Publication date: February 2018
Source:Neoplasia, Volume 20, Issue 2
Author(s): J.H. Gibcus, L.P. Tan, G. Harms, R.N. Schakel, D. de Jong, T. Blokzijl, P. Möller, S. Poppema, B.J. Kroesen, A. van den Berg
http://ift.tt/2GqOuYT
Σάββατο 27 Ιανουαρίου 2018
Corrigendum to “Hodgkin Lymphoma Cell Lines Are Characterized by a Specific miRNA Expression Profile.” Neoplasia 2009, Feb;11(2):167-176
c-RAF Ablation Induces Regression of Advanced Kras/Trp53 Mutant Lung Adenocarcinomas by a Mechanism Independent of MAPK Signaling
Publication date: Available online 27 January 2018
Source:Cancer Cell
Author(s): Manuel Sanclemente, Sarah Francoz, Laura Esteban-Burgos, Emilie Bousquet-Mur, Magdolna Djurec, Pedro P. Lopez-Casas, Manuel Hidalgo, Carmen Guerra, Matthias Drosten, Monica Musteanu, Mariano Barbacid
A quarter of all solid tumors harbor KRAS oncogenes. Yet, no selective drugs have been approved to treat these malignancies. Genetic interrogation of the MAPK pathway revealed that systemic ablation of MEK or ERK kinases in adult mice prevent tumor development but are unacceptably toxic. Here, we demonstrate that ablation of c-RAF expression in advanced tumors driven by KrasG12V/Trp53 mutations leads to significant tumor regression with no detectable appearance of resistance mechanisms. Tumor regression results from massive apoptosis. Importantly, systemic abrogation of c-RAF expression does not inhibit canonical MAPK signaling, hence, resulting in limited toxicities. These results are of significant relevance for the design of therapeutic strategies to treat K-RAS mutant cancers.
Graphical abstract
Teaser
Sanclemente et al. generate oncogenic Kras mice that allow inducible deletion of Raf1, encoding c-RAF, and/or Braf in established KrasG12V or KrasG12V;Trp53−/− lung tumors. They show that systemic c-RAF ablation has limited toxicity and leads to significant tumor regression without having an impact on MAPK activity.http://ift.tt/2rKLhAf
Tumor Architecture and Notch Signaling Modulate Drug Response in Basal Cell Carcinoma
Publication date: Available online 27 January 2018
Source:Cancer Cell
Author(s): Markus Eberl, Doris Mangelberger, Jacob B. Swanson, Monique E. Verhaegen, Paul W. Harms, Marcus L. Frohm, Andrzej A. Dlugosz, Sunny Y. Wong
Hedgehog (Hh) pathway inhibitors such as vismodegib are highly effective for treating basal cell carcinoma (BCC); however, residual tumor cells frequently persist and regenerate the primary tumor upon drug discontinuation. Here, we show that BCCs are organized into two molecularly and functionally distinct compartments. Whereas interior Hh+/Notch+ suprabasal cells undergo apoptosis in response to vismodegib, peripheral Hh+++/Notch− basal cells survive throughout treatment. Inhibiting Notch specifically promotes tumor persistence without causing drug resistance, while activating Notch is sufficient to regress already established lesions. Altogether, these findings suggest that the three-dimensional architecture of BCCs establishes a natural hierarchy of drug response in the tumor and that this hierarchy can be overcome, for better or worse, by modulating Notch.
Graphical abstract
Teaser
Eberl et al. show that in mouse basal cell carcinoma models, interior Hh+/Notch+ suprabasal cells undergo apoptosis in response to vismodegib, whereas peripheral Hh+++/Notch− basal cells survive throughout treatment. Modulating Notch overcomes the drug response hierarchy established by tumor architecture.http://ift.tt/2GpgLPM
Graphene Oxide Elicits Membrane Lipid Changes and Neutrophil Extracellular Trap Formation
Publication date: Available online 27 January 2018
Source:Chem
Author(s): Sourav P. Mukherjee, Beatrice Lazzaretto, Kjell Hultenby, Leon Newman, Artur F. Rodrigues, Neus Lozano, Kostas Kostarelos, Per Malmberg, Bengt Fadeel
Understanding the biological interactions of graphene-based materials is important for the safe use of these materials. Previous studies have explored the interaction between graphene oxide (GO) and macrophages but not the impact of GO on neutrophils, key cells of the immune system. Here, we synthesized GO sheets with differing lateral dimensions and showed by using an array of analytical and imaging techniques, including transmission and scanning electron microscopy, confocal microscopy, and time-of-flight secondary ion mass spectroscopy (ToF-SIMS), that GO elicited the formation of neutrophil extracellular traps (NETs). ToF-SIMS revealed pronounced perturbations of plasma membrane lipids, including a decrease in cholesterol and increased levels of oxidized cholesterol species. The induction of NETs was size dependent and associated with the production of mitochondrial reactive oxygen species and calcium influx. Importantly, antioxidant treatment reduced the production of NETs. These studies provide evidence that a previously undescribed biological effect of GO manifests through direct effects on membrane lipids.
