from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2clzPB5
Melanoma central nervous system (CNS) metastases are increasing and the challenges presented by this patient population remain complex. In December 2015, the Melanoma Research Foundation and the Wistar Institute hosted the First Summit on Melanoma Central Nervous System (CNS) Metastases in Philadelphia, Pennsylvania. Here, we provide a review of the current status of the field of melanoma brain metastasis research; identify key challenges and opportunities for improving outcomes in patients with melanoma brain metastases; and set a framework to optimize future research in this critical area.
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The present study was conducted to develop and assess the quality of carrageenan incorporated chevon patties with the objective of reducing fat content. Efficacy of carrageenan as fat replacers (0.3, 0.6 & 0.9 %) was assessed for development of low fat chevon patties. Emulsion stability and cooking yield increased with the increase in levels of carrageenan. Significantly (P < 0.05) lower fat and cholesterol contents and higher moisture and fat retention were observed in formulation with carrageenan. No significant difference in the mineral content in either of the treatment was recorded. Incorporation of fat replacer in chevon patties demonstrated significant effect on all the textural parameters except adhesiveness. Results of color value illustrated that lightness (L*) value differ significantly. Sensory scores were higher or comparable for patties containing 0.6 % carrageenan as compared to control. Hence, carrageenan was observed to be suitable as fat replacer for producing low fat chevon meat patties.
The objective of this study was to investigate the effect of soy protein isolate on functional properties and consumer acceptance of gluten-free rice spaghetti (GFRS) made from rice flour. Dry-milled high-amylose (Chai Nat 1) rice flour was premixed with dry-milled waxy (RD 6) rice flour at a ratio of 90:10 (w/w) with the soy protein isolate (SPI) concentration varying between 0, 2.5, 5.0, 7.5, 10.0 %, db. The GFRS formulation was processed using a co-rotating twin-screw extruder up to 95 °C with a screw speed of 220 rpm, 32 % moisture content, and then dried at 40 °C. The GFRS samples were analyzed by differential scanning calorimetry (DSC), X-ray diffraction, scanning electron microscopy (SEM) and texture parameters. Increasing SPI decreased the starch retrogradation of GFRS, whereas the enthalpy change of the amylose–lipid complex increased and crystallinity decreased. SEM revealed that the surface of GFRS containing SPI was much more porous than that of GFRS without SPI. The cooked GFRS containing 5.0 % SPI showed the best eating quality with increased firmness and tensile strength, and decrease stickiness. The GFRS samples were evaluated on the bases of cooking qualities and sensory evaluation. The results showed that the GFRS containing 5.0 % SPI decrease the cooking time from 17.6 to 13.7 min and cooking loss from 25.4 to 17.0 %. Overall acceptability of cooked GFRS containing 5.0 % SPI was the highest among all GFRS samples.
In vitro research in the field of type I diabetes is frequently limited by the availability of a functional model for islets of Langerhans. This method shows that by the addition of theophylline to the glucose buffers, mouse insulinoma MIN6 and rat insulinoma INS1E pseudo-islets can serve as a model for islets of Langerhans for in vitro research. The effect of theophylline is dose- and cell line-dependent, resulting in a minimal stimulation index of five followed by a rapid return to baseline insulin secretion by reducing glucose concentrations after a first high glucose stimulation. This protocol solves issues concerning in vitro research for type I diabetes as donors and the availability of primary islets of Langerhans are limited. To avoid the limitations of using human donor material, cell lines represent a valid alternative. Many different β cell lines have been reported, but the lack of reproducible responsiveness to glucose stimulation remains a challenge.
Pigs have great potential to provide preclinical models for human disease in translational research because of their similarities with humans. In this regard, porcine pluripotent cells, which are able to differentiate into cells of all three primary germ layers, might be a suitable animal model for further development of regenerative medicine. Here, we describe the current state of knowledge on apoptosis in pluripotent cells including inner cell mass (ICM), epiblast, embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs). Information is focused on the apoptotic phenomenon in pluripotency, maintenance, and differentiation of pluripotent stem cells and reprogramming of somatic cells in pigs. Additionally, this review examines the multiple roles of apoptosis and summarizes recent progress in porcine pluripotent cells.
