Medicine by Alexandros G. Sfakianakis

Spores of Bacillus subtilis are encased in a protein coat composed of ∼80 different proteins. Recently, we reconstituted the basement layer of the coat, composed of two structural proteins (SpoVM and SpoIVA) around spore-sized silica beads encased in a lipid bilayer, to create synthetic spore-like particles termed 'SSHELs'. We demonstrated that SSHELs could display thousands of copies of proteins and small molecules of interest covalently linked to SpoIVA. In this study, we investigated the efficacy of SSHELs in delivering vaccines. We show that intramuscular vaccination of mice with undecorated 1 micron-diameter SSHELs elicited an antibody response against SpoIVA. We further demonstrate that SSHELs covalently modified with a catalytically inactivated staphylococcal alpha toxin variant (Hla^H35L), without an adjuvant, resulted in improved protection against S. aureus infection in a bacteremia model as compared to vaccination with the antigen alone. Although vaccination with either Hla^H35L or Hla^H35L conjugated to SSHELs similarly elicited the production of neutralizing antibodies to Hla, we found that a subset of memory T cells were differentially activated when the antigen was delivered on SSHELs. We propose that the particulate nature of SSHELs elicits a more robust immune response to the vaccine that results in superior protection against subsequent S. aureus infection.

The characteristics of Clostridium difficile ST81 (a new PCR ribotype of toxin A- B + strain) with high-level fluoroquinolones resistance and higher sporulation ability, compared to ST37/PCR ribotype 017

Abstract

Antibiotic exposure, Clostridium difficile toxins, and spore formation are key factors involved in the pathogenesis of Clostridium difficile infection (CDI). A high incidence of CDI due to toxin A- B + strains, which were classified in to two genotypes (ST81 and ST37) by multilocus sequence typing (MLST), was identified in Beijing friendship hospital in 2016–2017. ST81 was the most prevalent type, accounting for 81.25% of toxin A- B + strains. ST81 corresponded to a novel PCR ribotype PKI-017 with one less band than ST37/ribotype 017 in PCR ribotyping. All ST81 strains showed a high-level of ciprofloxacin resistance (MICs ≥ 64 μg mL⁻¹) and moxifloxacin resistance (MICs ≥ 128 μg mL⁻¹) with the amino acid substitutions Thr82 to Ile in GyrA and Ser416 to Ala in GyrB. There was no mutation or only the single amino acid mutation Thr82 to Ile in the GyrA subunit of ST37/ribotype 017 strains, which had lower MICs of ciprofloxacin (4–64 μg mL⁻¹) and moxifloxacin (4–16 μg mL⁻¹). In addition, ST81 strains exhibited higher spore formation ability than ST37/ribotype 017 strains. Overall, our results indicated that ST81 strains had unique characteristics distinguishable from ST37 strains and emphasized the importance of ongoing surveillance for this new genotype.

On display: autotransporter secretion and application

Abstract

The classical monomeric autotransporters are ubiquitously used by Gram-negative bacteria to export virulence and colonization factors to their cell surface or into their surroundings. They are expressed as monomeric proteins that pass the inner and outer membrane in two consecutive steps facilitated by the Sec translocon and the Bam complex, respectively. In this mini-review we discuss how autotransporters translocate their secreted functional domains across the outer membrane. We highlight the interactions with the Bam complex and discuss how specific features of the recently solved structure of Bam lead to a mechanistic model for autotransporter secretion. Furthermore, the autotransporter secretion pathway is the system of choice for surface display of heterologous proteins for biotechnical and biomedical purposes. We summarize recent advances in the application of autotransporters with a focus on outer membrane vesicle vaccine development and discuss its limitations in secreting more complex heterologous proteins. Finally, we present an exciting new technology to circumvent secretion limitations by ligating heterologous proteins of interests to autotransporters that are displayed on the cell surface.

