Αρχειοθήκη ιστολογίου

Παρασκευή 20 Οκτωβρίου 2017

Everolimus in advanced, progressive, well-differentiated, nonfunctional neuroendocrine tumors: RADIANT-4 lung subgroup analysis

Summary

In the phase 3, RADIANT-4 study, everolimus improved median progression-free survival (PFS) by 7.1 months in patients with advanced, progressive, well-differentiated (grade 1 or grade 2), nonfunctional lung or gastrointestinal neuroendocrine tumors (NETs) vs placebo (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.35-0.67; P < .00001). This exploratory analysis reports the outcomes of the subgroup of patients with lung NETs. In RADIANT-4, patients were randomized (2:1) to everolimus 10 mg/d or placebo, both with best supportive care. This is a post hoc analysis of the lung subgroup with PFS, by central radiology review, as the primary endpoint; secondary endpoints included objective response rate and safety measures. Ninety of the 302 patients enrolled in the study had primary lung NET (everolimus, = 63 and placebo, = 27). Median PFS (95% CI) by central review was 9.2 (6.8-10.9) months in everolimus arm vs 3.6 (1.9-5.1) months in placebo arm (HR, 0.50; 95% CI, 0.28-0.88). More patients who received everolimus (58%) experienced any tumor shrinkage compared with placebo (13%). Most frequently reported (≥ 5% incidence) grade 3-4 drug-related adverse events (everolimus vs placebo) included stomatitis (11% vs 0%), hyperglycemia (10% vs 0%), and any infections (8% vs 0%). In patients with advanced, progressive, well-differentiated, nonfunctional lung NET, treatment with everolimus was associated with a median PFS improvement of 5.6 months, with a safety profile similar to that of the overall RADIANT-4 population. These results support the use of everolimus in patients with advanced, nonfunctional lung NET.

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HIF-1α Promotes Breast Cancer Cell MCF-7 Proliferation and Invasion Through Regulating miR-210

Cancer Biotherapy & Radiopharmaceuticals Oct 2017, Vol. 32, No. 8: 297-301.


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PERK-Phosphorylated eIF2α Pathway Suppresses Tumor Metastasis Through Downregulating Expression of Programmed Death Ligand 1 and CXCL5 in Triple-Negative Breast Cancer

Cancer Biotherapy & Radiopharmaceuticals Oct 2017, Vol. 32, No. 8: 282-287.


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An Overview of Unfolded Protein Response Signaling and Its Role in Cancer

Cancer Biotherapy & Radiopharmaceuticals Oct 2017, Vol. 32, No. 8: 275-281.


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Imaging of Integrin αvβ3 Expression in Lung Cancers and Brain Tumors Using Single-Photon Emission Computed Tomography with a Novel Radiotracer 99mTc-IDA-D-[c(RGDfK)]2

Cancer Biotherapy & Radiopharmaceuticals Oct 2017, Vol. 32, No. 8: 288-296.


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Low Concentration of 5-Fluorouracil Increases the Effectiveness of Tumor RNA to Activate Murine Dendritic Cells

Cancer Biotherapy & Radiopharmaceuticals Oct 2017, Vol. 32, No. 8: 302-308.


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Switching Between Biological Treatments in Psoriatic Arthritis: A Review of the Evidence

Abstract

Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy. Therapy with anti-tumor necrosis factor (TNF)-α agents represents the first therapeutic choice for moderate and severe forms; however, PsA patients can experience anti-TNFα failure, lack of efficacy, or adverse events. Several evidences exist on the effectiveness of switching among different TNFα inhibitors, and we reviewed the published data on the effectiveness of anti-TNFα first-, second- and third-line. Most of the studies report that the main reason for switching to a second anti-TNFα agent is represented by lack of efficacy (primary or secondary) and, more rarely, adverse events. Switchers receiving their second anti-TNFα agent have considerably poorer responses compared with non-switchers. Survival of anti-TNFα treatment appears to be superior in PsA patients when compared with rheumatoid arthritis patients. Switching from anti-TNF agents to ustekinumab or secukinumab or apremilast can represent a valid alternative therapeutic strategy.