New approaches for visualisation of silicon nanoparticles (SiNPs) in cancer cells are realised by means of the linear and nonlinear optics in vitro. Aqueous colloidal solutions of SiNPs with sizes of about 10–40 nm obtained by ultrasound grinding of silicon nanowires were introduced into breast cancer cells (MCF-7 cell line). Further, the time-varying nanoparticles enclosed in cell structures were visualised by high-resolution structured illumination microscopy (HR-SIM) and micro-Raman spectroscopy. Additionally, the nonlinear optical methods of two-photon excited fluorescence (TPEF) and coherent anti-Stokes Raman scattering (CARS) with infrared laser excitation were applied to study the localisation of SiNPs in cells. Advantages of the nonlinear methods, such as rapid imaging, which prevents cells from overheating and larger penetration depth compared to the single-photon excited HR-SIM, are discussed. The obtained results reveal new perspectives of the multimodal visualisation and precise detection of the uptake of biodegradable non-toxic SiNPs by cancer cells and they are discussed in view of future applications for the optical diagnostics of cancer tumours.
The analysis of saliva as a diagnostic approach for systemic diseases was proposed just two decades ago, but recently great interest in the field has emerged because of its revolutionary potential as a liquid biopsy and its usefulness as a non-invasive sampling method. Multiple molecules isolated in saliva have been proposed as cancer biomarkers for diagnosis, prognosis, drug monitoring and pharmacogenetic studies. In this review, we focus on the current status of the salivary diagnostic biomarkers for different cancers distant to the oral cavity, noting their potential use in the clinic and their applicability in personalising cancer therapies.
Guizhi decoction (GZD), a well-known traditional Chinese medicine (TCM) prescription consisting of Ramulus Cinnamomi, Radix Paeoniae Alba, Radix Glycyrrhizae, Fructus Jujubae and Rhizoma Zingiberis Recens, is usually used for the treatment of common colds, influenza, and other pyretic conditions in the clinic. However, the absorbed ingredients and metabolic compounds of GZD have not been reported. In this paper, a method incorporating rapid resolution liquid chromatography (RRLC) with quadrupole-time-of-flight mass spectrometry (Q-TOF-MS) was used to identify ingredients after oral administration of GZD. Identification of the primary components in GZD, drug-containing serum and urine samples was carried out in order to investigate the assimilation and metabolites of the decoction in vivo. By comparing the total ion chromatograms (TICs) of GZD, a total of 71 constituents were detected or characterized. By comparing TICs of blank and dosed rat plasma, a total of 15 constituents were detected and identified as prototypes according to their retention time (tR) and MS, MS/MS data. Based on this, neutral loss scans of 80 and 176 Da in samples of rat plasma and urine helped us to identify most of the metabolites. Results showed that the predominant metabolic pathways of (epi) catechin and gallic acid were sulfation, methylation, glucuronidation and dehydroxylation; the major metabolic pathways of flavone were hydrolysis, sulfation and glucuronidation. Furthermore, degradation, oxidation and ring fission were found to often occur in the metabolism process of GZD in vivo.
Little information exists about the evaluation of potential developmental immunotoxicity induced by perfluorooctane sulfonate (PFOS), a synthetic persistent and increasingly ubiquitous environmental contaminant. To assess potential sex-specific impacts of PFOS on immunological health in the offspring, using male and female C57BL/6 mice, pups were evaluated for developmental immunotoxic effects after maternal oral exposure to PFOS (0.1, 1.0 and 5.0 mg PFOS/kg/day) during Gestational Days 1–17. Spontaneous TH1/TH2-type cytokines, serum levels of testosterone and estradiol were evaluated in F1 pups at four and eight weeks of age. The study showed that male pups were more sensitive to the effects of PFOS than female pups. At eight weeks of age, an imbalance in TH1/TH2-type cytokines with excess TH2 cytokines (IL-4) was found only in male pups. As for hormone levels, PFOS treatment in utero significantly decreased serum testosterone levels and increased estradiol levels only in male pups, and a significant interaction between sex and PFOS was observed for serum testosterone at both four weeks of age (pinteraction = 0.0049) and eight weeks of age (pinteraction = 0.0227) and for estradiol alternation at four weeks of age (pinteraction = 0.0351). In conclusion, testosterone-mediated endocrine function may be partially involved in the TH1/TH2 imbalance induced by PFOS, and these deficits are detectable among both young and adult mice and may affect males more than females.
The short ACTH stimulation test (250μg) is the dynamic test most frequently used to assess adrenal function. It is possible that a single basal cortisol could be used to predict the dynamic response, but research has been hampered by the use of different assays and thresholds.
To propose a morning baseline cortisol criterion of three of the most commonly-used modern cortisol immunoassays - Advia Centaur (Siemens), Architect (Abbott) and the Roche Modular System (Roche) - that could predict adrenal sufficiency.
Observational, retrospective cross-sectional study at two centres.
