 in 284 plasma samples of 54 patients with advanced PC receiving gemcitabine-based chemotherapy. Absolute levels and kinetics of ^mutKRAS ctDNA, CA 19-9, CEA and CYFRA 21-1 were correlated to radiological response, progression-free and overall survival.

Results

^mutKRAS ctDNA was present in a majority of advanced PC patients (n = 36/54, 67%) and indicated tissue KRAS mutation status with a high sensitivity (75%) and specificity (100%). The presence of ^mutKRAS ctDNA, as well as higher levels of CA 19-9, CEA and CYFRA 21-1 before initiation of the first-line chemotherapy, was significantly correlated to an adverse overall survival. During therapy, changes in ^mutKRAS ctDNA levels were more rapid and pronounced than changes in protein-based tumor markers. A decrease in ^mutKRAS ctDNA levels during therapy was an early indicator of response to therapy, while there was no significant correlation between kinetics of CA 19-9, CEA or CYFRA 21-1 and response to chemotherapy during the first four weeks of treatment. Repeated ^mutKRAS ctDNA measurements during follow-up appeared to be superior to protein-based tumor markers in detecting progressive disease (sensitivity: 83%, specificity: 100%).

Conclusion

^mutKRAS ctDNA kinetics appear to be a powerful and highly specific tool in early response prediction and therapy monitoring of advanced PC patients receiving chemotherapy.

Low-dose sulfasalazine in a case of Pyodermatitis-pyostomatitis Vegetans

Publication date: Available online 21 October 2018

Source: Journal of the American Academy of Dermatology

Author(s): Suo Li, Zhiliang Li, Suying Feng

Lack of evidence for feminization of males exposed to spironolactone in utero: a systematic review

Publication date: Available online 21 October 2018

Source: Journal of the American Academy of Dermatology

Author(s): Walter Liszewski, Christina Boull

Morphea and systemic sclerosis are associated with an increased risk of melanoma and non-melanoma skin cancer

Publication date: Available online 21 October 2018

Source: Journal of the American Academy of Dermatology

Author(s): Emily Boozalis, Ami A. Shah, Fredrick Wigley, Sewon Kang, Shawn G. Kwatra

Efficacy and safety of Etanercept for postoperative Pyoderma Gangrenosum after infliximab serum sickness

Dermatologic Therapy, Volume 0, Issue ja, -Not available-.

The Emerging Roles of Steroid Hormone Receptors in Ductal Carcinoma in Situ (DCIS) of the Breast

Abstract

Ductal carcinoma in situ (DCIS) is a non-obligate precursor to most types of invasive breast cancer (IBC). Although it is estimated only one third of untreated patients with DCIS will progress to IBC, standard of care for treatment is surgery and radiation. This therapeutic approach combined with a lack of reliable biomarker panels to predict DCIS progression is a major clinical problem. DCIS shares the same molecular subtypes as IBC including estrogen receptor (ER) and progesterone receptor (PR) positive luminal subtypes, which encompass the majority (60–70%) of DCIS. Compared to the established roles of ER and PR in luminal IBC, much less is known about the roles and mechanism of action of estrogen (E2) and progesterone (P4) and their cognate receptors in the development and progression of DCIS. This is an underexplored area of research due in part to a paucity of suitable experimental models of ER+/PR + DCIS. This review summarizes information from clinical and observational studies on steroid hormones as breast cancer risk factors and ER and PR as biomarkers in DCIS. Lastly, we discuss emerging experimental models of ER+/PR+ DCIS.

STAT5-Driven Enhancers Tightly Control Temporal Expression of Mammary-Specific Genes

Abstract

The de novo formation of milk-secreting mammary epithelium during pregnancy is regulated by prolactin through activation of the transcription factor STAT5, which stimulates the expression of several hundred mammary-specific genes. In addition to its key role in activating gene expression in mammary tissue, STAT5, which is ubiquitously expressed in most cell types, implements T cell-specific programs controlled by interleukins. However, the mechanisms by which STAT5 controls cell-specific genetic programs activated by distinct cytokines remain relatively unknown. Integration of data from genome-wide surveys of chromatin markers and transcription factor binding at regulatory elements may shed light on the mechanisms that drive cell-specific programs. Here, we have illustrated how STAT5 controls cell-specific gene expression through its concentration and an auto-regulatory enhancer supporting its high levels in mammary tissue. The unique genomic features of STAT5-driven enhancers or super-enhancers that regulate mammary-specific genes and their dynamic remodeling in response to pregnancy hormone levels are described. We have further provided biological evidence supporting the in vivo function of a STAT5-driven super-enhancer with the aid of CRISPR/Cas9 genome editing. Finally, we discuss how the functions of mammary-specific super-enhancers are confined by the zinc finger protein, CTCF, to allow exclusive activation of mammary-specific genes without affecting common neighboring genes. This review comprehensively summarizes the molecular pathways underlying differential control of cell-specific gene sets by STAT5 and provides novel insights into STAT5-dependent mammary physiology.

Beyond DNA: the Role of Epigenetics in the Premalignant Progression of Breast Cancer

Abstract

Ductal Carcinoma in Situ (DCIS) is an early breast cancer lesion that is considered a nonobligate precursor to development of invasive ductal carcinoma (IDC). Although only a small subset of DCIS lesions are predicted to progress into a breast cancer, distinguishing innocuous from minacious DCIS lesions remains a clinical challenge. Thus, patients diagnosed with DCIS will undergo surgery with the potential for radiation and hormone therapy. This has led to a current state of overdiagnosis and overtreatment. Interrogating the transcriptome alone has yet to define clear functional determinants of progression from DCIS to IDC. Epigenetic changes, critical for imprinting and tissue specific development, in the incorrect context can lead to global signaling rewiring driving pathological phenotypes. Epigenetic signaling pathways, and the molecular players that interpret and sustain their signals, are critical to understanding the underlying pathology of breast cancer progression. The types of epigenetic changes, as well as the molecular players, are expanding. In addition to DNA methylation, histone modifications, and chromatin remodeling, we must also consider enhancers as well as the growing field of noncoding RNAs. Herein we will review the epigenetic interactions that have been uncovered in early stage lesions that impact breast cancer progression, and how these players may be utilized as biomarkers to mitigate overdiagnosis and overtreatment.

Dissecting Tissue-Specific Super-Enhancers by Integrating Genome-Wide Analyses and CRISPR/Cas9 Genome Editing

Abstract

Recent advances in genome-wide sequencing technologies have provided researchers with unprecedented opportunities to discover the genomic structures of gene regulatory units in living organisms. In particular, the integration of ChIP-seq, RNA-seq, and DNase-seq techniques has facilitated the mapping of a new class of regulatory elements. These elements, called super-enhancers, can regulate cell-type-specific gene sets and even fine-tune gene expression regulation in response to external stimuli, and have become a hot topic in genome biology. However, there is scant genetic evidence demonstrating their unique biological relevance and the mechanisms underlying these biological functions. In this review, we describe a robust genome-wide strategy for mapping cell-type-specific enhancers or super-enhancers in the mammary genome. In this strategy, genome-wide screening of active enhancer clusters that are co-occupied by mammary-enriched transcription factors, co-factors, and active enhancer marks is used to identify bona fide mammary tissue-specific super-enhancers. The in vivo function of these super-enhancers and their associated regulatory elements may then be investigated in various ways using the advanced CRISPR/Cas9 genome-editing technology. Based on our experience targeting various mammary genomic sites using CRISPR/Cas9 in mice, we comprehensively discuss the molecular consequences of the different targeting methods, such as the number of gRNAs and the dependence on their simultaneous or sequential injections. We also mention the considerations that are essential for obtaining accurate results and shed light on recent progress that has been made in developing modified CRISPR/Cas9 genome-editing techniques. In the future, the coupling of advanced genome-wide sequencing and genome-editing technologies could provide new insights into the complex genetic regulatory networks involved in mammary-gland development.

Magnetic hyperthermia of breast cancer cells and MRI relaxometry with dendrimer-coated iron-oxide nanoparticles

Recently, some studies have focused on dendrimer nanopolymers as a magnetic resonance imaging (MRI) contrast agent or a vehicle for gene and drug delivery. Considering the suitable properties of these material...