Graphical abstract
Teaser
Graphene oxide (GO) is a promising material for a variety of biomedical and other applications. The increasing use of GO necessitates careful assessment of potential health hazards. Using primary neutrophils as a model, Mukherjee et al. show that GO elicits neutrophil extracellular traps. Furthermore, by using ToF-SIMS, the authors noted pronounced perturbations of plasma membrane lipids in cells exposed to GO.http://ift.tt/2FndFKI
Adverse Prognostic Factors of Advanced Esophageal Cancer in Patients Undergoing Induction Therapy with Docetaxel, Cisplatin and 5-Fluorouracil
Background/Aim: The purpose of this study was to identify adverse prognostic factors for patients with advanced esophageal cancer undergoing chemotherapy with docetaxel, cisplatin and 5-fluorouracil (DCF). Patients and Methods: The study cohort comprised of 45 patients with advanced esophageal cancer who underwent induction DCF therapy followed by esophagectomy or chemoradiotherapy. Treatment outcomes and factors affecting early recurrence and death were analyzed. Results: Overall 3-year survival was 61.4%, and 3-year disease-free survival was 44.7%. Clinically evident lymph node metastasis and clinical stage were associated with recurrence within 1 year and death within 2 years. Low maximum standardized uptake value (SUVmax) after induction DCF therapy and small decreases in SUVmax from pre- to post-DCF therapy were also predictors of recurrence and poor prognosis. Conclusion: Induction DCF therapy may be ineffective for advanced-stage esophageal cancer and clinical lymph node metastasis (≥N2, ≥stage IIIB). Moreover, small decreases in SUVmax DCF therapy are associated with early disease relapse and death.
http://ift.tt/2GneuEB
Gut-associated Lymphoid Tissue (GALT) Carcinoma in Ulcerative Colitis
Background: In ulcerative colitis (UC), the majority of colorectal carcinomas (CRC) arise in the vast colorectal mucosal domain built with mucus-producing goblet cells and columnar cells. Conversely, CRC in UC rarely evolve in the tiny, spotty gut-associated lymphoid tissue (GALT) mucosal domain. Here we review the four reported cases of colonic carcinoma developing in GALT mucosa in UC, searching for possible precursor lesions connected with the evolution of these tumours. Materials and Methods: The clinical history, age, gender, endoscopic descriptions, and the pathology (localization, gross and histological descriptions of the luminal surface) of the four UC-GALT carcinomas reported in the literature were reviewed. Results: The luminal surface in three out of the four carcinomas revealed conventional (tubular/villous) adenomas or high-grade dysplasia. All four UC-GALT-carcinomas were detected at an early stage (T1N0). Conclusion: GALT carcinomas do occur, albeit infrequently, in patients with UC. The finding that three out of the four GALT carcinomas on record were covered by conventional adenomas or by high-grade dysplasia strongly suggests that non-invasive conventional neoplasias might often precede GALT carcinomas in UC.
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Tandem Affinity Purification and Nano HPLC-ESI-MS/MS Reveal Binding of Vitamin D Receptor to p53 and other New Interaction Partners in HEK 293T Cells
While nuclear cofactors that contribute to vitamin D receptor (VDR)-mediated gene transcription, including retinoid X receptors, nuclear co-activators and co-repressors, have been extensively investigated, little is known about cytoplasmic VDR-binding partners and the physiological relevance of their interaction. To gain new insight into this topic, we isolated whole-cell protein extracts of 1,25-dihydroxyvitamin D3 stimulated and UV-B-irradiated vs. non-irradiated HEK 293T cells transfected with a plasmid called pURB VDR C-Term TAP tag. VDR complex was purified by tandem affinity purification (TAP). The nuclear tumor-suppressor protein p53 and its negative regulator novel INHAT repressor (NIR), in addition to 43 other nuclear or cytoplasmatic VDR binding partners, were identified using nano high-performance liquid chromatography–electrospray ionization tandem mass spectrometric analysis. VDR binding to p53 was confirmed by western blot analysis. Future studies are required to further elucidate the functional significance of these interactions.
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Effects of Combined Treatment with Vitamin D and COX2 Inhibitors on Breast Cancer Cell Lines
Background: Vitamin D is known for its anticancer potential. Prostaglandin E2 (PGE2) is a proliferative and inflammation-activating agent. The production of PGE2 is dependent on the activity of cyclooxygenase-2 (COX2). A link between vitamin D and PGE2 metabolism was shown recently. Materials and Methods: In MDA-MB-231 and MCF-7 breast cancer cell lines, we investigated the influence of calcitriol and the COX2 inhibitor celecoxib on cell growth via the MTT test, as well as on the protein and mRNA expression of COX2 using western blot and quantitative real-time polymerase chain reaction (qRT-PCR). Results: The proliferation of MCF-7 and MDA-MB-231 was inhibited by both calcitriol and the COX2 inhibitor celecoxib and even more strongly by their combination. Moreover, calcitriol inhibited COX2 protein expression in MDA-MB-231 cells, as well as COX2 mRNA expression in both cell lines. Conclusion: The combination of calcitriol and celecoxib demonstrated a synergistic growth-inhibitory effect in breast cancer cell lines.
http://ift.tt/2rLcWRl
Partial Body UV Exposure in Chronic Kidney Disease and Extrarenal Vitamin D Metabolism
Background/Aim: Exposure of the skin to sunshine is the major natural source of vitamin D. In order to imitate this natural production of vitamin D for patients with chronic kidney disease, hemodialysis patients were exposed three times a week to radiation of the front part of both legs to normalize the vitamin D status. Patients and Methods: Partial body UVB irradiation was performed during the routine dialysis session. Twenty-two patients took part, with a mean age of 61.7 (range=35-81) years. Results: Serum levels of 25(OH)D3 and 1,25(OH)2D3 increased into the mid normal range. Intact parathyroid hormone decreased by 25% and osteocalcin by 45%. 24-Hour blood-pressure monitoring demonstrated decreases in systolic and diastolic blood pressure. Conclusion: Partial body exposure to UVB radiation normalized not only the serum level of 25(OH)D3, but also that of 1,25(OH)2D3, which resulted in a significant decrease in parathyroid hormone, osteocalcin levels, and also in blood pressure. Sunshine imitating UVB exposure utilizes the capacity of the skin to convert extrarenally vitamin D3 to 25(OH)D3 and 1,25(OH)2D3.