Retrospective analysis of the results of 1019 SSTs with the Advia Centaur, 449 SSTs with the Architect, and 2050 SSTs with the Roche Modular System assay. Serum cortisol levels were measured prior to injection of 250μg Synacthen and after 30 minutes. Overall, we were able to collate data from a total of 3518 SSTs in 3571 patients.
Using receiver-operator curve analysis, baseline cortisol levels for predicting passing the SST with 100% specificity were 358 nmol/l for Siemens, 336 nmol/l for Abbott and 506 nmol/l for Roche. Utilising these criteria: 589, 158 and 578 SSTs respectively for Siemens, Abbott and Roche immunoassays could have been avoided.
We have defined assay-specific morning cortisol levels that are able to predict the integrity of the hypothalamo-pituitary-adrenal axis. We propose that this represents a valid tool for the initial assessment of adrenal function and has the potential to obviate the need for dynamic testing in a significant number of patients.
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Congenital hypogonadotropic hypogonadism (CHH) with either normal olfaction or anosmia (Kallmann syndrome (KS)) is a cause of pubertal failure secondary to pituitary gonadotropin deficiency. It appears during fetal life and persists throughout the postnatal, pre- and post-pubertal periods (1). For many years KS was considered to be a genetic disorder in which CHH persists throughout life, but case series of KS/CHH reported over the past 15 years show that gonadotropin and testicular functions can recover spontaneously, partially or completely (2,3).
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Comparison of the efficacy of different treatment modalities for Kimura's disease.
Int J Oral Maxillofac Surg. 2016 Sep 7;
Authors: Ye P, Ma DQ, Yu GY, Gao Y, Peng X
The objective of this study was to investigate the clinical features of Kimura's disease in the head and neck region and to compare the local recurrence rate between three therapies used for the treatment of this disease. The clinicopathological information of 46 hospitalized patients suffering from Kimura's disease in the head and neck region over a 10-year period was reviewed retrospectively. All lesions were clinically observed in the head and neck region. These 46 patients underwent a total of 58 treatments; nine patients underwent multiple treatments due to local recurrence. Of the 58 treatments, 32 involved surgical excision alone, 24 involved surgical excision and postoperative low-dose radiotherapy (20-40Gy), one was a combination of ultrasound-guided core needle biopsy and radiotherapy, and one was a combination of incisional biopsy and subsequent radiotherapy. During the follow-up period, nine patients suffered 16 local recurrences. The recurrence rate of surgical excision combined with low-dose radiotherapy was much lower than that of surgical excision alone or radiotherapy alone (both P<0.05). It is concluded that Kimura's disease is a benign condition with a good prognosis, and surgical excision combined with postoperative low-dose radiotherapy is associated with the lowest local recurrence rate in the treatment of this disease.
PMID: 27614905 [PubMed - as supplied by publisher]
A comprehensive study of oxidative stress in sudden hearing loss.
Eur Arch Otorhinolaryngol. 2016 Sep 10;
Authors: Gul F, Muderris T, Yalciner G, Sevil E, Bercin S, Ergin M, Babademez MA, Kiris M
Little is known about the association between idiopathic sudden sensorineural hearing loss (ISSNHL) and oxidative stress. We investigated changes in a wide range of oxidants and antioxidants to create a comprehensive picture of oxidative imbalance. In the peripheral blood of 50 ISSNHL patients and 50 healthy subjects, total oxidant status (TOS), total antioxidant status (TAS), paraoxonase (PON), thiol/disulphide levels were measured. Moreover, a global oxidative stress index, reflecting both oxidative and antioxidant counterparts, was also calculated. One-way analysis between oxidative markers and severity of hearing loss were evaluated. The ISSNHL patients showed significantly higher TOS levels than controls (6.02 ± 3.17 vs. 4.5 ± 2.22; p = 0.018). The oxidative index was also significantly higher in patients than controls (0.39 ± 0.19 vs. 0.3 ± 0.14; p = 0.035). TAS, PON, native thiol, and total thiol were not altered. There was no statistical significance between oxidative markers and severity of hearing loss. The binary logistic regression model revealed that disulphide and TOS were associated with ISSNHL. There are alterations in a wide array of oxidants and antioxidants, with balance shifting toward increased oxidative stress in ISSNHL. Our findings may suggest endothelial dysfunction in ISSNHL etiopathogenesis.
PMID: 27614879 [PubMed - as supplied by publisher]
Multivariable normal tissue complication probability model-based treatment plan optimization for grade 2-4 dysphagia and tube feeding dependence in head and neck radiotherapy.