Möglichkeiten und Grenzen der Eigenfetttransplantation

Mithilfe der autologen Transplantation von abgesaugtem subkutanem Fettgewebe lassen sich gute Ergebnisse zum Beispiel bei der Brustvergrößerung erzielen. Der folgende Beitrag beschreibt verschiedene Möglichkeiten, wie Patientinnen und Patienten erfolgreich mit der sogenannten BEAULI™-Methode behandelt werden können.

Aus dem Nähkästchen: fünf Tipps und Tricks für Eingriffe an der Haut

FOBI präsentiert breites Spektrum der ästhetischen Medizin

Die 26. Fortbildungswoche für praktische Dermatologie und Venerologie bot ihren Besuchern in München Ende Juli auch eine Vielzahl ästhetischer Fortbildungsthemen an. Einige der Highlights finden Sie im folgenden Kongressbericht.

Sklerosierung statt Operation

Neues Verfahren gegen Cellulite

Pflege bei irritierender Aknetherapie

Symptomorientierte Therapie der Rosazea

Allergan benennt neue Führungskräfte für Deutschland

Was brennt Ihren Patienten unter den Nägeln?

Nägel dienen dem Schutz und der Stabilität der Finger- und Zehenkuppen sowie der taktilen Sensibilität und fungieren an den Fingern als Greifwerkzeuge. Gleichzeitig stellen kranke Nägel eine kosmetische Einschränkung dar. Nagelerkrankungen verdienen daher ausreichende Beachtung und eine intensive Behandlung.

Zusatz zur Lokalanästhesie und Notfallmedikation

Lifestyle und der Einfluss auf die ästhetische Medizin

Jennifer Ceaser ist eine US-amerikanische Journalistin mit Sitz in Berlin. Seit über 15 Jahren veröffentlicht sie regelmäßig in Print- und Online-Publikationen wie New York Magazine, New York Post, The Independent, London Evening Standard, Conde Nast Traveler. Mit dem Experten Dr. Dirk Gröne spricht sie über den Einfluss der modernen Medien auf das Patientenverhalten.

Inhaltsverzeichnis

Auf stürmischer See

Therapie der androgenetischen Alopezie

Alopecia androgenetica der Frau

Zusammenfassung

Aufgrund der Vielgestaltigkeit der Ausfallsmuster und der zahlreichen möglichen Ursachen betrachten viele Ärzte Haarausfall bei Frauen als crux medicorum. Doch das Problem ist beherrschbar. Grundsätzlich ist zu unterscheiden, ob der Haarausfall durch hormonelle oder nicht hormonelle Ursachen bedingt ist und ob im Fall einer androgenetischen Alopezie eine manifeste Hyperandrogenämie oder nur eine erhöhte Sensitivität der Haarfollikel gegenüber Androgenen vorliegt.

Speicherung und Aufbewahrung von Patientendaten vs. DSGVO

Die Datenschutzgrundverordnung (DSGVO) hat nicht nur der Ärzteschaft umfassende neue Verpflichtungen auferlegt, sondern auch den Patienten neue Auskunfts- und Löschungsansprüche eingeräumt. Diese Ansprüche stehen nun neben den bisherigen gesetzlichen Regelungen im Raum, sodass zu beleuchten ist, welche Rangordnung unter den Normen besteht. Nur dadurch lässt sich klären, ob die neuen Regelungen der DSGVO die Verpflichtungen der Ärzteschaft auch an dieser Stelle erweitern und was künftig zu beachten ist.

Laserlipolyse zur selektiven Fettzerstörung und Fettgewinnung

In der letzten Zeit sorgt die Laserlipolyse als minimalinvasives Verfahren für einen Aufwärtstrend dieser operativen Technik, wobei diese vorrangig zur Fettreduktion und Straffung der Haut eingesetzt werden kann. Neuerdings wird die Laserlipolyse auch für die Gewinnung von vitalen kleinzelligen Fettzellen und „stromal vascular fraction"(SVF)-Zellen gezielt verwendet, welche anschließend für den regenerativen Gewebeaufbau im Rahmen eines autologen Lipotransfers zur Verfügung stehen.

Narbenbehandlung mit Radiofrequenz-Needling

Cup Feeding as a Supplemental, Alternative Feeding Method for Preterm Breastfed Infants: An Integrative Review

Abstract

Background The benefits of human milk for the preterm infant are well established. Preterm infants have lower breastfeeding rates and often face breastfeeding challenges. It is important that feeding practices for preterm infants optimize their chances of breastfeeding. Objective The purpose of this integrated review is to synthesize and critically analyze research related to the safety and efficacy of cup feeding as an alternative, supplemental feeding method for breastfed infants. Data Sources The electronic data bases of PubMed, CINAHL and were used to identify studies published in English from 1998- 2017. Design Using inclusion and exclusion criteria, 27 articles were initially assessed. After further screening 19 articles were included in the full review and of these 5 more were excluded. Lastly, an in-depth review of these 14 studies resulted in 2 more exclusions, for a total of 12 studies that met full inclusion and exclusion criteria. Review Methods Studies were examined for information on safety and efficacy of cup feeding as an alternative, supplemental feeding method for preterm breastfed infants. Studies were grouped into categories of outcomes that included (a) safety and physiologic properties; (b) breastfeeding outcomes. Results Use of cup feeding resulted in more stable heart rate and oxygen saturation than bottle feeding with similar weight gain. Additionally, breastfeeding rates were higher at discharge with continued higher rates at 3 and 6 months post-discharge for cup fed infants. Conclusions Premature infants face more breastfeeding obstacles than term infants. The potential for cup feeding as an alternative to bottle-feeding for breast fed preterm infants is positively supported by these results It is fundamentally important for NICU professionals to establish a protocol, education and training for the potential use of this feeding method for this vulnerable population.

Sexuell übertragbare Infektionen in den Tropen

Zusammenfassung

Sexuell übertragbare Infektionen (STI) sind weltweit häufig; allein die Inzidenz für Chlamydien-Infektionen, Gonorrhö, Syphilis und Trichomoniasis wird auf 500 Mio. Fälle/Jahr geschätzt. Drei Viertel dieser Infektionen entfallen auf tropische Länder in Lateinamerika, Subsahara-Afrika sowie Süd- bzw. Südostasien. Unter „tropischen Geschlechtskrankheiten" werden die bakteriellen Infektionen Ulcus molle, Lymphogranuloma venereum und Granuloma inguinale zusammengefasst. Diese treten vornehmlich in den Ländern zwischen den Wendekreisen auf – Regionen, die zum einen durch ein feucht-heißes Klima, zum anderen vielfach durch Armut und Unterentwicklung gekennzeichnet sind. Die 3 Erkrankungen gehen primär mit Ulzera einher; ihr Vorliegen stellt daher ein erhöhtes Risiko für die Übertragung von HIV und anderen STI dar. Wie bei allen STI gilt auch für die Tropeninfektionen, dass Risikominimierung durch Verzicht auf riskante Sexualpraktiken und Kondombenutzung essenziell sind.

Capsaicinoide und Cayennepfeffer-Extrakte

Erratum zu: Monolokuläres Erythema elevatum et diutinum am Handrücken

Erratum zu:

Hautarzt 2018, Suppl 1

https://ift.tt/2xPnvDQ

Sehr geehrte Leserin, sehr geehrter Leser,

im oben genannten Beitrag ist es leider zu einem Fehler im Titel gekommen. Wir bitten Sie, den aktualisierten Beitragstitel zu berücksichtigen und den Fehler zu …

The doctrine of specific etiology

Abstract

Modern medicine is often said to have originated with nineteenth century germ theory, which attributed diseases to bacterial contagions. The success of this theory is often associated with an underlying principle referred to as the "doctrine of specific etiology". This doctrine refers to specificity at the level of disease causation or etiology. While the importance of this doctrine is frequently emphasized in the philosophical, historical, and medical literature, these sources lack a clear account of the types of specificity that it involves and why exactly they matter. This paper argues that nineteenth century germ theory involves two types of specificity at the level of etiology. One type receives significant attention in the literature, but its influence on modern medicine has been misunderstood. A second type is present in this model, but it has been completely overlooked in the extant literature. My analysis clarifies how these types of specificity led to a novel conception of etiology that continues to figure in medicine today.