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Importance of neoadjuvant chemotherapy in olfactory neuroblastoma treatment: Series report and literature review

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Publication date: Available online 20 October 2017
Source:Acta Otorrinolaringológica Española
Author(s): Ricardo Bartel, Xavier Gonzalez-Compta, Enric Cisa, Francesc Cruellas, Alberto Torres, Aleix Rovira, Manel Manos
Introduction and objectivesOlfactory neuroblastoma (ONB) is a rare entity that constitutes less than 5% of nasosinusal malignancies. Mainstream treatment consists in surgical resection+/−adjuvant radiotherapy. By exposing results observed with apparition of new therapeutic options as neoadjuvant chemotherapy, the objective is to evaluate a series and a review of the current literature.MethodsA retrospective review was conducted including patients diagnosed and followed-up for ONB from 2008 to 2015 in our institution.Results9 patients were included. Mean follow-up of 52.5 months (range 10–107). Kadish stage: A, 1 patient (11.1%) treated with endoscopic surgery; B, 2 patients (22.2%) treated with endoscopic surgery (one of them received adjuvant radiotherapy); C, 6 patients (66.7%), 4 patients presented intracranial extension and were treated with neoadjuvant chemotherapy followed by surgery and radiotherapy. The other 2 patients presented isolated orbital extension, treated with radical surgery (endoscopic or craniofacial resection) plus radiotherapy. The 5-year disease free and overall survival observed was 88.9%.ConclusionNeoadjuvant chemotherapy could be an effective treatment for tumor reduction, improving surgical resection and reducing its complications.



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Importance of neoadjuvant chemotherapy in olfactory neuroblastoma treatment: Series report and literature review

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Publication date: Available online 20 October 2017
Source:Acta Otorrinolaringológica Española
Author(s): Ricardo Bartel, Xavier Gonzalez-Compta, Enric Cisa, Francesc Cruellas, Alberto Torres, Aleix Rovira, Manel Manos
Introduction and objectivesOlfactory neuroblastoma (ONB) is a rare entity that constitutes less than 5% of nasosinusal malignancies. Mainstream treatment consists in surgical resection+/−adjuvant radiotherapy. By exposing results observed with apparition of new therapeutic options as neoadjuvant chemotherapy, the objective is to evaluate a series and a review of the current literature.MethodsA retrospective review was conducted including patients diagnosed and followed-up for ONB from 2008 to 2015 in our institution.Results9 patients were included. Mean follow-up of 52.5 months (range 10–107). Kadish stage: A, 1 patient (11.1%) treated with endoscopic surgery; B, 2 patients (22.2%) treated with endoscopic surgery (one of them received adjuvant radiotherapy); C, 6 patients (66.7%), 4 patients presented intracranial extension and were treated with neoadjuvant chemotherapy followed by surgery and radiotherapy. The other 2 patients presented isolated orbital extension, treated with radical surgery (endoscopic or craniofacial resection) plus radiotherapy. The 5-year disease free and overall survival observed was 88.9%.ConclusionNeoadjuvant chemotherapy could be an effective treatment for tumor reduction, improving surgical resection and reducing its complications.



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Vorinostat-eluting poly(DL-lactide-co-glycolide) nanofiber-coated stent for inhibition of cholangiocarcinoma cells

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Identification of lncRNAs involved in biological regulation in early age-related macular degeneration

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Targeted delivery of ginsenoside compound K using TPGS/PEG-PCL mixed micelles for effective treatment of lung cancer

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Light-triggered methylcellulose gold nanoparticle hydrogels for leptin release to inhibit fat stores in adipocytes

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In vitro and in vivo protein release and anti-ischemia/reperfusion injury properties of bone morphogenetic protein-2-loaded glycyrrhetinic acid-poly(ethylene glycol)-b-poly(L-lysine) nanoparticles

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The Sustainable Development Goals and Health Equity.

No abstract available

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Campylobacter jejuni

Campylobacter jejuni: A bacterium that typically infects the bowels. Now the leading cause of bacterial food poisoning, Campylobacter jejuni is most often spread by contact with raw or undercooked poultry. A single drop of juice from a contaminated chicken is enough to make someone sick. Symptoms tend to start 2 to 5 days after exposure and typically last a week. They resemble the symptoms of viral gastroenteritis'diarrhea, fever, abdominal pain, cramping, nausea, and vomiting'but with campylobacter, fever is typical and the diarrhea is often bloody. Antibiotics can be helpful treatment. Most people recover completely. However, some suffer long-term consequences, such as arthritis or Guillain-Barr' syndrome. Both are thought to occur when a person's immune system is activated by the Campylobacter jejuni and misdirected to attack the person's own body.