Radiother Oncol. 2016 Sep 7;
Authors: Kierkels RG, Wopken K, Visser R, Korevaar EW, van der Schaaf A, Bijl HP, Langendijk JA
BACKGROUND AND PURPOSE: Radiotherapy of the head and neck is challenged by the relatively large number of organs-at-risk close to the tumor. Biologically-oriented objective functions (OF) could optimally distribute the dose among the organs-at-risk. We aimed to explore OFs based on multivariable normal tissue complication probability (NTCP) models for grade 2-4 dysphagia (DYS) and tube feeding dependence (TFD).
MATERIALS AND METHODS: One hundred head and neck cancer patients were studied. Additional to the clinical plan, two more plans (an OFDYS and OFTFD-plan) were optimized per patient. The NTCP models included up to four dose-volume parameters and other non-dosimetric factors. A fully automatic plan optimization framework was used to optimize the OFNTCP-based plans.
RESULTS: All OFNTCP-based plans were reviewed and classified as clinically acceptable. On average, the Δdose and ΔNTCP were small comparing the OFDYS-plan, OFTFD-plan, and clinical plan. For 5% of patients NTCPTFD reduced >5% using OFTFD-based planning compared to the OFDYS-plans.
CONCLUSIONS: Plan optimization using NTCPDYS- and NTCPTFD-based objective functions resulted in clinically acceptable plans. For patients with considerable risk factors of TFD, the OFTFD steered the optimizer to dose distributions which directly led to slightly lower predicted NTCPTFD values as compared to the other studied plans.
PMID: 27614681 [PubMed - as supplied by publisher]
Safety of Outpatient vs Inpatient Percutaneous Radiological Gastrostomy Tubes in Patients with Head and Neck Cancers.
Can Assoc Radiol J. 2016 Sep 7;
Authors: Odedra D, Nasirzadeh R, Menard A
PMID: 27614609 [PubMed - as supplied by publisher]
Cytoreductive surgery for head and neck squamous cell carcinoma in the new age of immunotherapy.
Oral Oncol. 2016 Sep 7;
Authors: Bryan Bell R, Gough MJ, Seung SK, Jutric Z, Weinberg AD, Fox BA, Crittenden MR, Leidner RS, Curti B
Cytoreductive surgery is an approach to cancer treatment that aims to reduce the number of cancer cells via resection of primary tumor or metastatic deposits, in an effort to minimize a potentially immunosuppressive tumor burden, palliate symptoms, and prevent complications. Furthermore, it provides a platform for investigation of biomarkers with the goal of optimizing immunotherapy to reverse the immunosuppressive tumor microenvironment and enhance adaptive immune responses. Ultimately, our group aims to exploit the concept that successful cancer therapy is dependent upon an effective immune response. Surgery will remain an integral part of head and neck squamous cell carcinoma (HNSCC) treatment in the future, even as checkpoint inhibitors, co-stimulatory molecules, vaccines, adoptive T cell therapy and other novel agents enter clinical routine. Cytoreductive resection may provide an effective platform for immunotherapy and biomarker directed interventions to improve outcomes for patients with HNSCC.
PMID: 27614589 [PubMed - as supplied by publisher]
[Intensity-modulated radiotherapy of head and neck cancers. Dose constraint for spinal cord and brachial plexus].
Cancer Radiother. 2016 Sep 7;
Authors: Boisselier P, Racadot S, Thariat J, Graff P, Pointreau Y
Given the ballistic opportunities it offers, intensity-modulated radiotherapy has emerged as the gold standard treatment for head and neck cancers. Protection of organs at risk is one of the objectives of optimization during the planning process. The compliance of dose constraints to the nervous system must be prioritized over all others. To avoid complications, it is recommended to respect a maximum dose of 50Gy to the spinal cord, and 60Gy to the brachial plexus using conventional fractionation of 2Gy per fraction. These constraints can be adapted depending on the clinical situation; they will probably be refocused by the follow-up of the IMRT studies.
PMID: 27614529 [PubMed - as supplied by publisher]
[Intensity-modulated radiotherapy for head and neck cancer. Dose constraint for salivary gland and mandible].
Cancer Radiother. 2016 Sep 7;
Authors: Pointreau Y, Lizée T, Bensadoun RJ, Boisselier P, Racadot S, Thariat J, Graff P
Intensity-modulated radiation therapy (IMRT) is the gold standard for head and neck irradiation. It allows better protection to the organs at risk such as salivary glands and mandible, and can reduce the frequency of xerostomia, trismus and osteoradionecrosis. At the time of treatment planning, the mean dose to a single parotid gland should be kept below 26Gy, the mean dose to a single submandibular gland below 39Gy, the mean dose to the mandible below 60 to 65Gy and the D2% to a single temporomandibular joint below 65Gy. These dose constraints could be further improved with data extracted from cohorts of patients receiving IMRT exclusively. The dose administered to the target volumes should not be lessened to spare the salivary glands or mandible.