Radiomics: is it time to compose the puzzle?

Use of Stem Cells in Wound Healing

Abstract

Purpose of Review

This review provides an overview of the principal stages of wound healing, the populations of endogenous and therapeutic stem cells, applications of stem cells in specific types of wounds, and current approaches of stem cell delivery for tissue regeneration.

Recent Findings

New uses of progenitor stem cells have been developed for the treatment of wounds. Stem cells improve wound healing through both local and paracrine effects. Stem cell populations of therapeutic utility include embryonic stem cells, induced pluripotent stem cells, adult bone marrow and adipose-derived mesenchymal stem cells, as well as stem cells from skin, cord blood, and extra fetal tissue. Induced pluripotent stem cells mitigate many of the ethical and immunogenic concerns related to use of embryonically derived stem cells.

Summary

Skin, the largest organ in the human body, serves as a protective barrier for mammals. Both aging and disease contribute to loss of skin barrier function, which can result in consequences such as chronic wounds. Recent advances in many types of stem cell therapy may revolutionize treatment of difficult wounds. Optimal techniques for obtaining and delivering stem cells are still being refined.

Current Psoriasis Efficacy Outcome Measures in Clinical Trials

Abstract

Purpose of Review

This review sought to examine currently used psoriasis efficacy outcome measures. In particular, we wanted to know what outcome measures are currently being used most frequently, in addition to the advantages and disadvantages of each outcome measure.

Recent Findings

In the past year, Psoriasis Area and Severity Index (PASI) was the most frequently used outcome measure in phase III and IV clinical trials evaluating psoriasis treatments. PASI scores were also the most frequently used primary outcome measure. Psoriasis Scalp Severity Index (PSSI) was the most commonly utilized regional physician reported outcome measure and Dermatology Quality of Life Index (DLQI) was the most commonly used patient reported outcome.

Summary

It is important for clinical trials to utilize outcome measures that are both accurate and take into account patients' perspectives. Standardization of outcome measures will allow for better comparison of treatments across clinical trials.

Erythroderma and Figurate Erythemas

Abstract

Purpose of Review

Erythroderma and figurate erythemas are common reasons for inpatient dermatologic consultation. This review provides an overview of the frequent causes of erythroderma and figurate erythemas in adults and children as well as highlights recent advances in our understanding of the pathomechanisms of these entities.

Recent Findings

With the advent of immunotherapy for the treatment of cancer, there are new medications that may result in drug-induced erythroderma. Additionally, the pathophysiology and immunologic milieu of erythroderma in psoriasis and cutaneous lymphoma has been investigated. More recent biologic agents may be used to treat erythroderma.

Summary

The differential diagnosis of erythroderma and figurate erythemas is broad and often related to underlying systemic diseases. Workup and treatment should focus on identifying and treating an underlying cause when applicable.

Pretarsal roll augmentation with dermal hyaluronic acid filler injection

Abstract

Pretarsal roll augmentation with dermal hyaluronic acid filler injection focuses on restoring pretarsal fullness. This study aimed to introduce a method of pretarsal roll augmentation with dermal hyaluronic acid filler injection and establish the level of difficulty, safety, and effectiveness of this method. Eighty female patients were enrolled in this study. Hyaluronic acid filler was used to perform pretarsal roll augmentation. Physician and patient satisfaction at 1 month and 4 months after surgery was investigated. The level of satisfaction was graded from points 1 to 5. The patient satisfaction and physician scores were 4.7 ± 1.1 (mean ± standard deviation) points at 1 month and 4.8 ± 0.9 points at 4 months and 4.6 ± 0.9 points at 1 month and 4.8 ± 1.0 points at 4 months, respectively. No major complications were observed. Our technique provided a natural and younger appearance with pretarsal fullness. This technique was easy to perform for the restoration of pretarsal fullness, and it improved periorbital contouring, rejuvenated the pretarsal roll, and provided excellent esthetic results.

Level of Evidence: Level V, therapeutic study.

Congenital absence of the deep inferior epigastric system: a case report

Abstract

Preoperative computerised tomographic angiography (CTA) in free flap breast reconstruction outlines the deep inferior epigastric perforator (DIEP). It can identify a single or twin system, measure vessel calibre, and identify iatrogenic/congenital anatomical variations. Evidence of the effect of previous abdominal incisions on this vessel system remain inconclusive. We present the case of a congenital absence of the system identified from routine preoperative CTA. A 61-year-old female presented for immediate unilateral breast reconstruction following mastectomy for ductal carcinoma in situ. She previously had a right-sided Kocher's incision performed for an open cholecystectomy and a gridiron incision. Coincidentally, preoperative CTA demonstrated congenital absence of the left DIEP system, and marked atrophy of the upper right rectus abdominis (RA). As a result, the superior gluteal artery perforator (SGAP) flap was planned. Intraoperatively, a 1.318-kg SGAP was raised on three perforators and coupled to the internal mammary vessels. In the postoperative period, there were no complications. Preoperative CTA demonstrated multiple hazards in raising a DIEP flap, CTA permitted surgical planning, improving patient safety and surgical efficiency. Preoperative CTA identifies vessel abnormalities resulting from abdominal scarring. The rate of congenital anomalies is unknown. This incidental discovery highlights the role CTA has in reducing operative time, facilitating a successful free tissue transfer, therefore improving patient safety.

Level of Evidence: Level V, diagnostic study.

A rare case of finger ischemia following bypass procedure with autologous vein graft for thumb revascularization: a case report and brief review of the literature

Abstract

This case report aims to point out the importance of having in mind anatomical variation in the blood supply to the hand even in emergency settings. A 39-year-old patient presented at our emergency department with a wound on the distal anterolateral third of the left forearm with skin loss, degloving injury of the thumb starting from the 1st metacarpal, exposure of the proximal two thirds of the 1st metacarpal bone, and both radial and ulnar digital arteries of the thumb damaged. A 10-cm-long vein graft was anastomosed in termino-later fashion between the dorsal branch of the radial artery and the uninjured distal part of the ulnar collateral digital artery of the thumb, successfully re-establishing its blood supply. Starting from the 1st postoperative day, the thumb was warm and pink while the other fingers were pale and capillary filling was absent. An urgent arteriography of the left upper extremity demonstrated the presence of normal radial artery, hypoplastic ulnar artery, dominant median artery, and absence of vascularization of the 2nd, 3rd, 4th, and 5th fingers. By the end of 2nd week, the patient underwent amputation of the four fingers at the distal metacarpal level. Anatomical anomalies of hand arterial blood supply are not uncommon, even though rarely reported in literature. Therefore, an instrumental study should be performed before attempting any arterial intervention even in emergency settings. Nevertheless, further studies should be performed to identify ready-to-use tools to make surgeons aware of any anatomic variations in order to avoid such complications.

Level of Evidence: Level V, therapeutic study.

Contributing effect of lymphatic disruption in trapdoor deformity in nasolabial flaps—superiorly based vs. inferiorly based flap: A case report

Abstract

The nasolabial flap is well suited for reconstruction of the lower third of the nose. In one-stage reconstruction used as transposition flap, complications can be caused by blunting of the normal concavity of the nasofacial sulcus, but also by trapdoor formation. Various theories have attempted to explain this phenomenon of bulging tissue occurring in transposition flaps. The contributing effect of lymphatic dysfunction is not clear. In our case performed after excision of basal cell carcinoma, both lower thirds of the nose of a 77-year-old patient were reconstructed with a nasolabial transposition flap using an inferior base on one and a superior base on the other side. A follow-up showed greater trapdoor deformity on the superiorly based transposition flap. Assuming that the inferiorly based flap has better drainage than the superiorly based due to intact vertical lymphatics, our case suggests that lymphatic disruption may significantly contribute to the development of trapdoor deformity.

Level of Evidence: Level V, risk/prognostic study.

Correction to: Fragrances as allergens

Correction to:

Allergo J Int 2018

https://ift.tt/2R6LUvV

The conflicts of interest of the authors Axel Schnuch and Peter Griem had been omitted.