Prophylaxe des Vulva- und des Vaginalkarzinoms und ihrer Vorstufen

Zusammenfassung

Hintergrund

Vulva- und Vaginalkarzinome sind zunehmend diagnostizierte Tumorentitäten in Deutschland. Vulva- und Vaginalkarzinome entstehen über zwei unterschiedliche pathogenetische Mechanismen: Zum einen kann eine persistierende Infektion mit dem humanen Papillomvirus (HPV, v. a. Typ 16, 31, 33) über eine undifferenzierte vulväre/vaginale intraepitheliale Neoplasie (VIN/VAIN) zum invasiven Vulva‑/Vaginalkarzinom führen. Diese Tumoren finden sich eher bei jüngeren Frauen. Davon abzugrenzen ist das Vulvakarzinom der älteren Frauen, das auf dem Boden einer chronischen Hauterkrankung (z. B. Lichen sclerosus et atrophicus, LSA) über Mutationen im Tumorsuppressorgen p53 entsteht. Auch beim Vaginalkarzinom ist einer der Risikofaktoren ein Lichen sclerosus oder Lichen planus, diese Tumoren sind HPV-negativ. Daneben gibt es eine ganze Reihe von Tumoren, deren Ursache nicht bekannt ist.

Fragestellung

Gibt es primäre oder sekundäre Präventionsmaßnahmen, die die Entstehung dieser Tumoren verhindern können?

Ergebnisse

Die HPV-induzierten Vulva- und Vaginalkarzinome können zu einem bedeutenden Teil durch eine HPV-Impfung von HPV-naiven Frauen primär verhindert werden. Der nonavalente Impfstoff deckt die relevanten HPV-Typen 16, (18), 31 und 33 mit einer Wirksamkeit von 97 % ab, der bivalente Impfstoff hat eine vergleichbar hohe Effektivität aber nur für HPV16 und HPV18.

Ob das licheninduzierte Vulva‑/Vaginalkarzinom durch eine konsequente lokale Dauertherapie mit Kortison oder Calcineurininhibitoren primär präventiv verhindert werden kann wird diskutiert. Erste Daten, die darauf hindeuten, liegen vor.

Bildgeführte radiologische Interventionen beim HCC

Zusammenfassung

Hintergrund

Bildgeführte Interventionen wie Radiofrequenz- oder Mikrowellenablation, CT-gesteuerte Brachytherapie oder Stereotaxie (SBRT), Chemoembolisation oder Yttrium-90(⁹⁰Y)-Radioembolisation sind Teil aktueller Leitlinien zur Therapie des hepatozellulären Karzinoms (HCC) und unterliegen beständiger Validierung in aktuellen klinischen Studien.

Ziel

Dieser Artikel gibt einen Überblick über den aktuellen Stand der Evidenz und Leitlinienempfehlungen zu den genannten radiologischen, nuklearmedizinischen oder auch strahlentherapeutischen Verfahren.

Ergebnisse

Sowohl lokale Tumorablationen als auch die lokoregionäre Chemoembolisation sind Teil aller wesentlichen Leitlinien zur Behandlung des HCC. Die bildgeführten Tumorablationen im Stadium BCLC A oder auch BCLC 0 stellen sich mittlerweile als gleichwertige Alternative zur chirurgischen Resektion dar, wenn die Patientenselektion entsprechend adaptiert wird. Als lokoregionäre Therapie ist die Chemoembolisation im Stadium BCLC B bei gut erhaltener Leberfunktion und begrenzter Tumorlast Therapiestandard. Zum Einsatz der ⁹⁰Y-Radioembolisation liegen bei BCLC B keine randomisierten Daten vor. Für BCLC C-Patienten ist die Chemoembolisation nicht indiziert. Als Alternativtherapie bei Systemtherapieversagen oder Kontraindikation für Sorafenib, aber auch mit Blick auf die deutlich verbesserte Verträglichkeit gegenüber Sorafenib kann die ⁹⁰Y-Radioembolisation erwogen werden.

Update zu uterinen Sarkomen

Zusammenfassung

Uterine Sarkome bilden eine inhomogene Gruppe seltener Tumoren der Uterusmuskulatur. Es sind meist aggressive Neoplasien, die vom uterinen Bindegewebe oder vom endometrialen Stroma ausgehen. Histologisch werden folgende Subtypen unterschieden: das Leiomyosarkom (LMS), das low-grade endometriale Stromasarkom (LG-ESS) und das high-grade endometriale Stromasarkom (HG-ESS) sowie das undifferenzierte Stromasarkom (UES). Die Inzidenz liegt bei 0,5–3,3 pro 100.000 Frauen pro Jahr; insgesamt bilden sie mit 1–2 % nur einen kleinen Anteil der uterinen Malignome. Eine andere Kategorie bilden uterine Sarkome gemischten Ursprungs, wie Adenosarkome, Karzinosarkome (maligne Müller-Mischtumoren) und andere heterologe Sarkome (z. B. Chondrosarkome, Liposarkome, Fibrosarkome etc.). Im Beitrag wird auf das spezifische Management der häufigen Entitäten (LMS, LG-ESS, HG-ESS und UES) Bezug genommen. Im August 2015 wurde die erste Version einer S2k-Leitlinie zu uterinen Sarkomen herausgegeben.