PMID: 27614524 [PubMed - as supplied by publisher]
[Intensity modulated radiotherapy for head and neck cancer, dose constraint for normal tissue: Cochlea vestibular apparatus and brainstem].
Cancer Radiother. 2016 Sep 7;
Authors: Guimas V, Thariat J, Graff-Cailleau P, Boisselier P, Pointreau Y, Pommier P, Montbarbon X, Laude C, Racadot S
Modern techniques such as intensity modulated radiation therapy (IMRT) have been proven to significantly decrease the dose delivered to the cochleovestibular apparatus, limiting consecutive toxicity especially for sensorineural hearing loss. However, recent data still report a 42% rate of radio-induced hypoacusia underscoring the need to protect the cochleovestibular apparatus. Due to the small size of the cochlea, a precise dose-volume analysis could not be performed, and recommendations only refer to the mean dose. Confusing factors such as age, concomitant chemotherapy, primary site and tumor stage should be taken into account at the time of treatment planning. (Non-coplanar) VMAT and tomotherapy have been proven better at sparing the cochlea in comparison with 3D CRT. Brainstem radio-induced injuries were poorly studied because of their infrequency and the difficulty of distinguishing between necrosis and tumor progression in the case of a primary tumor located at the base of skull. The following toxicities have been described: brainstem focal radionecrosis, cognitive disorders without dementia, cranial nerve injuries and sensori motor disability. Maximal dose to the brainstem should be kept to < 54Gy for conventional fractionation. This dose could be exceeded (no more than 10mL should receive more than 59Gy), provided this hot spot is located in the peripheral area of the organ.
PMID: 27614519 [PubMed - as supplied by publisher]
[Role of radiotherapy in the treatment of NK/T-cell nasal type and primary cerebral lymphomas].
Cancer Radiother. 2016 Sep 7;
Authors: Boros A, Michot JM, Hoang-Xuan K, Mazeron R
The head and neck are common sites for extranodal non-Hodgkin lymphomas. Radiotherapy plays an important role in the treatment of low-grade lymphomas, with curative or palliative intent. In the case of high-grade lymphomas, its combination with chemotherapy is debated. Its role is however undeniable in two specific entities: NK/T-cell lymphoma NK/T nasal type, and primary central nervous system lymphomas, which are the subject of this review.
PMID: 27614517 [PubMed - as supplied by publisher]
[Intensity-modulated radiotherapy of head and neck cancers: Dose effects on the ocular, orbital and eyelid structures].
Cancer Radiother. 2016 Sep 7;
Authors: Thariat J, Racadot S, Pointreau Y, Boisselier P, Grange JD, Graff P, Weber DC
Radiation-induced damage of ocular, orbital and eyelid structures are mainly reported for the optic nerve, retina, lens and lacrimal gland. Dose-volume relationships are, however, inaccurate due to the small volume of most of the organs at risk involved and limited ability of irradiation techniques to spare these structures in the pre-IMRT (intensity-modulated radiation therapy) era. The ability of newest radiation techniques including IMRT and proton therapy to generate steep dose gradients may yield more accurate models in the future. Some toxicities are severe and irreversible, leading to vision loss, as in the case of radiation-induced optic neuropathy for which curative treatments are suboptimal. Other toxicities can lead to reversible vision loss but can be surgically corrected, as is the case for radiation-induced cataract. In this paper, we will review the dose effects for the ocular; orbital and eyelid structures.
PMID: 27614507 [PubMed - as supplied by publisher]
Regulatory T cells function at the early stage of tumor progression in a mouse model of tongue squamous cell carcinoma.
Cancer Immunol Immunother. 2016 Sep 10;
Authors: Miki K, Orita Y, Gion Y, Takao S, Ohno K, Takeuchi M, Ito T, Hanakawa H, Tachibana T, Marunaka H, Makino T, Minoura A, Matsukawa A, Nishizaki K, Yoshino T, Sato Y
The objective of this study was to observe the distribution of regulatory T cells (Tregs) in the development of tongue squamous cell carcinoma (SCC) and to determine the role of Tregs in the progression of tongue SCC. A mouse model of 4-nitroquinoline-1-oxide (4NQO)-induced-tongue SCC was established. The expression of Forkhead box P3 (Foxp3), interleukin 10, transforming growth factor-β, chemokine CC motif ligands 17, 20, and CC chemokine receptor 4 was determined using real-time quantitative polymerase chain reaction. Foxp3 expression was also analyzed using immunohistochemistry. The results were compared with those of control mice and of 4NQO-treated mice treated with a cyclooxygenase-2 (COX-2) inhibitor. Well to moderately differentiated tongue SCC was induced in all of the experimental mice. The amount of Tregs of the experimental mice was over 10 times as much as control mice at the early stage of tumor progression. COX-2 inhibitor did not prevent the progression of tongue SCC and did not reduce the total amount of Tregs. Tregs function at the early stage of the development of tongue SCC, and it may be effective to suppress Tregs at the early stage of tumor progression for the treatment and/or prevention of tongue SCC.