The correct information is given …

Reminder system for adrenaline autoinjectors does not work

What’s new in the Global Initiative for Asthma 2018 report and beyond

Abstract

Background

The Global Initiative for Asthma (GINA) has regularly published and annually updated a global strategy for asthma management and prevention that has formed the basis for many national guidelines. The 2018 update of the GINA report incorporates new evidence following the routine twice-yearly cumulative review of the literature by the GINA Scientific Committee.

Methods

Recommendations in the 2018 edition were examined for new content and updates, and the scientific evidence behind these recommendations was examined and discussed. Focus was given to the management of asthma in adults in the general population and children more than 5 years of age. Selected new studies related to the management of asthma that may affect future recommendations were also discussed.

Results and discussion

There have been updates in the assessment of asthma, the role of fractional exhaled nitric oxide, and the stepwise treatment of asthma. Key messages from previous versions of the guidelines were also reiterated and updated with new evidence supporting previous recommendations. Changes and new recommendations may be expected in future editions based on new scientific evidence which has emerged in the recent months.

Air pollutants and primary allergy prevention

Abstract

Background

Air pollutants such as particulate matter (PM_2.5) and nitrogen dioxide (NO₂) in outdoor air have long been suspected of causing the development of asthma and allergic rhinitis. However, a variety of systematic reviews have reached different conclusions in the last 15 years on whether these air pollutants do in actual fact play a causal role in the onset of asthma, allergic rhinitis, and eczema.

Methods

Based on published systematic reviews and the most recent publications, the current state of knowledge on epidemiological evidence is presented and the potential for primary prevention of these allergic diseases by reducing or avoiding exposure to these air pollutants evaluated.

Results

Despite conducting an extensive literature search, analyzing the most recent results, and focusing on the birth cohort studies most relevant to the question in hand, epidemiological results do not adequately support the concept of a causal relationship between the two air pollutants in question, PM_2.5 and NO₂, and asthma. Epidemiological studies predominantly show no effect of these air pollutants on allergic sensitization and the onset of allergic rhinitis. The small number of studies that have investigated the link between air pollutants and eczema largely revealed there to be no link.

Conclusion

If the evidence for the causal role of air pollutants in the onset of allergies is inconclusive, one must assume that it is probably not possible to achieve primary prevention of allergies by improving air quality. However, there is sufficient evidence to show that air pollutants can trigger exacerbations of allergic diseases. This alone justifies ensuring that the existing threshold values for air pollutants are adhered to, in order to protect particularly allergy sufferers from health impairments.

Characteristics of iodine-123 IQ-SPECT/CT imaging compared with conventional SPECT/CT

Abstract

Objectives

Although the utility of IQ-SPECT imaging using ^99mTc and ²⁰¹Tl myocardial perfusion SPECT has been reported, ¹²³I-labeled myocardial SPECT has not been fully evaluated. We determined the characteristics and utility of ¹²³I IQ-SPECT imaging compared with conventional SPECT (C-SPECT).

Methods

Two myocardial phantom patterns were used to simulate normal myocardium and myocardial infarction. SPECT acquisition was performed using a hybrid dual-head SPECT/CT system equipped with a SMARTZOOM collimator for IQ-SPECT or a low-medium energy general purpose collimator for C-SPECT. Projection data were reconstructed using ordered subset expectation maximization with depth-dependent 3-dimensional resolution recovery for C-SPECT and ordered subset conjugate gradient minimizer method for IQ-SPECT. Three types of myocardial image were created; namely, no correction (NC), with attenuation correction (AC), and with both attenuation and scatter corrections (ACSC). Five observers visually scored the homogeneity of normal myocardium and defect severity of the myocardium with inferior defects by a five-point scale: homogeneity scores (5 = homogeneous to 1 = inhomogeneous) and defect scores (5 = excellent to 1 = poor). We also created a 17-segment polar map and quantitatively assessed segmental %uptake using a myocardial phantom with normal findings and defects.

Results

The average visual homogeneity scores of the IQ-SPECT with NC and ACSC were significantly higher than that of C-SPECT, whereas the average visual defect scores of IQ-SPECT with AC and ACSC were significantly lower. The %uptake of all segments for IQ-SPECT with NC was significantly higher than that of C-SPECT. Furthermore, the subtraction of %uptake for C-SPECT and IQ-SPECT was the largest in inferior wall, which was approximately 10.1%, 14.7% and 14.4% for NC, AC and ACSC, respectively. The median % uptake values of the inferior wall with defect areas for C-SPECT and IQ-SPECT were 46.9% and 50.7% with NC, 59.8% and 69.2% with AC, and 54.7% and 66.5% with ACSC, respectively.

Conclusion

¹²³I IQ-SPECT imaging significantly improved the attenuation artifact compared with C-SPECT imaging. Although the defect detectability of IQ-SPECT was inferior to that of C-SPECT, ¹²³I IQ-SPECT images with NC and ACSC met the criteria for defect detectability. Use of ¹²³I IQ-SPECT is suitable for routine examinations.

18 F-fluorodeoxyglucose positron emission tomography is correlated with the pathological necrosis and decreased microvessel density in lung adenocarcinomas

Abstract

Objective

We explored the relationship between preoperative ¹⁸F-FDG-PET parameters, tumor necrosis, and microvessel density (MVD) in patients with pulmonary adenocarcinomas.

Methods

A total of 164 patients, who underwent surgical resection for lung adenocarcinoma, were reviewed retrospectively. The maximum standardized uptake value (SUV_max), peak SUV corrected for lean body mass (SUL_peak), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) values were measured by preoperative ¹⁸F-FDG-PET. The extent of tumor necrosis was examined and CD31 expression was evaluated to count the MVD.

Results

The SUV_max, SUL_peak, MTV, and TLG levels were significantly lower in patients exhibiting no necrosis compared to those with necrosis. When we divided the patients into two groups based on high vs. low PET parameter values, elevated SUV_max, SUL_peak, MTV, and TLG values were significantly more associated with partial or diffuse necrosis than were lower values (p < 0.001). A negative correlation was evident between the MVD and SUV_max, MVD and SUL_peak, MVD and MTV, and MVD and TLG. Tumor necrosis was correlated with a shorter overall survival (OS) (p = 0.007) and recur-free survival (RFS) (p < 0.001). However, multivariate analysis revealed that necrosis was not of prognostic significance. The SUV_max, MTV and TLG were associated with inferior OS or RFS rates in univariate analysis, however, not in multivariate analysis.

Conclusion

High-level FDG accumulation is correlated with tumor necrosis in lung adenocarcinoma.

Accuracy of an artificial neural network for detecting a regional abnormality in myocardial perfusion SPECT

Abstract

Objectives

The patient-based diagnosis with an artificial neural network (ANN) has shown potential utility for the detection of coronary artery disease; however, the region-based accuracy of the detected regions has not been fully evaluated. The aim of this study was to demonstrate the accuracy of all detected regions compared with expert interpretation.

Methods

A total of 109 abnormal regions including 33 regions with stress defects and 76 regions with ischemia were examined, which were derived from 21 patients who underwent myocardial perfusion SPECT within 45 days of coronary angiography. The gray and color scale images, a polar map of stress, rest and difference, and left ventricular function were displayed on the monitor to score the extent and severity of stress defect and ischemia. Two experienced nuclear medicine physicians (Observers A and B) scored the abnormality with a 4-point scale and draw abnormal regions on a polar map. The gold standard was determined by the final judgment of normal or abnormal by the consensus of two other independent expert nuclear cardiologists, and was compared with the stress defect and ischemia derived from ANN.

Results

The concordance rate of ANN to the gold standard was higher than that of two observers. Furthermore, the κ coefficient indicated moderate to substantial agreement for stress defect and slight to the fair agreement for ischemia. The area under the curve (AUC) of ANN was the highest for both stress defect and ischemia; in particular, the ANN of ischemia showed significantly higher AUC than Observer A (p = 0.005). The ANN of stress defect showed higher specificity compared with two observers, while the ANN of ischemia showed higher sensitivity. Consequently, the accuracy of ANN showed the highest in this study.