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Vitamin D Status, Supplementation and Cardiovascular Disease
This review was conducted to assess the dose–response relationship between vitamin D and cardiovascular disease (CVD) outcomes in humans: Prospective cohort studies indicate a multivariable-adjusted non-linear increase in CVD events at levels of circulating 25-hydroxyvitamin D [25(OH)D] of less than 50 nmol/l. However, Mendelian randomization studies do not support these findings. Although meta-analyses of randomized controlled trials (RCTs) do not rule out small beneficial vitamin D effects on surrogate parameters of CVD risk, such as arterial stiffness, at vitamin D doses equivalent to 1,000-5,333 IU daily, other meta-analyses of RCTs show no reduction in CVD events by vitamin D supplementation. Notably, some cohort studies and a recent RCT provide evidence for harmful effects of vitamin D on CVD outcomes at 25(OH)D levels in excess of 100 nmol/l. In conclusion, more studies in individuals with a deficient 25(OH)D level (i.e. <30 nmol/l) are needed, but caution is necessary regarding supplementation with vitamin D doses achieving a 25(OH)D level which exceeds 100 nmol/l.
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The Winding Path Towards an Inverse Relationship Between Sun Exposure and All-cause Mortality
For a long time, skin cancer has been known to be related to extensive UV exposure. New emerging data have, however, shown low UV exposure/low vitamin D levels to be related to increased mortality rate due to skin cancer. In addition, low sun exposure habits in regions of low solar intensity have been shown to be a major risk factor for all-cause mortality in the same range as that for smoking. This is mainly due to lower all-cause mortality due to cardiovascular disease (CVD) and non-CVD/non-cancer disease among women with active sun exposure. Women with active sun exposure habits were estimated to have a 1- to 2-year longer life-expectancy during the Melanoma in Southern Sweden study interval. These findings are in line with those to be expected from an evolutionary perspective and research findings, but in opposition to present guidelines and recommendations.
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Solarium Use and Risk for Malignant Melanoma: Meta-analysis and Evidence-based Medicine Systematic Review
Background: There is an ongoing debate whether solarium use (indoor tanning/artificial UV) may increase the risk for primary cutaneous malignant melanoma. Aim: A systematic literature search was conducted using MEDLINE and ISI Web of Science. Included studies were critically assessed regarding their risk of bias, and methodological shortcomings. Levels of evidence and grades of recommendation were determined according to guidelines of the Oxford Centre for Evidence-Based Medicine. Summary risk estimates and 95% confidence intervals for four different outcomes (ever exposure, exposure at younger age, high/low exposure vs. non-exposure) were derived from random-effects meta-analyses to account for possible heterogeneity across studies. Results: Two cohort and twenty-nine case–control studies were eligible. Overall, quality of included studies was poor as a result of severe limitations, including possible recall and selection bias, and due to lack of interventional trials. Summary risk estimates suggested a weak association (odds ratio (OR)=1.19, 95% confidence interval (CI)=1.04-1.35, p=0.009) for ever-exposure to UV radiation from a solarium with melanoma risk. However, sensitivity analyses did not show an association for studies from Europe (OR=1.10; 95%CI=0.95-1.27, p=0.218), studies with low risk of bias (OR=1.15; 95%CI=0.94-1.41, p=0.179), and studies conducted after 1990 (OR 1.09; 95%CI=0.93-1.29, p=0.295). Moreover, moderate associations were found for first exposure to UV radiation from a solarium at younger age (<25 years) and high exposure (>10 sessions in lifetime) with melanoma risk. However, for all outcomes analyzed, overall study quality and resulting levels of evidence (3a–) and grades of recommendation (D) were low due to lack of interventional studies and severe limitations including unobserved or unrecorded confounding. Conclusion: Current scientific knowledge is mainly based on observational studies with poor quality data, which report associations but do not prove causality. At present, there is no convincing evidence that moderate/responsible solarium use increases melanoma risk.
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Xeroderma Pigmentosum - Facts and Perspectives
Ultraviolet (UV)-induced DNA lesions are almost exclusively removed by the nucleotide excision repair (NER) pathway, which is essential for prevention of skin cancer development. Patients with xeroderma pigmentosum (XP) are extremely sun sensitive due to a genetic defect in components of the NER cascade. They present with first signs of premature skin aging at an early age, with a considerably increased risk of developing UV-induced skin cancer. XP belongs to the group of DNA repair defective disorders that are mainly diagnosed in the clinic and in hindsight confirmed at the molecular level. Unfortunately, there are no causative treatment options for this rare, autosomal-recessive disorder, emphasizing the importance of an early diagnosis. Subsequently, UV-protective measures such as the reduction of exposure to environmental UV and regular skin cancer screenings should be undertaken to substantially improve prognosis as well as the disease course.