PMID: 27614428 [PubMed - as supplied by publisher]
The Effects of the Menstrual Cycle on Vibratory Characteristics of the Vocal Folds Investigated With High-Speed Digital Imaging.
J Voice. 2016 Sep 7;
Authors: Kunduk M, Vansant MB, Ikuma T, McWhorter A
OBJECTIVES: This study investigated the effect of menstrual cycle on vocal fold vibratory characteristics in young women using high-speed digital imaging. This study examined the menstrual phase effect on five objective high-speed imaging parameters and two self-rated perceptual parameters. The effects of oral birth control use were also investigated.
METHODS: Thirteen subjects with no prior voice complaints were included in this study. All data were collected at three different time periods (premenses, postmenses, ovulation) over the course of one menstrual cycle. For five of the 13 subjects, data were collected for two consecutive cycles. Six of 13 subjects were oral birth control users. From high-speed imaging data, five objective parameters were computed: fundamental frequency, fundamental frequency deviation, harmonics-to-noise ratio, harmonic richness factor, and ratio of first and second harmonics. They were supplemented by two self-rated parameters: Reflux Severity Index and perceptual voice quality rating. Analysis included mixed model linear analysis with repeated measures.
RESULTS: Results indicated no significant main effects for menstrual phase, between-cycle, or birth control use in the analysis for mean fundamental frequency, fundamental frequency deviation, harmonics-to-noise ratio, harmonic richness factor, first and second harmonics, Reflux Severity Index, and perceptual voice quality rating. Additionally, there were no interaction effects.
CONCLUSIONS: Hormone fluctuations observed across the menstrual cycle do not appear to have direct effect on vocal fold vibratory characteristics in young women with no voice concerns. Birth control use, on the other hand, may have influence on spectral richness of vocal fold vibration.
PMID: 27614383 [PubMed - as supplied by publisher]
Breast and ovarian cancer (BC/OC) predisposition has been attributed to a number of high- and moderate to low-penetrance susceptibility genes. With the advent of next generation sequencing (NGS) simultaneous testing of these genes has become feasible. In this monocentric study we report results of panel-based screening of 14 BC/OC susceptibility genes (BRCA1, BRCA2, RAD51C, RAD51D, CHEK2, PALB2, ATM, NBN, CDH1, TP53, MLH1, MSH2, MSH6 and PMS2) in a group of 581 consecutive individuals from a German population with BC and/or OC fulfilling diagnostic criteria for BRCA1 and BRCA2 testing including 179 with a triple-negative tumor. Altogether we identified 106 deleterious mutations in 105 (18%) patients in 10 different genes, including 7 different exon deletions. Of these 106 mutations, 16 (15%) were novel and only six were found in BRCA1/2. To further characterize mutations located in or nearby splicing consensus sites we performed RT-PCR analysis which allowed confirmation of pathogenicity in 7 of 9 mutations analyzed. In PALB2 we identified a deleterious variant in six cases. All but one were associated with early onset BC and a positive family history indicating that penetrance for PALB2 mutations is comparable to BRCA2. Overall, extended testing beyond BRCA1/2 identified a deleterious mutation in further 6% of patients. As a downside, 89 variants of uncertain significance were identified highlighting the need for comprehensive variant databases. In conclusion, panel testing yields more accurate information on genetic cancer risk than assessing BRCA1/2 alone and wide-spread testing will help improve penetrance assessment of variants in these risk genes. This article is protected by copyright. All rights reserved.