Conclusion

The ANN-based regional diagnosis showed a high concordance rate with the gold standard and comparable or even higher than the interpretation by nuclear medicine physicians.

Usefulness of both PET/CT with F18-FDG and whole-body diffusion-weighted imaging in cancer screening: a preliminary report

Abstract

Objective

Positron emission tomography/computed tomography (PET/CT) with fluorodeoxyglucose (F18-FDG) is useful for the detection of malignant lesions, including metastatic lesions, and this technique is widely used in cancer screening. However, this approach may occasionally yield false-positive and false-negative findings. At our PET center, to increase the accuracy of PET/CT, we use PET/CT and whole-body diffusion-weighted imaging (WB-DWI) together. This study aimed to assess the usefulness of this combination.

Methods

We examined 29 subjects with confirmed diagnosis. All of them had undergone PET/CT and WB-DWI on the same day. Twenty-seven of them also underwent ultrasonography, blood testing, and upper gastrointestinal series on the same day and two fecal occult blood tests on another day. WB-DWI was performed on a 1.5-T MRI unit with a b value of 0 and 800 or 1000 s/mm². For all 29 cases, PET/CT and WB-DWI were classified to be positive or negative, and the diagnostic ability was calculated for each modality.

Results

Among the 29 subjects, 17 had malignant tumors and 12 had benign tumors or no abnormalities. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of PET/CT were 65%, 25%, 55%, 33%, and 48%, respectively; while the corresponding values for WB-DWI were 59%, 100%, 100%, 63%, and 76%, respectively. By considering the result to be negative when PET/CT findings were positive but WB-DWI findings were negative, specificity increased from 25 to 100%, and accuracy increased from 48 to 76%. On the other hand, by considering the result to be positive when the findings of either PET/CT or WB-DWI were positive, sensitivity increased from 65 to 76%, and accuracy increased from 48 to 55%.

Conclusions

Our results suggest that using both PET/CT and WB-DWI together can increase accuracy in cancer screening. However, this approach was not able to detect malignant lesions in some cases, indicating that there were limitations with imaging certain organs. Therefore, it is important to further understand the features of PET/CT and WB-DWI and use them appropriately for each organ. Additionally, given that the study sample was relatively small, further research is needed to validate these findings.

PET imaging of noradrenaline transporters in Parkinson’s disease: focus on scan time

Abstract

Objective

In subjects with idiopathic Parkinson's disease (PD) the functional state of the locus coeruleus and the subtle derangements in the finely tuned dopamine–noradrenaline interplay are largely unknown. The PET ligand (S,S)-[¹¹C]-O-methylreboxetine (C-11 MRB) has been described to reliably bind noradrenaline transporters but long scanning protocols might hamper its use, especially in patients with PD. We aimed to assess the feasibility of reducing C-11 MRB scans to 30 min.

Methods

Ten patients with idiopathic PD underwent dynamic C-11 MRB PET (120 min duration) and brain magnetic resonance imaging. Model-based (i.e., simplified and multilinear reference tissue model 2) non-displaceable binding potentials (BP) of selected brain regions were analyzed for a 90 min scan protocol and compared with BP derived from static 30-min data with different starting times (30, 40, 50 and 60 min) after C-11 MRB injection. Intraclass correlation coefficient and linear regression analysis were used to explore the association between BP of different scan durations. Spearman's ρ served to describe the correlation of BP with demographic and clinical parameters.

Results

With respect to kinetic models, BP_50–80 and BP_60–90 showed the best correlation in several brain areas (R² range 0.95–98; p < 0.001). The thalamus showed the highest BP on average. No correlation between BP, clinical and demographic characteristics was observed.

Conclusions

An acquisition time of 30 min, starting 50 or 60 min after C-11 MRB injection, allows a reliable estimation of noradrenaline transporter binding values in Parkinsonian people. A short acquisition time can significantly reduce the discomfort of Parkinsonian patients and facilitate PET studies, especially in the medication-off-state.

Count-based method for specific binding ratio calculation in [I-123]FP-CIT SPECT analysis

Abstract

Objective

To calculate the specific binding ratio (SBR) appropriately in dopamine transporter (DAT) imaging, a method for extracting the striatal volume of interest (VOI) was developed.

Methods

This study included 200 patients (72 ± 10 years) who were suspected of parkinsonian syndromes (PS) or dementia with Lewy body (DLB). The patients were divided into three groups of PS with dopaminergic degeneration, DLB and non-PS after [¹²³I]ioflupane (FP-CIT) SPECT and clinical follow-up. The image data were reconstructed with CT attenuation correction and scatter correction, and with only CT attenuation correction (CTAC). The new method extracted striatal VOI according to the high-level counts and the average striatum volume, and calculated SBR using the reference occipital counts. The SBR values for each patient were obtained using the Tossici-Bolt method (SBR_Bolt) and our method. Reproducibility of SBR calculation using our method was compared by two operators.

Results

The mean SBR values for the PS and DLB groups were significantly different from that of the non-PS group with both methods. The coefficients of variation of the SBR were significantly smaller with the proposed method compared with those of SBR_Bolt (p < 0.001), except for the CTAC images. There were no differences in SBR between the two operators using our method. The diagnostic accuracies with our method for the PS and DLB groups were 98.4 and 96.0%, respectively.

Conclusion

Our new method for SBR calculation in the FP-CIT SPECT showed less coefficients of variation with high reproducibility, which would be useful for clinical diagnosis and in assessing the severity of diseases in follow-up studies.

Intraoperative Manipulation of Bony Segments: An Innovative Method

Abstract

Introduction

Various methods are deployed by an oral and maxillofacial surgeon to control the osteotomised/ fractured bony segments intraoperatively till the time a stable fixation in the desired position is achieved. Few of these include the use of bone holding crocodile forceps, towel clips, reduction forceps, wires, digital control (Thota and Mitchell in Br J Orthod 26(4):325, 1999). In our technique, we present the use of an IMF screw to manipulate bony segments intraoperatively.

Materials and Methods

We used this novel technique in a series of 12 patients. An IMF screw was fixed in the greatest bulk of the bony fragment so as to control it and hold it in the desired position in various surgical procedures.

Conclusion

This technique was found to be minimally invasive and easy to perform to achieve a good hold and control of the bony segments.

How to Anscombe a Frege-Wittgenstein: Responses to Littlejohn, Peterman, and Geisz

What is Abstraction in Photography?

Abstract

There is confusion about what counts as abstraction in photography: art theorists class very different kinds of photographs as abstract, and common philosophical views of photography, if true, should cause us to doubt their very possibility. I address two questions here: 'What is Abstraction?' and 'What is Abstraction in Photography?' To the answer the second, I briefly consider a third: 'What is Photography?' so that the resulting account is not undermined by a poor theory of photography. In answer to my target question, I outline a schematic (and non-exhaustive) typology of kinds of work generically typed as 'abstract' in order to bring out some differences between them. I distinguish 'proto', 'faux', 'constructed faux', 'weak', 'strong', 'constructed' and 'concrete' abstraction, although the differences between them are not always clear-cut and there is room for debate about borderline cases. My goal is not to resolve all such cases, but to show: (i) that there is a range of broadly identifiable kinds of abstraction in photography; (ii) that images can be abstract in a variety of ways and for a variety of reasons; and (iii) why certain images are not abstract, despite being widely typed as such.

On Looking through Wollheim’s Bifocals: Depiction, Twofolded Seeing and the Trompe-l’œil

Abstract

Richard Wollheim was hardly alone in supposing that his account of pictorial depiction implies that a trompe-l'œil is not a depiction. I recommend removing this apparent implication by inserting a Kant-style version of aspect-perception into his account. I characterize the result as Neo-Wollheimian and retain the centrality of Wollheim's notion of twofoldedness in the theory of depiction, but I demote it to a contingent feature of depictions and I criticize his employment of it for determining the category of both the trompe-l'œil and depictions in general.