Verhaltensstörung oder Schmerz?

Zusammenfassung

Hintergrund

Bei Menschen mit geistiger Beeinträchtigung werden Schmerzen zu selten und zu spät diagnostiziert. Diese Patienten erhalten trotz größerer Krankheitslast wesentlich weniger Schmerzmittel als Menschen ohne Behinderung.

Ergebnisse

An die Möglichkeit des Vorliegens von Schmerzen zu denken, ist dabei genauso entscheidend wie eine adäquate und sensible Diagnostik. Neben der Nutzung aller Mittel zur Verbesserung der Kommunikation (Erklärungen in leichter Sprache, Arbeiten mit Bildern und Symbolen) ist die Fremdauskunft zusätzlich oder ersatzweise häufig unverzichtbar (Befragung von Nahestehenden, spezielle Assessment-Instrumente). Jede Veränderung des Verhaltens muss als mögliche Ursache von Schmerzen (oder anderen Symptomen) aufmerksam registriert und weiter abgeklärt werden.

Schlussfolgerung

Die Schmerztherapie kann und sollte grundsätzlich wie bei nichtbehinderten Menschen durchgeführt werden, nichtmedikamentöse Maßnahmen stehen dabei im Vordergrund. Die Medikamentengabe sollte wie bei alten Menschen niedrig begonnen und nur langsam gesteigert werden. Mit häufigerem Einsatz von – ggf. auch probatorischer – Schmerztherapie lassen sich viele sog. Verhaltensstörungen adäquat und besser als mit Psychopharmaka behandeln.

Homo faber Revisited: Postphenomenology and Material Engagement Theory

Abstract

Humans, more than any other species, have been altering their paths of development by creating new material forms and by opening up to new possibilities of material engagement. That is, we become constituted through making and using technologies that shape our minds and extend our bodies. We make things which in turn make us. This ongoing dialectic has long been recognised from a deep-time perspective. It also seems natural in the present in view of the ways new materialities and digital ecologies increasingly envelop our everyday life and thinking. Still the basic idea that humans and things are co-constituted continues to challenge us, raising important questions about the place and meaning of materiality and technical change in human life and evolution. This paper bridging perspectives from postphenomenology and Material Engagement Theory (MET) is trying to attain better understanding about these matters. Our emphasis falls specifically on the human predisposition for technological embodiment and creativity. We re-approach the notion Homo faber in a way that, on the one hand, retains the power and value of this notion to signify the primacy of making or creative material engagement in human life and evolution and, on the other hand, reclaims the notion from any misleading connotations of human exceptionalism (other animals make and use tools). In particular, our use of the term Homo faber refers to the special place that this ability has in the evolution and development of our species. The difference that makes the difference is not just the fact that we make things. The difference that makes the difference is the recursive effect that the things that we make and our skills of making seem to have on human becoming. We argue that we are Homo faber not just because we make things but also because we are made by them.

Airborne MRSA and Total Staphylococcus aureus as Associated With Particles of Different Sizes on Pig Farms