Cancer-associated fibroblasts (CAFs) are known to contribute to cancer progression. We have reported that cell surface expression of hepatocyte growth factor activator inhibitor 1 (HAI-1) is decreased in invasive oral squamous cell carcinoma (OSCC) cells. This study examined if HAI-1-insufficiency contributes to CAF recruitment in OSCC. Serum-free conditioned medium (SFCM) from a human OSCC line (SAS) stimulated the migration of 3 human fibroblast cell lines, NB1RGB, MRC5 and KD. SFCM from HAI-1-knockdown SAS showed an additive effect on the migration of NB1RGB and MRC5, but not KD. SAS SFCM induced protease-activated receptor-2 (PAR-2) expression in NB1RGB and MRC5, but not in KD, and a PAR-2 antagonist blocked the stimulatory effect of HAI-1 knockdown on migration of the PAR-2 expressing cell lines. Moreover, HAI-1-deficient SFCM showed additive stimulatory effects on the migration of wild-type but not PAR-2-deficient mouse fibroblasts. Therefore, the enhanced migration induced by HAI-1-insufficiency was mediated by PAR-2 activation in fibroblasts. This activation resulted from the deregulation of the activity of matriptase, a PAR-2 agonist protease. HAI-1 may thus prevent CAF recruitment to OSCC by controlling matriptase activity. When HAI-1 expression is reduced on OSCC, matriptase may contributed to CAF accumulation by paracrine activation of fibroblast PAR-2. Immunohistochemical analysis of resected OSCC revealed increased PAR2-positive CAFs in 35% (33/95) of the cases studied. The increased PAR-2 positive CAFs tended to correlate with infiltrative histology of the invasion front and shorter disease-free survival of the patients. This article is protected by copyright. All rights reserved.
Melanoma is a highly lethal cutaneous tumor, killing affected patients through development of multiple poorly immunogenic metastases. Suboptimal activation of immune system by melanoma cells is often due to molecular modifications occurring during tumor progression that prevent efficient recognition of melanoma cells by immune effectors. Statins are HMG-CoA reductase inhibitors, which block the mevalonate synthesis pathway, used by millions of people as hypocholesterolemic agents in cardiovascular and cerebrovascular diseases. They are also known to inhibit Rho GTPase activation and Rho dependent signaling pathways. Rho GTPases are regarded as molecular switches that regulate a wide spectrum of cellular functions and their dysfunction has been characterized in various oncogenic process notably in melanoma progression. Moreover, these molecules can modulate the immune response. Since ten years we have demonstrated that Statins and other Rho GTPases inhibitors are critical regulators of molecules involved in adaptive and innate anti-melanoma immune response. In this review we summarize our major observations demonstrating that these pharmacological agents stimulate melanoma immunogenicity and suggest a potential use of these molecules to promote anti-melanoma immune response. This article is protected by copyright. All rights reserved.
Interval breast cancer (IC) has a more aggressive phenotype and higher mortality than screen-detected cancer (SDC). In this case-case study, we investigated whether the size of longitudinal fluctuations in mammographic percent density (PD fluctuation) was associated with the ratio of IC vs. SDC among screened women with breast cancer. The primary study population consisted of 1,414 postmenopausal breast cancer cases, and the validation population of 1,241 cases. We calculated PD fluctuation as the quadratic mean of deviations between actual PD and the long-term trend estimated by a mixed effects model. In a logistic regression model we examined the association between PD fluctuation and interval vs. screen-detected cancer including adjustments for PD at last screening, age at diagnosis, BMI and hormone replacement therapy. All statistical tests were two-sided. There were 385 IC and 1029 SDC in the primary study population, with PD fluctuations of 0.44 and 0.41 respectively (p=0.0309). After adjustments, PD fluctuation was associated with an increased ratio of IC vs. SDC, with an estimated per-standard deviation odds ratio of 1.17 (95% CI = 1.03 to 1.33), compared to 1.19 (95% CI = 1.04 to1.38) in the validation population. In screened women with breast cancer, high fluctuation in mammographic percent density was associated with an increased ratio of IC vs. SDC. Whether this is entirely related to a reduced mammographic detectability or to a biological phenotype promoting faster tumor growth remains to be elucidated. This article is protected by copyright. All rights reserved.