Effect of live oral attenuated Typhoid vaccine, Ty21a, on systemic and terminal ileum mucosal CD4+ T memory responses in humans

Abstract

Our current understanding of CD4+ T cell mediated immunity (CMI) elicited by the oral live attenuated typhoid vaccine Ty21a is primarily derived from studies using peripheral blood. Very limited data is available in humans regarding mucosal immunity (especially CD4+ T) at the site of infection (e.g., terminal ileum; TI). Here using multiparametric flow cytometry, we examined the effect of Ty21a immunization on TI lamina propria mononuclear cells (LPMC) and peripheral blood CD4+ T memory (T_M) subsets in volunteers undergoing routine colonoscopy. Interestingly, we observed significant increases in the frequencies of LPMC CD4+ T cells following Ty21a-immunization, restricted to the T-effector/memory (T_EM)-CD45RA+ (T_EMRA) subset. Importantly, Ty21a-immunization elicited S. Typhi responsive LPMC CD4+ T cells in all major T_M subsets (interferon (IFN) and interleukin (IL)-17A in T effector/memory -T_EM-; IFN and macrophage inflammatory protein (MIP)-1 in T central/memory -T_CM-; and IL-2 in T_EMRA). Subsequently, we analyzed LPMC S. Typhi responsive CD4+ T cells in depth for multifunctional (MF) effectors. We found that LPMC CD4+ T_EM responses were mostly MF, except for those cells exhibiting the characteristics associated with IL-17A responses. Finally, we compared mucosal to systemic responses and observed that LPMC CD4+ S. Typhi-specific responses were unique and distinct from their systemic counterparts. This study provides the first demonstration of S. Typhi-specific CD4+ T_M responses in the human terminal ileum mucosa and provides valuable information about the generation of mucosal immune responses following oral Ty21a-immunization.

Host NAD+ metabolism and infections: therapeutic implications

Abstract

Nicotinamide adenine dinucleotide (NAD⁺) is both a crucial coenzyme and a cosubstrate for various metabolic reactions in all living cells. Maintenance of NAD⁺ levels is essential for cell energy homeostasis, survival, proliferation and function. Mounting evidence points to NAD⁺ as one of the major modulators of immuno-metabolic circuits, thus regulating immune responses and functions. Recent studies delineate impaired host NAD⁺ metabolism during chronic infections and inflammation, suggesting NAD⁺ replenishment as an avenue to ameliorate deleterious inflammatory responses. Here, we discuss aspects of NAD⁺ biosynthesis and consumption, NAD⁺ biology during infections and how NAD⁺ metabolism can be intervened with pharmacologically to enhance the host's immunological fitness against pathogens.

Low-dose sulfasalazine in a case of Pyodermatitis-pyostomatitis Vegetans

Lack of evidence for feminization of males exposed to spironolactone in utero: a systematic review

Morphea and systemic sclerosis are associated with an increased risk of melanoma and non-melanoma skin cancer

Demonstratives, definite descriptions and non-redundancy

Abstract

In some sentences, demonstratives can be substituted with definite descriptions without any change in meaning. In light of this, some have maintained that demonstratives are just a type of definite description. However, several theorists have drawn attention to a range of cases where definite descriptions are acceptable, but their demonstrative counterparts are not. Some have tried to account for this data by appealing to presupposition. I argue that such presuppositional approaches are problematic, and present a pragmatic account of the target contrasts. On this approach, demonstratives take two arguments and generally require that the first, covert argument is non-redundant with respect to the second, overt argument. I derive this condition through an economy principle discussed by Schlenker (in: Maier, Bary, Huitink (eds) Proceedings of Sub9, 2005).

Intraarticular injection of dexamethasone promotes bone erosion in collagen-induced arthritis in mice through up-regulation of RANKL expression

Abstract

Background

Dexamethasone (DEX) is an effective therapeutic option commonly used in the treatment of many inflammatory diseases. However, DEX could impair proliferation or differentiation of osteoblasts, suggesting a pivotal role of DEX in bone destruction.

Objective

To investigate whether intraarticular injection of DEX could exacerbate bone erosion during CIA development.

Setting

Collagen-induced arthritis (CIA) mice were divided into PBS-treated and DEX-treated groups (n = 5/group). Negative control group: DBA/1 mice (n = 5) were used as age-matched, healthy, untreated controls.

Method

CIA was induced in male DBA/1 mice. Intraarticular injected DEX (0.01 mg/Kg, 10 μl) into the knee joint of CIA on Day 28, Day 35, Day 42 and Day 49 post the 1st immunization.

Results

The severity of the arthritic disease was ameliorated in DEX-treated mice, accompanied by the decreased expression of IL-6, IL-8 and TNF-α. However, DEX treatment accelerates bone erosion and osteoporosis during CIA development and triggers higher expression of RANKL, IL-17 in vitro and vivo.

Main outcome measure

The effect of DEX on bone structure was analyzed using Haematoxylin & Eosin (H&E) staining and Micro-CT. The levels of receptor activator for nuclear factor-κ B ligand (RANKL) and osteoprotegerin (OPG) were investigated by real-time PCR, Western Blot and immunohistochemical analysis. RASFs were stimulated with Interleukin (IL)-1β and then treated with different concentrations of DEX for 72 h.

Conclusion

Intraarticular injection of DEX could exacerbate bone erosion in CIA model via up-regulation of RANKL expression.

Pirfénidone (Esbriet®) : attention au soleil !

Publication date: Available online 19 October 2018

Source: Annales de Dermatologie et de Vénéréologie

Author(s): J.-L. Schmutz

Interactive patient-customized curvilinear reformatting for improving neurosurgical planning

Abstract

Purpose

Visualizing a brain in its native space plays an essential role during neurosurgical planning because it allows the superficial cerebral veins and surrounding regions to be preserved. This paper describes the use of a visualization tool in which single gadolinium contrast-enhanced T1-weighted magnetic resonance imaging was applied in nondefective and nonresective skulls to promote visualization of important structures.

Methods

A curvilinear reformatting tool was applied on the supratentorial compartment to peel the tissues to the depth of the dura mater and thereby revealing cortical and vascular spatial relationships. The major advantage of our proposed tool is that it does not require coregistration of anatomical and vascular volumes.

Results

The reliability of this technique was supported by comparisons between preoperative images and digital photographs of the brain cortical surface obtained after the dura mater was removed in 20 patients who underwent surgery in the Clinics Hospital of the University of Campinas from January 2017 to April 2018.

Conclusion

Single fat-suppressed GAD contrast-enhanced T1-weighted magnetic resonance scans provide accurate preoperative 3D views of cortical and vascular relationships similar to neurosurgeons' intraoperative views. In developing countries with limited access to state-of-the-art health technologies, this imaging approach may improve the safety of complex neurosurgeries.

Second primary melanomas: Increased risk and decreased time to presentation in patients exposed to tanning beds

Publication date: Available online 19 October 2018

Source: Journal of the American Academy of Dermatology

Author(s): Yang Li, Mukti Kulkarni, Kathryn Trinkaus, Lynn A. Cornelius

Background

Melanoma incidence has increased; the primary modifiable risk factor is ultraviolet radiation (UVR) from the sun or artificial UVR (arUVR) from tanning beds.

Objective

To determine whether patients who developed melanoma after arUVR exposure from tanning beds have unique characteristics.

Methods

A retrospective study of 434 melanoma patients was performed. Patients who consented at the initial appointment completed a questionnaire regarding phenotypic traits, medical history, and UVR exposure.

Results

Compared with patients aged ≥40 years, younger patients, especially women, had greater lifetime exposure to arUVR. At any age, patients with multiple primary melanomas had a higher probability of exposure to arUVR. For all patients with additional primary melanomas, those exposed to arUVR acquired their second primary melanoma significantly earlier; 67% of patients exposed to arUVR through tanning beds had their second primary diagnosed at the time of or within 1 year of their original diagnosis compared with 28% of nontanners (P = .011). Median time to diagnosis of second primary melanoma in patients exposed to arUVR versus those not exposed was 225 days versus 3.5 years, respectively (P = .027).

Limitations

The study was conducted in 1 geographic area with a relatively small sample size.

Conclusion

Our findings provide evidence for heightened surveillance in melanoma patients exposed to arUVR.