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Photocarcinogenesis and Skin Cancer Prevention Strategies: An Update
UV radiation is acknowledged as the primary cause of photocarcinogenesis and therefore contributes to the development of skin cancer entities such as squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and melanoma. Typical DNA photoproducts and indirect DNA damage caused by reactive oxygen species are the result of UV radiation. UV-induced DNA damage is repaired by nucleotide excision repair, which consequently counteracts the development of mutations and skin carcinogenesis. Tumour-suppressor genes are inactivated by mutation and growth-promoting pathways are activated leading to disruption of cell-cycle progression. Depending on the skin cancer entity, some genes are more frequently affected than others. In BCC mutations in Patched or Smoothened are common and affect the Sonic hedgehog pathway. In SCC, cell regulator protein p53 (TP53) mutations are prevalent, as well as mutations of the epidermal growth factor receptor (EGFR), cyclin-dependent kinase 2A (CDKN2A), Rat sarcoma (RAS), or the tyrosine kinase Fyn (FYN). UV-induced mutations in TP53 and CDKN2A are frequent in melanoma. UV-induced inflammatory processes also facilitate photocarcinogenesis. Recent studies showed a connection between photocarcinogenesis and citrus consumption, phytochemicals, alcohol consumption, hormone replacement therapy, as well as oral contraceptive use. Preventative measures include adequate use of sun protection and skin cancer screening at regular intervals, as well as the use of chemopreventative agents.
http://ift.tt/2DE3Rvm
The Impact of UV-dose, Body Surface Area Exposed and Other Factors on Cutaneous Vitamin D Synthesis Measured as Serum 25(OH)D Concentration: Systematic Review and Meta-analysis
Background/Aim: To optimize public health campaigns concerning UV exposure, it is important to characterize factors that influence UV-induced cutaneous vitamin D production. This systematic review and meta-analysis investigated the impact of different individual and environmental factors including exposed body surface area (BSA), UVB dose and vitamin D status, on serum 25(OH)D concentration. Materials and Methods: In accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses, and Meta-analysis of Observational studies in Epidemiology guidelines, a systematic literature search was conducted (MEDLINE; 01/1960-07/2016) investigating the impact of these factors on vitamin D status after artificial UV exposure as main outcome measure. Summary mean differences [and 95% confidence interval (CI)] were derived from random-effects meta-analysis to account for possible heterogeneity across studies. Meta-regression was conducted to account for impact of UVB dose, baseline 25(OH)D level and BSA. Results: We identified 15 studies, with an estimated mean 25(OH)D rise per standard erythema dose (SED) of 0.19 nmol/l (95% CI 0.11-0.26 nmol/l). Results from meta-regression suggest a significant impact of UV dose and baseline 25(OH)D concentration on serum 25(OH)D level (p<0.01). Single UVB doses between 0.75 and 3 SED resulted in the highest rise of serum 25(OH)D per dose unit. BSA exposed had a smaller, non-proportional, not significant impact. Partial BSA exposure resulted in relatively higher rise compared to whole-body exposure (e.g. exposure of face and hands caused an 8-fold higher rise of serum 25(OH)D concentration/SED/1% BSA compared to whole-body exposure). Our findings support previous reports, estimating that the half-life of serum 25(OH)D varies depending on different factors. Conclusion: Our results indicate that partial BSA exposure (e.g. 10%) with moderate UV doses (e.g. 1 SED) is effective in generating or maintaining a healthy vitamin D status. However, due to limitations that include possible confounding factors such as skin type, which could not be considered, these findings should be interpreted with caution.
http://ift.tt/2EbVPuB
Analytical Methods for Quantification of Vitamin D and Implications for Research and Clinical Practice
A plethora of contradictory research surrounds vitamin D and its influence on health and disease. This may, in part, result from analytical difficulties with regard to measuring vitamin D metabolites in serum. Indeed, variation exists between analytical techniques and assays used for the determination of serum 25-hydroxyvitamin D. Research studies into the effects of vitamin D on clinical endpoints rely heavily on the accurate assessment of vitamin D status. This has important implications, as findings from vitamin D-related studies to date may potentially have been hampered by the quantification techniques used. Likewise, healthcare professionals are increasingly incorporating vitamin D testing and supplementation regimens into their practice, and measurement errors may be also confounding the clinical decisions. Importantly, the Vitamin D Standardisation Programme is an initiative that aims to standardise the measurement of vitamin D metabolites. Such a programme is anticipated to eliminate the inaccuracies surrounding vitamin D quantification.
http://ift.tt/2DFA7OP
A Review of the Evidence Supporting the Vitamin D-Cancer Prevention Hypothesis in 2017
The vitamin D–cancer prevention hypothesis has been evaluated through several types of studies, including geographical ecological studies related to indices of solar ultraviolet-B (UVB) dose (the primary source of vitamin D for most people), observational studies related to UVB exposure or serum 25-hydroxyvitamin D [25(OH)D] concentrations, laboratory studies of mechanisms, and clinical trials. Each approach has strengths and limitations. Ecological studies indirectly measure vitamin D production and incorporate the assumption that vitamin D mediates the effect of UVB exposure. Findings from observational studies with long follow-up times are affected by changing 25(OH)D concentrations over time. Most clinical trials have been poorly designed and conducted, based largely on guidelines for pharmaceutical drugs rather than on nutrients. However, three clinical trials do support the hypothesis. In general, the totality of the evidence, as evaluated using Hill's criteria for causality in a biological system, supports the vitamin D–cancer prevention hypothesis.