The aim of this study is to investigate the effects of CAPOX and capecitabine on recurrence-free survival (RFS) and overall survival (OS) among elderly stage III colon cancer patients and to evaluate the effect of (non-)completion. Patients aged ≥70 years who underwent resection only or who were subsequently treated with CAPOX or capecitabine in 10 large non-academic hospitals were included. RFS and OS were analyzed with Kaplan-Meier curves and multivariable Cox regression adjusted for patient and tumor characteristics. 982 patients were included: 630 underwent surgery only, 191 received CAPOX and 161 received capecitabine. Five-year RFS and OS did not differ between capecitabine and CAPOX (RFS: 63% vs. 60% (p=0.91), adjusted HR=0.99 (95%CI 0.68-1.44); OS: 66% vs. 66% (p=0.76), adjusted HR=0.93 (95%CI 0.64-1.34)). After resection only, RFS was 38% and OS 37%. Completion rates were 48% for CAPOX and 68% for capecitabine. Three-year RFS and OS did not differ between patients who discontinued CAPOX early and patients who completed treatment with CAPOX (RFS: 61% vs. 69% (p=0.21), adjusted HR=1.42 (95%CI 0.85-2.37); OS: 68% vs. 78% (p=0.41), adjusted HR=1.17 (95%CI 0.70-1.97)). Three-year RFS and OS differed between patients who discontinued capecitabine early and patients who completed treatment with capecitabine (RFS: 54% vs. 72% (p=0.01), adjusted HR=2.07 (95%CI 1.11-3.84); OS: 65% vs. 80% (p=0.01), adjusted HR=2.00 (95%CI 1.12-3.59)). Receipt of CAPOX or capecitabine is associated with improved RFS and OS. The advantage does not differ by regimen. The addition of oxaliplatin might not be justified in elderly stage III colon cancer patients. This article is protected by copyright. All rights reserved.
The identification and validation of a targeted therapy for patients with triple-negative breast cancer (TNBC) is currently one of the most urgent needs in breast cancer therapeutics. One of the key reasons for the failure to develop a new therapy for this subgroup of breast cancer patients has been the difficulty in identifying a highly prevalent, targetable molecular alteration in these tumors. Recently however, the p53 gene was found to be mutated in approximately 80% of basal/TNBC, raising the possibility that targeting the mutant p53 protein product might be a new approach for the treatment of this form of breast cancer. In this study, we investigated the anti-cancer activity of PRIMA-1 and PRIMA-1MET (APR-246), two compounds which were previously reported to reactivate mutant p53 and convert it to a form with wild-type (WT) properties. Using a panel of 18 breast cancer cell lines and 2 immortalized breast cell lines, inhibition of proliferation by PRIMA-1 and PRIMA-1MET was found to be cell-line dependent, but independent of cell line molecular subtype. Although response was independent of molecular subtype, p53 mutated cell lines were significantly more sensitive to PRIMA-1MET than p53 WT cells (p=0.029). Furthermore, response (measured as IC50 value) correlated significantly with p53 protein level as measured by ELISA (p=0.0089, r=-0.57, n=19). In addition to inhibiting cell proliferation, PRIMA-1MET induced apoptosis and inhibited migration in a p53 mutant-dependent manner. Based on our data, we conclude that targeting mutant p53 with PRIMA-1MET is a potential new approach for treating p53-mutated breast cancer, including the subgroup with triple-negative (TN) disease. This article is protected by copyright. All rights reserved.
In tumor microenvironments, the macrophage population is heterogeneous, but some macrophages can acquire tumor-promoting characteristics. These tumor-associated macrophages (TAM) exhibit an M2-like profile, with deficient production of NO and ROS, characteristics of pro-inflammatory M1 cytotoxic macrophages. Lipoxins (LX) and 15-epi-lipoxins are lipid mediators which can induce certain features of M2 macrophages in mononuclear cells, but their effects on TAM remain to be elucidated. This study tested the hypothesis that ATL-1, a synthetic analogue of 15-epi-lipoxin A4, could modulate TAM activity profile. We show that human macrophages (MΦ) differentiated into TAM-like cells after incubation with conditioned medium from MV3, a human melanoma lineage cell. Contrasting with the effects observed in other M2 subsets and M1 profile macrophages, ATL-1 selectively decreased M2 surface markers in TAM, suggesting unique behaviour of this particular M2 subset. Importantly, these results were replicated by the natural lipoxins LXA4 and the aspirin induced 15-epi-LXA4 (ATL). In parallel, ATL-1 stimulated TAM to produce NO by increasing the iNOS/arginase ratio and activated NADPH oxidase, triggering ROS production. These alterations in TAM profile induced by ATL-1 led to loss of the anti-apoptotic effects of TAM on melanoma cells and increased their cytotoxic properties. Finally, ATL-1 was found to inhibit tumor progression in a murine model in vivo, which was accompanied by alterations in TAM profile and diminished angiogenesis. Together, the results show an unexpected effect of lipoxin, which induces in TAM a change from an M2- to an M1-like profile, thereby triggering tumor cell apoptosis and down-modulating the tumor progression. This article is protected by copyright. All rights reserved.
Publication date: 5 November 2016
Publication date: 5 December 2016
Publication date: 5 December 2016
Publication date: 5 December 2016
Publication date: 5 December 2016
Publication date: 5 November 2016