Abstract

Airborne methicillin-resistant Staphylococcus aureus (MRSA) have previously been found on pig farms, which may lead to nasal deposition of MRSA in humans via inhalation. The anterior nares are the main niche for S. aureus, and S. aureus can cause, e.g. wound infection and pneumonia. The aim of this study was to acquire knowledge about the potential deposition of airborne MRSA, specifically, and of total S. aureus (including both methicillin-sensitive S. aureus and MRSA, in the following called S. aureus) in the different parts of the airways during occupancy on pig farms. Measurements of airborne MRSA and S. aureus were performed on four pig farms using a six and a three-stage sampler during different work tasks, such as high-pressure cleaning and everyday inspection. MRSA were quantified using MRSA-selective agar, and S. aureus were quantified using Staphylococcus selective agar. The identity of the bacteria were confirmed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The geometric mean (GM) concentrations of MRSA and S. aureus were 447 cfu/m³ air and 1.8 × 10³ cfu/m³ air, respectively. The highest concentrations of MRSA and S. aureus were found among pigs in a weaner stable and during high-pressure cleaning of an empty stable, respectively. The lowest concentrations of MRSA and S. aureus were found in a stable with sick pigs and in feed-storages, respectively. Most MRSA and S. aureus were associated with particles between 7 and 12 µm. On average, the particle size fractions potentially depositing in the upper airways constituted 70%, in the primary and secondary bronchi 22%, and in the terminal bronchi and alveoli 8% of the inhalable MRSA and S. aureus concentration. Across the sampled areas, the geometric mean diameter (D_g) of particles with MRSA and S. aureus were 7.2 and 6.4 µm, respectively, and no significant difference was found between these D_gs. The D_g of the airborne particles with the studied bacterium was significantly associated with the different locations on the farms. The largest D_gs were found in the air samples from the aisles and on the fence to the pens, while the smallest D_gs were found in samples from the pens among the pigs and in samples taken at greater distances from the pigs: in the hallway, feed-storage, and entry room. In conclusion, airborne MRSA and S. aureus were found in sample fractions potentially depositing in all six parts of the airways. However, the majority was found to potentially deposit in the upper airways. The concentration of airborne MRSA and S. aureus and MRSA, as well as the fraction potentially depositing in the different parts of the airways, depended on the specific work task being performed and the location on the farm.

Occupational Exposure to Diesel and Gasoline Engine Exhausts and the Risk of Kidney Cancer in Canadian Men

Abstract

Introduction

Kidney cancer is the fifth most common incident cancer in Canadian men. Diesel and gasoline exhausts are common workplace exposures that have been examined as risk factors for non-lung cancer sites, including the kidney, but limitations in exposure assessment methods have contributed to inconsistent findings. The objective of this study was to assess the relationship between occupational gasoline and diesel engine exhausts and the risk of kidney cancer in men.

Methods

The National Enhanced Cancer Surveillance System (NECSS) is a Canadian population-based case–control study conducted in 1994–1997. Incident kidney cancer cases were identified using provincial registries, while the control series was identified through random-digit dialing, or provincial administrative databases. Self-reported questionnaires were used to obtain information on lifetime occupational history and cancer risk factors. Two hygienists, blinded to case status, coded occupational histories for diesel and gasoline exhaust exposures using concentration, frequency, duration, and reliability. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) separately by exhaust type. The separate and combined impacts of both engine exhausts were also examined. ORs were adjusted for age, province, body mass index, occupational secondhand smoke exposure, and education.

Results

Of the kidney cancer cases (n = 712), 372 (52%) had exposure to both exhausts at some point, and 984 (40%) of the controls (n = 2457) were ever exposed. Workers who had ever been exposed to engine exhausts were more likely to have kidney cancer than those who were never exposed (OR diesel = 1.23, 95% CI = 0.99–1.53; OR gasoline = 1.51, 95% CI = 1.23–1.86). Exposure to gasoline exhaust was consistently associated with kidney cancer in a dose–response manner (P value for trends in highest attained and cumulative exposure both <0.0001). Those men with high cumulative exposure to both gasoline and diesel exhaust had a 76% increased odds of kidney cancer (95% CI = 1.27–2.43).

Conclusions

This study provides evidence that occupational gasoline, and to a lesser extent, diesel exhaust exposure may increase the risk of kidney cancer.

Importance and Explanatory Relevance: The Case of Mathematical Explanations

Abstract

A way to argue that something (e.g. mathematics, idealizations, moral properties, etc.) plays an explanatory role in science is by linking explanatory relevance with importance in the context of an explanation. The idea is deceptively simple: a part of an explanation is an explanatorily relevant part of that explanation if removing it affects the explanation either by destroying it or by diminishing its explanatory power, i.e. an important part (one that if removed affects the explanation) is an explanatorily relevant part. This can be very useful in many ontological debates. My aim in this paper is twofold. First of all, I will try to assess how this view on explanatory relevance can affect the recent ontological debate in the philosophy of mathematics—as I will argue, contrary to how it may appear at first glance, it does not help very much the mathematical realists. Second of all, I will show that there are big problems with it.