http://ift.tt/2EiJBAJ
Vitamin D: Current Guidelines and Future Outlook
Vitamin D is of public health interest because its deficiency is common and is associated with musculoskeletal diseases, as well as extraskeletal diseases, such as cancer, cardiovascular diseases, and infections. Several health authorities have reviewed the existing literature and published nutritional vitamin D guidelines for the general population. There was a wide consensus that serum 25-hydroxyvitamin D [25(OH)D] concentration should be used to assess vitamin D status and intake, and that musculoskeletal, and not extraskeletal, effects of vitamin D should be the basis for nutritional vitamin D guidelines. Recommended target levels for 25(OH)D range from 25 to 50 nmol/l (10 to 20 ng/ml), corresponding to a vitamin D intake of 400 to 800 International Units (10 to 20 μg) per day. It is of concern that significant sections of the general population do not meet these recommended vitamin D levels. This definitely requires action from a public health perspective.
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Is Ki-67 of Diagnostic Value in Distinguishing Between Partial and Complete Hydatidiform Moles? A Systematic Review and Meta-analysis
Background/Aim: To demonstrate the value of Ki-67 in distinguishing between partial and complete hydatidiform moles. Materials and Methods: We searched electronic databases included Medline, WOK, Cochrane Library and CNKI, through January 24, 2015. Experts were consulted, and references from related articles were examined. The meta-analysis was conducted with RevMan5.3, according to the PRISMA guidelines. Mantel-Haenszel estimates were calculated and pooled under a random effect model, with data expressed as odds ratio (OR) and 95% confidence interval (CI). Results: We analyzed eight trials with a total of 337 participants who underwent uterine curettage and met the inclusion criteria. A significantly higher expression of Ki-67 was observed in complete than in partial hydatidiform moles (OR=3.28; 95%CI=1.80-5.96; p<0.0001). Conclusion: The Ki-67 expression was higher in complete than in partial hydatidiform moles. Therefore, Ki-67 may be of diagnostic value in distinguishing between partial and complete hydatidiform moles. However, the present study had only a limited number of samples, so investigation of a greater number of cases is needed to confirm this conclusion.
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Fibrinogen Levels Are Associated with Lymph Node Involvement and Overall Survival in Gastric Cancer Patients
Background/Aim: Combination of perioperative chemotherapy with gastrectomy with D2 lymphadenectomy improves long-term survival in patients with gastric cancer. The aim of this study was to investigate the predictive value of preoperative levels of CRP, albumin, fibrinogen, neutrophil-to-lymphocyte ratio and routinely used tumor markers (CEA, CA 19-9, CA 72-4) for lymph node involvement. Materials and Methods: This retrospective study was conducted in 136 patients who underwent surgery between 2007 and 2015. Bivariable and multivariable analyses were performed in order to identify important characteristics associated with the risk of lymph node involvement. Kaplan-Meier survival curves and log-rank tests were used to compare overall survival. Results: Lymph node involvement was significantly affected by preoperative fibrinogen (p=0.008) and albumin (p=0.023). Poor clinical condition, T and N staging and fibrinogen level above 3.5 g/l were significantly associated with worse overall survival. Conclusion: Preoperative fibrinogen and albumin levels are significantly associated with lymphoid metastases in patients with gastric cancer.
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A Critical Appraisal of the Recent Reports on Sunbeds from the European Commission's Scientific Committee on Health, Environmental and Emerging Risks and from the World Health Organization
The European Commission's Scientific Committee on Health, Environmental and Emerging Risks and the World Health Organization recently published reports which concluded that a large proportion of melanoma and non-melanoma skin cancer is attributable to sunbed use, and that there is no need to use sunbeds as there are no health benefits and they are not needed to achieve an optimal vitamin D level. The overall conclusion from both bodies was that there is no safe limit for UV irradiance from sunbeds. We are, however, deeply concerned that these assessments appear to be based on an incomplete, unbalanced and non-critical evaluation of the literature. Therefore, we rebut these conclusions by addressing the incomplete analysis of the adverse health effects of UV and sunbed exposure (what is 'safe'?) and the censored representation of beneficial effects, not only but especially from vitamin D production. The stance taken by both agencies is not sufficiently supported by the data and in particular, current scientific knowledge does not support the conclusion sunbed use increases melanoma risk.