A Technique to Provide Enhanced Visualization For Suture Cutting In Dermatologic Surgery

Publication date: Available online 19 October 2018

Source: Journal of the American Academy of Dermatology

Author(s): Brett C. Neill, Isadore S. Tarantino, Jason Stevens, Thomas L.H. Hocker

Patient Requests to Alter the Medical Record

Publication date: Available online 19 October 2018

Source: Journal of the American Academy of Dermatology

Author(s): Marissa L.H. Baranowski, Sarah Chisolm, Benjamin K. Stoff

Potential protective effects of rhEGF against ultraviolet A irradiation-induced damages on human fibroblasts

Correlation between DNA/HSA-interactions and antimalarial activity of acridine derivatives: Proposing a possible mechanism of action

Publication date: Available online 19 October 2018

Source: Journal of Photochemistry and Photobiology B: Biology

Author(s): Marina de M. Silva, Taís S. Macedo, Helena Mariana P. Teixeira, Diogo Rodrigo M. Moreira, Milena B.P. Soares, Ana Ligia da C. Pereira, Vanessa de L. Serafim, Francisco J.B. Mendonça-Júnior, Maria do Carmo A. de Lima, Ricardo O. de Moura, Edeildo F. da Silva-Júnior, João Xavier de Araújo-Júnior, Maria Dayanne de A. Dantas, Eduarda de O. O. Nascimento, Thamilla Maria S. Maciel, Thiago Mendonça de Aquino, Isis M. Figueiredo, Josué C.C. Santos

Abstract

Acridines are considered an important class of compounds due to their wide variety of biological activities. In this work, we synthesized four acridine derivatives (1–4) and evaluated their biological activity against the Plasmodium falciparum W2 line, as well as studied the interaction with ctDNA and HSA using spectroscopic techniques and molecular docking. The acridine derivative 2 (IC₅₀ = 0.90 ± 0.08 μM) was more effective against P. falciparum than primaquine (IC₅₀ = 1.70 ± 0.10 μM) and similar to amsacrine (IC₅₀ = 0.80 ± 0.10 μM). In the fluorescence and UV–vis assays, it was verified that the acridine derivatives interact with ctDNA and HSA leading to a non-fluorescent supramolecular complex formation. The non-covalent binding constants ranged from 2.09 to 7.76 × 10³ M⁻¹, indicating moderate interaction with ctDNA. Through experiments with KI, fluorescence contact energy transfer and competition assays were possible to characterize the main non-covalent binding mode of the acridines evaluated with ctDNA as intercalation. The binding constants obtained showed a high linear correlation with the IC₅₀ values against the antimalarial activity, suggesting that DNA may be the main biological target of these molecules. Finally, HSA interaction studies were performed and all evaluated compounds bind to the site II of the protein. The less active compounds (1 and 3) presented the highest affinity to HSA, indicating that the interaction with carrier protein can affect the (bio)availability of these compounds to the biological target.

Graphical Abstract

Transferring An Organ From An HIV-Positive Donor

Surgeons in South Africa transplanted part of a liver from an HIV-positive mother to her uninfected daughter — a medical first. Scott Simon talks to Dr. Harriet Etheredge, a medical bioethicist.

A Climate Scientist On 'Slaying The Climate Dragon'

Kate Marvel, a climate scientist at Columbia University and NASA, talks to NPR's Scott Simon about her fairy tale on climate change and reads passages from the story.

Correction to: The fitting attitudes analysis of value: an explanatory challenge

Few errors were identified in the original publication of the article. The corrections are as follows.

Cryolipolysis: patient selection and special considerations

Clinical and Genetic Risk Factors Associated with Psoriatic Arthritis among Patients with Psoriasis

Abstract

Introduction

Psoriatic arthritis (PsA) is a chronic, inflammatory arthritis that affects an estimated 30% of patients with psoriasis. PsA is underdiagnosed in primary care and dermatology clinics due to a variety of reasons, including failure of healthcare providers to ask about symptoms, overlap of symptoms and signs with other rheumatologic conditions, and lack of a specific diagnostic test. A delay in PsA diagnosis and treatment, even as short as 6 months, can lead to decreased quality of life, increased joint damage, and worse long-term physical function. In this study, we sought to identify the clinical and genetic factors that help discriminate patients with PsA from those with cutaneous psoriasis only.

Methods

We analyzed a cohort of 974 psoriasis patients at an academic medical center, of whom 175 had confirmed PsA, and performed univariate, multivariate, and predictive modeling to determine factors associated with PsA.

Results

The univariate analysis revealed significant positive associations of PsA with age, nail involvement, scalp involvement, skin fold involvement, elbow/knee involvement, psoriasis severity, plaque subtype, erythrodermic subtype, hypertension, type 2 diabetes, and coronary artery disease, and a significant negative association of PsA with the human leukocyte antigen (HLA)-C*06:02 allele. In the multivariate analysis, nail involvement, type 2 diabetes, and pustular psoriasis remained significantly associated with PsA, while HLA-C*06:02 positivity remained protective. There was a trend towards an association of PsA with older age, younger age of psoriasis onset, and skin fold involvement, while there was protective trend for smoking. A predictive model including both clinical and genetic factors showed reasonable discriminative ability between psoriasis and PsA, with an area under the curve of 0.87 for a receiver operating characteristic curve.

Conclusion

This study identified a number of clinical and genetic features that could help stratify patients who are at higher risk for having PsA and for whom rheumatology referral may be beneficial.

Beating tumour drug resistance: “Lamarckian” induction in the spotlight

Pigment Cell &Melanoma Research, Volume 0, Issue ja, -Not available-.

A curated gene list for expanding the horizons of pigmentation biology

Pigment Cell &Melanoma Research, Volume 0, Issue ja, -Not available-.

The 1918 Influenza Pandemic: Looking Back, Looking Forward

Abstract

In commemoration of the centennial of the 1918 influenza pandemic, the American Journal of Epidemiology has convened a collection of 12 articles that further illuminate the epidemiology of that pandemic and consider whether we would be more prepared if an equally deadly influenza virus were to emerge again. In the present commentary, we place these 12 articles in the context of a growing body of work on the archeo-epidemiology of past pandemics, the socioeconomic and geographic drivers of influenza mortality and natality impact, and renewed interest in immune imprinting mechanisms and the development of novel influenza vaccines. We also highlight persisting mysteries in the origins and impact of the 1918 pandemic and the need to preserve rapidly decaying epidemiologic and serological information that may provide treasure troves for future generations.

Spectral Properties of Fluorogenic Thiophene‐Derived Triarylmethane Dyes

Photochemistry and Photobiology, Volume 0, Issue ja, -Not available-.

The Xanthophyll Carotenoid Astaxanthin has Distinct Biological Effects to Prevent the Photo‐aging of the Skin Even by its Post‐irradiation Treatment

Photochemistry and Photobiology, Volume 0, Issue ja, -Not available-.

Axitinib Versus Placebo as an Adjuvant Treatment for Renal Cell Carcinoma: Results From the Phase III, Randomized ATLAS Trial

Abstract

Background

The ATLAS trial compared axitinib versus placebo in patients with locoregional renal cell carcinoma (RCC) at risk of recurrence after nephrectomy.

Patients and Methods

In a phase III, randomized, double-blind trial, patients had >50% clear-cell RCC, had undergone nephrectomy, and had no evidence of macroscopic residual or metastatic disease (independent review committee [IRC] confirmed). The intent-to-treat population included all randomized patients (≥pT2 and/or N+, any Fuhrman grade [FG], Eastern Cooperative Oncology Group status 0/1). Patients (stratified by risk group/country) received (1:1) oral twice-daily axitinib 5 mg or placebo for ≤3 years, with a 1-year minimum unless recurrence, occurrence of second primary malignancy, significant toxicity, or consent withdrawal. The primary end point was disease-free survival (DFS) per IRC. A prespecified DFS analysis in the highest-risk subpopulation (pT3, FG ≥ 3 or pT4 and/or N+, any T, any FG) was conducted.