The Gulf War Era Cohort and Biorepository: A Longitudinal Research Resource of Veterans of the 1990-1991 Gulf War Era

Abstract

The United States Department of Veterans Affairs Gulf War Era Cohort and Biorepository (GWECB) is a nationally representative longitudinal cohort of United States Veterans who served during the 1990-1991 Gulf War era. The GWECB combines survey data, such as demographic, health behavior, and environmental exposure data; medical records; and a linked biorepository of blood specimens that can support a broad range of future research regarding health concerns unique to Veterans of this era. To build this resource, the Veterans Affairs Cooperative Studies Program initiated a pilot study (2014-2016) to establish the GWECB and evaluate the processes required to build and maintain the resource. Participants (n=1,275) consented to future sharing of their data and biospecimens for research purposes. We describe the pilot study, including recruitment and enrollment procedures, data collection and management, quality control, and challenges experienced. The GWECB data available to investigators under approved sharing mechanisms, and the procedures for accessing them, are extensively detailed. The study's consenting documents and a website link for the research survey are provided. Our hope is that new research drawing on the GWECB data and biospecimens will result in effective treatments and improved approaches to address the health concerns of Gulf War Era Veterans.

A Neuromechanical Model of Larval Chemotaxis

Synopsis

Larval Drosophila move up attractive chemical gradients, and down aversive ones. Although their movement is often characterised as a series of runs and directed turns, it can also be modelled as a continuous modulation of turning extent by the detected change in stimulus intensity as the animal moves through the gradient. We show that a neuromechanical model of peristaltic crawling and spontaneous bending in the larva can be adapted to produce taxis behaviour by the simple addition of a local segmental reflex to modulate transverse viscosity (or 'bendiness') proportionally to the intensity change detected in the head. Altering the gain produces weaker or stronger, negative or positive taxis, with behavioural statistics that qualitatively match the larva.

Ophthalmic Plastic Surgery in Patients 100 Years and Older

Purpose: The centenarian population is growing and ophthalmic plastic surgeons are providing care to an increasing number of elderly patients. Outcomes of centenarians have not been previously studied in the ophthalmic plastic surgery literature. The goal of the current review was to examine the baseline characteristics, surgical problems, and outcomes of this select group of patients. Methods: A retrospective chart review was performed. Patients who underwent ophthalmic plastic surgery at age 100 or older between January 2000 and June 2016 by a member of the New England Oculoplastics Society were included in the study. Results: Fifteen patients met inclusion criteria. The majority (66%) were female. More than half (60%) presented with a surgical problem of an urgent nature. Most disorders involved the lacrimal system or eyelids, and many were the result of trauma or infection. There were no cases of orbital tumor or thyroid eye disease. There were no surgical or anesthesia-related complications. Most patients (80%) had no documented history of dementia, and only 1 was diabetic. Notably, 33% of patients presented with no light perception vision in at least 1 eye. Conclusions: Ophthalmic plastic surgery can be performed safely in select patients 100 years of age and older. Formal prospective studies are needed to improve surgical care in this group. Accepted for publication May 24, 2018. N.W. is supported by a Heed Ophthalmic Fellowship. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Suzanne K. Freitag, MD, 243 Charles Street, Boston, MA 02114. E-mail: suzanne_freitag@meei.harvard.edu © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Minimally Invasive Corneal Neurotization With Acellular Nerve Allograft: Surgical Technique and Clinical Outcomes

Purpose: To describe a minimally invasive surgical technique and its clinical outcomes with the use of acellular nerve allograft to re-establish corneal sensibility in patients with neurotrophic keratopathy. Methods: Acellular nerve allograft was coapted to an intact supraorbital, supratrochlear, or infraorbital nerve and transferred to the affected eye. Donor nerve pedicles were isolated through a transpalpebral or transconjunctival approach. Retrospective evaluation of preoperative and postoperative corneal sensibility, ocular surface, and best-corrected visual acuity was performed in all patients. Mean follow-up period was 6 months (range: 3–10 months). Results: Corneal neurotization with acellular nerve allograft was successfully performed in 7 patients with restoration of corneal sensibility and corneal epithelial integrity. In vivo confocal microscopy demonstrated increased nerve density in corneal stroma at 4 months after surgery. Conclusions: The use of acellular nerve allograft allows for a minimally invasive approach to successful corneal neurotization. Accepted for publication June 5, 2018. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Ilya M. Leyngold, M.D., Duke Aesthetic Center, DUMC 3810, Durham, NC 27710. E-mail: ileyngo1@gmail.com © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Endonasal Approach to Orbital Pathology