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Image Quality Assessment of 2D versus 3D T2WI and Evaluation of Ultra-high b-Value (b=2,000 mm/s2) DWI for Response Assessment in Rectal Cancer
Aim: The purpose of this IRB-approved, retrospective study was to compare image quality between 2D and high-resolution 3D, T2-weighted (T2WI) magnetic resonance imaging (MRI) sequences and to investigate the additional value of ultra-high b-value diffusion-weighted imaging (DWI; b=2,000 mm/s2) for both rectal cancer staging and evaluating treatment response. Materials and Methods: From 12 February to 24 August 2016, 26 consecutive patients (22 males, four females; mean age: 61.9±14.0 years) with histologically-proven rectal cancer. In total 31 examinations [12 prior to and 19 after chemoradiation (CRT)] were included. The patients underwent pelvic MRI on a 3.0-T scanner (Magnetom Skyra, Erlangen, Germany). Three radiologists (3, 4, and 5 years of experience in MRI, respectively) independently assessed all images and rated the image quality of DWI (b=800 mm/s2), apparent diffusion coefficient map, DWI (b=2,000 mm/s2), 3D sagittal T2WI, 3D axial T2WI, 2D sagittal T2WI, and 2D axial T2WI of each patient, respectively. In addition, signal intensity ratios (SIR) were calculated between rectal cancer and obturator internus muscle (background) in all patients after CRT on DWI (b=2,000 mm/s2) and correlated with histopathological regression grade (RG). Results: Tumor delineation was significantly better by 2D T2WI than 3D T2WI both before and after CRT (before CRT: Z=–3.2, p=0.02; after CRT: Z=–4.408, p<0.001; all: Z=–5.192; p<0.001) and was the preferred method, although image quality ratings were not significantly different (3D sagittal: 4.00±0.48; 2D sagittal: 4.03±0.34, p=0.713; 3D axial: 3.85±0.61, 2D axial: 3.78±0.64, p=0.537). Independent t-test showed significantly higher SIR between those with RG 1 or 2 (moderate response: mean score=2.02) and those with RG 3+4 (good response: mean score=0.8) (t=3.044, p=0.011). In those with RG 4 (complete response), SIR of b2000 was 0.946 compared to a 1.41 average of the whole cohort. In two patients, tumor was invisible on b2000 following CRT (RG 3 and 4, respectively). Interobserver agreement was mostly good (≥0.6) regarding image quality assessment, except for poor agreement (=0.4) in DWI (b2000) between the two less-experienced readers. Conclusion: In conclusion, 3D T2WI might be useful for evaluating response to neoadjuvant therapy in a comprehensive, cost-effective protocol, where 2D imaging seems to be preferable. In addition, DWI (b2000) may be beneficial in assessing both the primary and the residual tumor after CRT in rectal cancer and SIR may be helpful in assessing response to CRT.
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Prognostic Significance of NSCLC and Response to EGFR-TKIs of EGFR-Mutated NSCLC Based on PD-L1 Expression
Background/Aim: Recent clinical trials have shown that immune checkpoint blockades that target either PD-1 or PD-L1 yield remarkable responses in a subgroup of patients with non-small cell lung cancer (NSCLC). Materials and Methods: We retrospectively examined, by immunohistochemical analysis, 211 NSCLC samples. Using 32 independent samples, we also evaluated PD-L1 expression in NSCLC patients with EGFR gene mutations treated by EGFR-TKIs. Results: Overall survival of PD-L1-positive stages I-III NSCLC and stage I NSCLC and stages I-III squamous cell carcinoma (SQ) were significantly shorter than those of PD-L1-negative NSCLC (p<0.01 and p=0.02 and p=0.01, respectively). In stage I NSCLC and stages I-III SQ, PD-L1 expression was found to be independent predictor of death after multivariate analysis. Response to EGFR-TKIs was not significantly different between PD-L1-positive and PD-L1-negative NSCLC patients with EGFR mutations. Conclusion: PD-L1 expression was a significant independent predictor of poor outcome in NSCLC patients.
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Intensity and Pattern of Enhancement on CESM: Prognostic Significance and its Relation to Expression of Podoplanin in Tumor Stroma - A Preliminary Report
Background/Aim: It is possible that the degree of enhancement on contrast-enhanced spectral mammography (CESM), a new diagnostic method, might provide prognostic information for breast cancer patients. Therefore, in a group of 82 breast cancer patients, we analyzed the prognostic significance of degree and pattern of enhancement on CESM as well as its relation to: (a) breast cancer immunophenotype (based on ER/PR/HER2 status) (b) podoplanin expression in cancer stroma (lymphatic vessel density plus podoplanin-positivity of cancer-associated fibroblasts), and (c) other histological parameters. Materials and Methods: For each tumor the intensity of enhancement on CESM was qualitatively assessed as strong or weak/medium, while the pattern – as homogenous and heterogenous. Results: Herein we report, for the first time, that strong and heterogenous enhancement on CESM was related to unfavorable disease-free survival of breast cancer patients (p=0.005). Moreover, the strong enhancement was more frequent in large and node-positive tumors (pT>1, pN>0) (p=0.002), as well as in carcinomas with podoplanin-sparse stroma (p=0.008). Conclusion: Intensity and pattern of enhancement on CESM might provide (together with the results of other diagnostic imaging methods) not only the confirmation of presence or absence of tumor, but also prognostic information.