Results

A total of 724 patients (363 versus 361, axitinib versus placebo) were randomized from May 8, 2012, to July 1, 2016. The trial was stopped due to futility at a preplanned interim analysis at 203 DFS events. There was no significant difference in DFS per IRC (hazard ratio [HR] = 0.870; 95% confidence interval [CI]: 0.660–1.147; P=0.3211). In the highest-risk subpopulation, a 36% and 27% reduction in risk of a DFS event (HR; 95% CI) was observed per investigator (0.641; 0.468–0.879; P=0.0051), and by IRC (0.735; 0.525–1.028; P=0.0704), respectively. Overall survival data were not mature. Similar adverse events (AEs; 99% versus 92%) and serious AEs (19% versus 14%), but more grade 3/4 AEs (61% versus 30%) were reported for axitinib versus placebo.

Conclusions

ATLAS did not meet its primary end point; however, improvement in DFS per investigator was seen in the highest-risk subpopulation. No new safety signals were reported.

Trial registration number

NCT01599754

Clearing the air: towards agreement about access to high cost cancer medicines

Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE, a global phase 3 study

Abstract

Background

Second-line treatment with ramucirumab+FOLFIRI improved overall survival (OS) versus placebo+FOLFIRI for patients with metastatic colorectal carcinoma (mCRC) (hazard ratio [HR]=0.84, 95%CI=0.73–0.98, P=0.022). Post-hoc analyses of RAISE patient data examined the association of RAS/RAF mutation status and the anatomical location of the primary CRC tumour (left versus right) with efficacy parameters.

Patients and methods

Patient tumour tissue was classified as BRAF mutant, KRAS/NRAS ("RAS") mutant, or RAS/BRAF wild-type. Left-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum; right-CRC included transverse, ascending colon and cecum.

Results

RAS/RAF mutation status was available for 85% of patients (912/1072) and primary tumour location was known for 94.4% of patients (1012/1072). A favourable and comparable ramucirumab treatment effect was observed for patients with RAS mutations (OS HR = 0.86, 95% CI = 0.71–1.04) and patients with RAS/BRAF wild-type tumours (OS HR = 0.86, 95% CI = 0.64–1.14). Among the 41 patients with BRAF-mutated tumours, the ramucirumab benefit was more notable (OS HR = 0.54, 95% CI = 0.25–1.13), although, as with the other genetic subgroup analyses, differences were not statistically significant. Progression-free survival (PFS) data followed the same trend. Treatment-by-mutation status interaction tests (OS P=0.523, PFS P=0.655) indicated that the ramucirumab benefit was not statistically different among the mutation subgroups, although the small sample size of the BRAF group limited the analysis. Addition of ramucirumab to FOLFIRI improved left-CRC median OS by 2.5 month over placebo (HR = 0.81, 95% CI = 0.68–0.97); median OS for ramucirumab-treated patients with right-CRC was 1.1 month over placebo (HR = 0.97, 95% CI = 0.75–1.26). The treatment-by-subgroup interaction was not statistically significant for tumour sidedness (P = 0.276).

Conclusions

In the RAISE study, the addition of ramucirumab to FOLFIRI improved patient outcomes, regardless of RAS/RAF mutation status and tumour sidedness. Ramucirumab treatment provided a numerically substantial benefit in BRAF-mutated tumours, although the p-values were not statistically significant. ClinicalTrials.gov, NCT01183780

Nanoscale Extracellular Vesicle-Derived DNA is Superior to Circulating Cell Free DNA for Mutation Detection in Early-Stage Non-Small Cell Lung Cancer

Abstract

Background

The comparison between relatively intact nanoscale extracellular vesicle derived DNA (nEV-DNA) and fragmented circulating cell free DNA (cfDNA) in mutation detection among patients with non-small cell lung cancer (NSCLC) has not been performed yet, and thus deserves investigation.

Patients and methods

Both nEV-DNA and cfDNA was obtained from 377 NSCLC patients with known EGFR mutation status and 69 controls. The respective EGFR^{E19del/T790M/L858R} mutation status was interrogated with amplification-refractory-mutation-system-based PCR assays (ARMS-PCR).

Results

Neither nEV-DNA nor cfDNA levels show a strong correlation with tumor volumes. There is no correlation between cfDNA and nEV-DNA levels either. The detection sensitivity of nEV-DNA and cfDNA using ARMS-PCR in early-stage NSCLC was 25.7% and 14.2%, respectively, with 96.6% and 91.7% specificity, respectively. In late-stage NSCLC, both nEV-DNA and cfDNA show ∼80% sensitivity and over 95% specificity.

Conclusions

nEV-DNA is superior to cfDNA for mutation detection in early-stage NSCLC using ARMS-PCR. However, the advantages vanish in late-stage NSCLC.

Identification of a novel crizotinib-sensitive MET-ATXN7L1 gene fusion variant in lung adenocarcinoma by next generation sequencing

Niacinamide and 12‐hydroxystearic acid prevented benzo(a)pyrene and squalene peroxides induced hyperpigmentation in skin equivalent

Experimental Dermatology, Volume 0, Issue ja, -Not available-.

Expression of Proton‐sensing G‐Protein‐coupled receptors in selected skin tumors

Experimental Dermatology, Volume 0, Issue ja, -Not available-.

On the relevance of an in vitro reconstructed human epidermis model for drug screening in atopic dermatitis

Experimental Dermatology, Volume 0, Issue ja, -Not available-.

Visualized identification of the maximal surgical delay effect in a rat flap model

Wound Repair and Regeneration, Volume 0, Issue ja, -Not available-.

A pilot study of oral tranexamic acid and Glycyrrhizin compound in the treatment of recalcitrant Riehl’s melanosis

Journal of Cosmetic Dermatology, EarlyView.

Genotypic diversity and antifungal susceptibility of Cryptococcus neoformans isolates from pediatric patients in China

Mycoses, Volume 0, Issue ja, -Not available-.

Thymic localization of erythrodermic cutaneous T‐cell lymphoma

British Journal of Dermatology, Volume 0, Issue ja, -Not available-.

The epithelial zinc transporter ZIP10 epigenetically regulates human epidermal homeostasis by modulating histone acetyltransferase activity

British Journal of Dermatology, Volume 0, Issue ja, -Not available-.

Letter in response: Mid‐face Toddler Excoriation Syndrome (MiTES) can be caused by autosomal recessive biallelic mutations in a gene for congenital insensitivity to pain, PRDM12

British Journal of Dermatology, Volume 0, Issue ja, -Not available-.

Alitretinoin in punctate palmoplantar keratoderma

British Journal of Dermatology, Volume 0, Issue ja, -Not available-.

Harnessing autophagy to overcome MEK‐inhibitor induced resistance in metastatic melanoma

British Journal of Dermatology, Volume 0, Issue ja, -Not available-.

Association of CCL2 with systemic inflammation in Schnitzler's syndrome

British Journal of Dermatology, Volume 0, Issue ja, -Not available-.

Reporting of sample size calculations for randomized trials in dermatology: comparison of publications with registries

British Journal of Dermatology, Volume 0, Issue ja, -Not available-.

Atopic dermatitis, educational attainment and psychological functioning: a national cohort study

British Journal of Dermatology, Volume 0, Issue ja, -Not available-.

Multiple ulcerated nodules on the leg

Clinical and Experimental Dermatology, EarlyView.

Black pepper and its bioactive constituent piperine: promising therapeutic strategies for oral lichen planus

Abstract

Oral lichen planus (OLP) is a common T cell-mediated chronic inflammatory disease with malignant potential and unclear etiology. The present study suggests that antigen-specific mechanisms in which dentritic cells, T lymphocytes and NF-κB signaling pathway play critical roles, are involved in the pathogenesis of OLP. Additionally, it has been indicated that altered expression of cyclooxygenase 2 (COX-2) and imbalanced oxidant-antioxidant status as well as psychological issue may act as promoters to the development of OLP. Therapies for OLP are primarily aimed to control symptoms and a specific cure is not yet available. Black pepper and its principle bioactive compound piperine have been reported to possess remarkable pharmacological activities. Not only has piperine been evidenced to exhibit repressive effects on the maturation of dentritic cells, the proliferation, activation and function of T lymphocytes as well as the NF-κB signaling pathway, but also to suppress the overproduction of COX-2 and weaken the oxidative stress. Furthermore, piperine might be a possible agent for alleviating psychological disorders and preventing carcinogenesis. Given all these into consideration, piperine may be a novel and effective therapeutic strategy for OLP.