Purpose: Transnasal endoscopic orbital surgery in an emerging surgical field. The surgical field has expanded from orbital decompression to excision of tumours from the medial orbit and over the last 20 years. As instrumentation has improved, the nature, location and size of tumours being excised has changed. Methods: This article discusses the salient surgical considerations when approaching an orbital lesion via a transnasal endoscopic route and reviews the literature. Results: An endonasal approach offers a potential space surgeons can utilise to access the orbit, possibly providing additional exposure, illumination and magnification to the medial and apical aspects of selected lesions. Conclusions: An endonasal approach may be useful as a sole or adjunctive approach in selected cases of orbital tumour excision. Accepted for publication June 5, 2018. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to David S. Curragh, F.R.C. OPHTH., Ophthalmology Department, Royal Adelaide Hospital, Port Road, Adelaide, South Australia 5000, Australia. E-mail: davidcurragh@hotmail.com © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Secretory Carcinoma of the Lacrimal Gland: A Rare Case Report

Secretory carcinoma is a salivary gland malignancy that recapitulates secretory carcinoma of the breast, along with its shared ETV6-NTRK3 gene fusion. Characterization of histopathologic, immunohistochemical, and molecular genetic features of this neoplasm has led to reclassification of a heterogeneous group of salivary gland carcinomas as secretory carcinoma and to identification of this neoplasm in other gland-containing tissues. The authors describe a 52-year-old man who presented with a 2-week history of diplopia and a well-circumscribed right orbital mass. The tumor was resected via lateral orbitotomy approach. Pathologic evaluation demonstrated secretory carcinoma, previously not described in the main lacrimal gland. Recognition of lacrimal gland secretory carcinoma may lead to reappraisal of morphologically similar, but biologically heterogeneous lacrimal gland neoplasms, providing an insight into this tumor's clinical presentation and prognosis. Accurate diagnosis of this malignancy has important management and prognostic implications, particularly with emergence of targeted therapies. Accepted for publication May 24, 2018. Ethics: The Institution Ethics Review Committee approval was waved for this retrospective case report study. The study was performed in compliance with the tenets of Declaration of Helsinki. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Tatyana Milman, M.D., Ophthalmology and Pathology, Wills Eye Hospital and Thomas Jefferson University Hospital, 840 Walnut Street, Suite 1410, Philadelphia, PA 19107. E-mail: tmilman@willseye.org. © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Κυριακή 29 Ιουλίου 2018

Psoriasis moderada-grave en la infancia y la adolescencia: un reto terapéutico

Publication date: Available online 29 July 2018

Source: Actas Dermo-Sifiliográficas

Author(s): P. de la Cueva Dobao

Characterization of anthocyanin and proanthocyanidin biosynthesis in two strawberry genotypes during fruit development in response to different light qualities

Publication date: Available online 29 July 2018

Source: Journal of Photochemistry and Photobiology B: Biology

Author(s): Yunting Zhang, Wenjie Hu, Xiaorui Peng, Bo Sun, Xiaorong Wang, Haoru Tang

Abstract

LED-based light sources that can provide narrowly-centered spectrum have been frequently applied to manipulate the plant growth, development and metabolism in recent years. This study aimed to find out the effect of different light qualities on the production of anthocyanins and proanthocyanidins. The results showed RL (red light), BL (blue light), RBL(red light: blue light = 1:1) induced the strawberry fruit coloration earlier by increasing the content of total anthocyanins as a result of high expression of related genes, which was also concluded from a^⁎, C^⁎, h° values in 'Tokun' at 28 DAF, and RBL significantly promoted anthocyanin and proanthocyanidin biosynthesis in these two strawberry genotypes during fruit development. Simultaneously, the contents of anthocyanins and proanthocyanidins in 'Toyonaka' were also remarkably upregulated by BL and RL, respectively, indicating different strawberry genotypes to some extent probably had a distinct response to light quality. Hence, genotype factor should be taken into consideration when supplement of light quality was used as practical application in strawberry cultivation. Taken together, this study provided an insight into a further understanding of roles of light quality in the color formation for strawberry and a potential means to increase the health-related values of strawberry through altering the anthocyanin and proanthocyanidin contents of the fruit.