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Loop-Mediated Isothermal Amplification test for the diagnosis of pertussis in Japan
Source:Vaccine, Volume 36, Issue 6
Author(s): Nobutoshi Nawa
http://ift.tt/2DR8wgI
Response to the letter by Dr. Nawa, Loop-Mediated isothermal amplification test for the diagnosis of pertussis in Japan
Source:Vaccine, Volume 36, Issue 6
Author(s): Hideyuki Ikematsu, Naoki Kawai, Shigehiro Yajima
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Editorial Board/Aims and Scope
Source:Vaccine, Volume 36, Issue 6
http://ift.tt/2DTTaby
Self-assembling protein nanoparticles with built-in flagellin domains increases protective efficacy of a Plasmodium falciparum based vaccine
Source:Vaccine, Volume 36, Issue 6
Author(s): Stephen A. Kaba, Christopher P. Karch, Labdhi Seth, Karen M.B. Ferlez, Casey K. Storme, Danielle M. Pesavento, Paige Y. Laughlin, Elke S. Bergmann-Leitner, Peter Burkhard, David E. Lanar
To eliminate the problems associated with the use of extraneous adjuvants we have designed a Self-Assembling Protein Nanoparticle (SAPN) containing epitopes from the Plasmodium falciparum circumsporozoite protein (PfCSP) (designated FMP014) and portions of the TLR5 agonist flagellin (designated FMP014D0D1) as an intrinsic adjuvant. By combining different molar ratios of FMP014 to FMP014D0D1 monomers before self-assembly, we generated multiple nanoparticles and investigated their biophysical characteristics, immunogenicity and protective efficacy. Immunization with the construct formulated with the ratio 58:2 of FMP014 to FMP014D0D1 had the highest protective efficacy against a challenge with a transgenic P. berghei sporozoite expressing PfCSP. Increasing the proportion of flagellin per particle resulted in an inverse relationship with levels of both antibody titers and protection. The cytokine profiles of the various immunization groups were evaluated and quantitative amounts of the cytokines IL-2, IFN-γ, IL-12/p70 (Th1); IL4, IL5 (Th2); TNF-α, IL1β, IL-6, KC/GRO (pro-inflammatory), and IL-10 (immunomodulatory) were measured. The relationship of the cytokines to each other revealed a strong immunomodulatory effect depending on the proportion of flagellin in the construct. Our results demonstrate that SAPNs with flagellin may be a promising strategy for the development and delivery of a safe vaccine for infectious diseases.
http://ift.tt/2FmYZei
Vascular Reconstruction in a Neonate after Iatrogenic Injury during Cardiac Catheterization
Summary: As technology and interventional techniques continue to evolve, both the volume and complexity of cardiac catheterizations will increase, leading to a rise in the number of complications. One of the most morbid complications of cardiac catheterization is vascular injury. We report the case of a 31-day-old, 3.0-kg infant with hypoplastic left heart syndrome who experienced a left common iliac artery disruption during cardiac catheterization resulting in a retroperitoneal hemorrhage. The extent of the vascular injury combined with the vessel caliber posed a technically challenging surgical scenario. Ultimately, the vascular supply to the left lower extremity was reconstructed by the plastic surgery team with a reverse autologous vein graft. To our knowledge, this multidisciplinary approach with the involvement of plastic surgery represents a unique case.http://ift.tt/2DF87KS
No Vertical Scar Breast Weight Transfer
Summary: Women desire beautiful breasts that are functional, pain free, and without foreign material. Vertical scars, insufficient elevation, inadequate upper pole fullness, nipple numbness, and loss of breast feeding are undesirable. Relieving pain attributed to enlarged breasts has required significant tissue removal. Software analysis of chest images, physical measurements, and desires are combined to generate a surgical blueprint. The breast is divided horizontally into two components preserving the neurovascular supply and major lactiferous ducts. The skin flap cephalad to the areola provides external coverage. The areola remains attached to a deepithelialized mound, which is rotated into a cone. Dermal straps originating from the base of the cone are looped through the pectoralis major muscle and the cone repeatedly. Weight transfer to the pectoralis major muscles eliminates pain in 54% and decreases pain in 38%. Incisions are concealed at the areola cutaneous junction and in the shadow of the breast. Upper pole fullness increased in 86% without implants or fat transfer. Nipple sensation was increased in 37% and unchanged in 44%. Overall results were excellent in 50% and good in 36%. Complications consisted of dog-ears, periareolar infection, and fat necrosis. No patient required a return to the operation room. Combing computer-aided design with plastic surgical principles creates beautiful, functional breasts without foreign material. Vertical scars are avoided, and weight transfer relieves pain.http://ift.tt/2EdzuNp
Short Takes
Source:Pediatric Neurology
Author(s): Steven G. Pavlakis
http://ift.tt/2rEI19o
Cosmetics, Vol. 5, Pages 15: Development of a Natural Anti-Age Ingredient Based on Quercus pubescens Willd. Leaves Extract—A Case Study
Cosmetics, Vol. 5, Pages 15: Development of a Natural Anti-Age Ingredient Based on Quercus pubescens Willd. Leaves Extract—A Case Study
Cosmetics doi: 10.3390/cosmetics5010015
Authors: Hortense Plainfossé Pauline Burger Stéphane Azoulay Anne Landreau Grégory Verger-Dubois Xavier Fernandez
Consumers pay more and more attention not just to the safety and health aspects of ingredients entering their cosmetics' formulations, but also to their potency, origin, processing, ethical value and environmental footprint. Sustainability of the supply chain, preservation of biodiversity, as well as greener extraction techniques are hence very popular with consumers. Consumers are primarily concerned by the efficacy of the cosmetic products they use and continuously scrutinize product labels, so marketing arguments need to be based on rigorous testing and reliable results to support claims (anti-age, anti-pollution, etc.) displayed on the product's packaging. As a result, the increasing demand for natural ingredients with assessed bioactivities has profoundly modified the strategies adopted by cosmetic professionals to innovate in terms of actives. Sourcing and developing new natural cosmetic actives is a long-term procedure that is thoroughly described in the present paper, via the example of the design of both liquid and solid ingredients based on Quercus pubescens Willd. leaves extract, for which anti-age properties were assessed by a combination of in vitro assays.