Photodynamic therapy activity of zinc phthalocyanine linked to folic acid and magnetic nanoparticles

Publication date: Available online 29 July 2018

Source: Journal of Photochemistry and Photobiology B: Biology

Author(s): Gauta Gold Matlou, David O. Oluwole, Earl Prinsloo, Tebello Nyokong

Abstract

In this work, the photodynamic therapy (PDT) activities (using human carcinoma adherent MCF-7 cells) of zinc phthalocyanine derivatives: complexes 1 (Zn mono cinnamic acid phthalocyanine) and 2 (zinc mono carboxyphenoxy phthalocyanine) when covalently linked to folic acid (FA) and amine functionalized magnetic nanoparticles (AMNPs) are reported. The covalent linkage of asymmetric zinc cinnamic acid Pc (1) to FA (1-FA) through an amide bond is reported for the first time. Complex 1 is insoluble in water, but upon linkage to FA, (to form 1-FA) the molecule become water soluble, hence the UV–Vis spectrum and singlet oxygen quantum yield for 1-FA were also done in water since water solubility is essential for biological applications. The reported 2-FA is also water soluble. Linking complexes 1 and 2 to FA and AMNPs decreased the dark toxicity of 1 and 2 on MCF-7 cells. Pc-FA (1-FA and 2-FA) conjugates had better singlet oxygen quantum yield (Φ_∆) in DMSO as compared to Pc-AMNPs (1-AMNPs and 2-AMNPs). The water- soluble 1-FA and 2-FA also achieved a better photodynamic therapy (PDT) activity as compared to 1-AMNPs and 2-AMNPs. Folic acid targeting on the tumor cells may have also facilitated better bioavailability of 1-FA and 2-FA and improved PDT activity on MCF-7 cells over AMNPs carriers.

Reporting in Experimental Philosophy: Current Standards and Recommendations for Future Practice

Abstract

Recent replication crises in psychology and other fields have led to intense reflection about the validity of common research practices. Much of this reflection has focussed on reporting standards, and how they may be related to the questionable research practices that could underlie a high proportion of irreproducible findings in the published record. As a developing field, it is particularly important for Experimental Philosophy to avoid some of the pitfalls that have beset other disciplines. To this end, here we provide a detailed, comprehensive assessment of current reporting practices in Experimental Philosophy. We focus on the quality of statistical reporting and the disclosure of information about study methodology. We assess all the articles using quantitative methods (n = 134) that were published over the years 2013–2016 in 29 leading philosophy journals. We find that null hypothesis significance testing is the prevalent statistical practice in Experimental Philosophy, although relying solely on this approach has been criticised in the psychological literature. To augment this approach, various additional measures have become commonplace in other fields, but we find that Experimental Philosophy has adopted these only partially: 53% of the papers report an effect size, 28% confidence intervals, 1% examined prospective statistical power and 5% report observed statistical power. Importantly, we find no direct relation between an article's reporting quality and its impact (numbers of citations). We conclude with recommendations for authors, reviewers and editors in Experimental Philosophy, to facilitate making research statistically-transparent and reproducible.

Σάββατο 28 Ιουλίου 2018

Improved EGFR mutation detection using combined exosomal RNA and circulating tumor DNA in NSCLC patient plasma

First-in-human study of LY3039478, an Oral Notch signaling inhibitor in advanced or metastatic cancer

Abstract

Background

Deregulated Notch signaling due to mutation or overexpression of ligands and/or receptors is implicated in various human malignancies. Gamma-secretase inhibitors inhibit Notch signaling by preventing cleavage of transmembrane domain of Notch protein. LY3039478 is a novel, potent Notch inhibitor decreases Notch signaling and its downstream biologic effects. In this first-in-human study, we report the safety, pharmacokinetic (PK) profile, pharmacodynamic effects, and antitumor activity of LY3039478 in patients with advanced or metastatic cancer.

Methods

This phase I, open-label, multicenter, nonrandomized, and dose-escalation phase study determined and confirmed the recommended phase II dose of LY3039478 (oral dose: 2.5–100 mg, TIW on a 28-day cycle). The primary objectives are to determine (part A) and confirm (part B) a recommended phase II dose that may be safely administered to patients with advanced or metastatic cancer, and secondary objectives include evaluation of safety, tolerability, PK parameters, and preliminary antitumor activity of LY3039478.

Results

A total of 110 patients were treated with LY3039478 monotherapy between 31 October 2012 and 15 July 2016. Dose-limiting toxicities were thrombocytopenia, colitis and nausea. Most adverse events were gastrointestinal. The recommended phase II dose was 50 mg TIW, because of its better tolerability compared to 75 mg. The pharmacokinetics of LY3039478 appeared dose proportional. Pharmacodynamic data indicate an approximately 80% inhibition of plasma Aβ, and >50% inhibition of Notch-regulated genes hairy and enhancer of split-1, cyclin D1 and Notch-regulated ankyrin repeat at 45-to 100-mg dose. Clinical activity (tumor necrosis, metabolic response or tumor shrinkage) was observed in patients with breast cancer, leiomyosarcoma, and adenoid cystic carcinoma.

Conclusion

Potent inhibition of Notch signaling by LY3039478 was well tolerated at doses associated with target engagement, and demonstrated evidence of clinical activity in heavily pretreated patients. Further investigation with LY3039478 as monotherapy and in combination with targeted agent or chemotherapy is ongoing.

Clinicaltrials.gov ID

NCT01695005

Venetoclax, bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase 1b dose-finding study

Abstract

Background

Venetoclax is a selective, potent inhibitor of the anti-apoptotic BCL-2 protein approved for treatment of chronic lymphocytic leukemia. We conducted a dose-finding study of venetoclax in combination with bendamustine-rituximab (BR) in patients with relapsed/refractory non-Hodgkin's lymphoma (NHL).

Patients and methods

BR was given for 6 cycles at standard doses. Intermittent and continuous oral venetoclax administration was explored at 50mg–1200mg daily doses. Co-primary objectives included safety, pharmacokinetics, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D); secondary objective was preliminary efficacy.

Results

Sixty patients were enrolled: 32 with follicular lymphoma (FL), 22 with diffuse large B-cell lymphoma (DLBCL), and 6 with marginal zone lymphoma (MZL). Nausea (70%), neutropenia (68%), diarrhea (55%), and thrombocytopenia (52%) were the most frequent adverse events (AEs). Most common grade 3/4 AEs were neutropenia (60%) and lymphopenia (38%). Serious AEs were reported in 24 patients; the most frequent were febrile neutropenia and disease progression (8% each). Five patients died from either disease progression (n = 4) or respiratory failure (n = 1). MTD was not reached; RP2D for venetoclax-BR combination was established as 800 mg daily continuously. Venetoclax pharmacokinetic exposure with and without BR was comparable. For all patients, overall response rate (ORR) was 65%. Median duration of overall response (DOR), overall survival (OS), and progression-free survival (PFS) was 38.3 months (95% confidence interval (CI): 10.4–NR), not yet reached, and 10.7 months (95% CI: 4.3–21.0), respectively.

Conclusions

This study established the safety profile of venetoclax in combination with BR, and results demonstrated tolerability and preliminary efficacy of the combination. Additional follow-up is needed to better determine the future role of BR plus venetoclax in the treatment of relapsed/refractory B-cell NHL.

Toxicity of oxaliplatin rechallenge in metastatic colorectal cancer

Phase 3, randomised trial of avelumab versus physician’s choice of chemotherapy as third-line treatment for patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300

Abstract

Background

There currently are no internationally recognised treatment guidelines for patients with advanced gastric cancer/gastro-oesophageal junction cancer (GC/GEJC) in whom two prior lines of therapy have failed. The randomised, phase 3 JAVELIN Gastric 300 trial compared avelumab vs physician's choice of chemotherapy as third-line therapy in patients with advanced GC/GEJC.

Patients and methods

Patients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomised to receive either avelumab 10 mg/kg by intravenous infusion every 2 weeks or physician's choice of chemotherapy (paclitaxel 80 mg/m² on days 1, 8, and 15 or irinotecan 150 mg/m² on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety.

Results

A total of 371 patients were randomised. The trial did not meet its primary endpoint of improving OS (median, 4.6 vs 5.0 months; hazard ratio [HR] = 1.1 [95% CI 0.9–1.4]; P = 0.81) or the secondary endpoints of PFS (median, 1.4 vs 2.7 months; HR = 1.73 [95% CI 1.4–2.2]; P > 0.99) or ORR (2.2% vs 4.3%) in the avelumab vs chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9%) and 131 patients (74.0%) in the avelumab and chemotherapy arms, respectively. Grade ≥3 TRAEs occurred in 17 patients (9.2%) in the avelumab arm and in 56 patients (31.6%) in the chemotherapy arm.

Conclusions

Treatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared to chemotherapy. Avelumab showed a more manageable safety profile than chemotherapy.

Trial registration

ClinicalTrials.gov: NCT02625623

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Δευτέρα 30 Ιουλίου 2018

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Κυριακή 29 Ιουλίου 2018

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Abstract

Σάββατο 28 Ιουλίου 2018