http://ift.tt/2rI3iPL
Scholar : These new articles for Spanish Journal of Finance and Accounting / Revista Española de Financiación y Contabilidad are available online
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Scholar : These new articles for Activities, Adaptation & Aging are available online
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Scholar : Journal of Museum Education, Volume 43, Issue 1, March 2018 is now available online on Taylor & Francis Online
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Scholar : These new articles for Aphasiology are available online
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Scholar : Acta Odontologica Scandinavica, Volume 76, Issue 2, March 2018 is now available online on Taylor & Francis Online
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Sox10 positive breast carcinoma metastatic to the skin
Abstract
Sox10 is a robust and sensitive immunostain for melanocytic neoplasia. The strong nuclear signal, the clean background, and the limited expression in normal cutaneous structures make it a highly useful marker in the histopathologic evaluation of skin tumors.
http://ift.tt/2rJfdN9
3D imaging of cleared human skin biopsies using light-sheet microscopy: A new way to visualize in-depth skin structure
Abstract
Background
Human skin is composed of the superimposition of tissue layers of various thicknesses and components. Histological staining of skin sections is the benchmark approach to analyse the organization and integrity of human skin biopsies; however, this approach does not allow 3D tissue visualization. Alternatively, confocal or two-photon microscopy is an effective approach to perform fluorescent-based 3D imaging. However, owing to light scattering, these methods display limited light penetration in depth. The objectives of this study were therefore to combine optical clearing and light-sheet fluorescence microscopy (LSFM) to perform in-depth optical sectioning of 5 mm-thick human skin biopsies and generate 3D images of entire human skin biopsies.
Materials and Methods
A benzyl alcohol and benzyl benzoate solution was used to successfully optically clear entire formalin fixed human skin biopsies, making them transparent. In-depth optical sectioning was performed with LSFM on the basis of tissue-autofluorescence observations. 3D image analysis of optical sections generated with LSFM was performed by using the Amira® software.
Results
This new approach allowed us to observe in situ the different layers and compartments of human skin, such as the stratum corneum, the dermis and epidermal appendages. With this approach, we easily performed 3D reconstruction to visualise an entire human skin biopsy. Finally, we demonstrated that this method is useful to visualise and quantify histological anomalies, such as epidermal hyperplasia.
Conclusion
The combination of optical clearing and LSFM has new applications in dermatology and dermatological research by allowing 3D visualization and analysis of whole human skin biopsies.
http://ift.tt/2DGhdep
Comparison of two kinds of skin imaging analysis software: VISIA® from Canfield and IPP® from Media Cybernetics
Abstract
Background
Skin imaging analysis, acting as a supplement to noninvasive bioengineering devices, has been widely used in medical cosmetology and cosmetic product evaluation. The main aim of this study is to assess the differences and correlations in measuring skin spots, wrinkles, vascular features, porphyrin, and pore between two commercially available image analysis software.
Materials and Methods
Seventy healthy women were included in the study. Before taking pictures, the dermatologist evaluated subjects' skin conditions. Test sites included the forehead, cheek, and periorbital skin. A 2 × 2 cm cardboard was used to make a mark on the skin surface. Pictures were taken using VISIA® under three kinds light conditions and analyzed using VISIA® and IPP® respectively.
Results
(1) Skin pore, red area, ultraviolet spot, brown spot, porphyrin, and wrinkle measured with VISIA® were correlated with those measured with IPP® (P < .01). (2) Spot, wrinkle, fine line, brown spot, and red area analyzed with VISIA® were correlated with age on the forehead and periorbital skin (P < .05). L-value, Crow's feet, ultraviolet spot, brown spot, and red area analyzed with IPP® were correlated with age on the periorbital skin (P < .05). (3) L-value, spot, wrinkle, fine line, porphyrin, red area, and pore analyzed with VISIA® and IPP® showed correlations with the subjective evaluation scores (P < .05).
Conclusions
VISIA® and IPP® showed acceptable correlation in measuring various skin conditions. VISIA® showed a high sensibility when measured on the forehead skin. IPP® is available as an alternative software program to evaluate skin features.
http://ift.tt/2niuMFR
Changes in dermal structure and skin oxidative stress in overweight and obese Japanese males after weight loss: a longitudinal observation study
Abstract
Background/Purpose
Previous studies have reported decreased dermal echogenicity and increased skin oxidative stress in overweight males. However, it is unknown whether these skin parameters of overweight and obese people are similar to those of individuals exhibiting a normal body weight following weight loss. The purpose of this study was to (1) compare the changes in the dermal structure parameters and levels of skin oxidative stress before and after weight loss in overweight and obese people in Japan and (2) to clarify how these aspects changed when body weight would be reduced to normal body weight.
Methods
Male volunteers with a body mass index of ≥25 kg/m2 were recruited. The dermal structure was visualized and dermal echogenicity and thickness were measured using ultrasound scanners. The mRNA expression level of heme oxygenase-1 in the hair follicles was quantitatively analyzed as a marker of skin oxidative stress.
Results
When overweight individuals in their 20s to 30s reduced their weight to normal, decreased dermal thickness in the abdominal region was observed in 50% of the subjects; however, no increase in dermal echogenicity was observed. A decrease in dermal thickness and an increase in dermal echogenicity in the thighs was observed in 83.3% of the subjects. No decrease in the level of dermal oxidative stress was observed.
Conclusion
The dermal structure in the thighs of overweight young individuals can be improved to the level of the structure in those of normal body weight individuals following weight loss.
http://ift.tt/2DGhbmN
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