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A new endoscopic technique to close big nasal septal perforations: prospective evaluation of the double meat hook technique in 19 consecutive cases

Abstract

Despite the variety of surgical techniques available to close big symptomatic septum perforations, closure rates of 30 to 70% indicate the difficulty of obtaining a good end result.

The double meat hook technique is a new endoscopically assisted technique that delivers excellent visualization and control of mucosal flap elevation, extension and suturing.

Mucosa from the nasal floor, lateral nasal wall and inferior turbinate bone are valuable donor site extensions.

There is no need for additional incisions into the nasal septal mucosa in order to perform a tension-free closure. Preservation of the structural integrity and blood supply of the mucosal flaps, possibly contributes to a high closure rate and delivers a physiological result.

This article is protected by copyright. All rights reserved.



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“Best-Guess” MRAD Provides Robust Evidence for a Limit to Human Lifespan: Reply to de Grey (Rejuvenation Res. 2017;20:261–262)

Rejuvenation Research Oct 2017, Vol. 20, No. 5: 437-440.


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Epigenetic Drift Is a Determinant of Mammalian Lifespan

Rejuvenation Research Oct 2017, Vol. 20, No. 5: 430-436.


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Effect of Laser Etching on Glass Fiber Posts Cemented with Different Adhesive Systems

Photomedicine and Laser Surgery , Vol. 0, No. 0.


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Photobiomodulation Therapy Alleviates Tissue Fibroses Associated with Chronic Graft-Versus-Host Disease: Two Case Reports and Putative Anti-Fibrotic Roles of TGF-β

Photomedicine and Laser Surgery , Vol. 0, No. 0.


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Is There a Need for Scientific Education in the Aging Field?

Rejuvenation Research Oct 2017, Vol. 20, No. 5: 365-366.


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Response to Milholland et al. (Rejuvenation Res. 2017;20:437–440)

Rejuvenation Research Oct 2017, Vol. 20, No. 5: 440-441.


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Paul McCartney pushes for release of greyhounds from a dog blood farm

Paul McCartney is on a mission: after a PETA US expos revealed that 150 or so greyhounds were suffering in squalor at a Texas outfit called The Pet Blood Bank, Inc, the company that distributed its blood products pledged to support efforts to ensure the dogs' care. But less than a week later, the company reneged on the pledge, prompting McCartney to send a letter on PETA US' behalf calling on Patterson's billion-dollar parent company to step up and help rescue the dogs.



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Current Use of Baseline Medical Treatment in Chronic Rhinosinusitis: Data from the National Chronic Rhinosinusitis Epidemiology Study (CRES)

Abstract

Objectives

According to clinical and comissioning guidelines for chronic rhinosinusitis (CRS), patients being referred to secondary care should have failed primary medical treatment with nasal douching (ND) and intranasal corticosteroids (INCS). The study objectives were to identify the rate of specific medical therapy in CRS patients and establish any differences in medication use, for both CRS and associated medical conditions, between CRS phenotypes.

Design and setting

Case-control study in a secondary care setting.

Methods

Participant-reported study-specific questionnaire capturing free text data on current medication use at the time of study entry. Qualitative interviews with 21 participants also explored their experience of CRS and its management.

Particpants

Patients with both without (CRSsNPs) and with polyps (CRSwNPs).

Main outcome measures

Reported use of CRS-related and non-related medications.

Results

Within a total of 1243 CRS participants, current INCS usage was low (18% in CRSwNPs, 12% in CRSsNPs); ND was being performed by only 1% of all participants. Bronchodilators and inhaled corticosteroids use was significantly higher in CRSwNPs participants (p < 0.0001). Antidepressants use was significantly higher in CRSsNPs (14% versus 7%, p < 0.0002). There were no significant regional variations in rates of INCS use, nor any significant influence of social deprivation.

Conclusions

The current use of baseline medical therapy in CRS appears to be very low, representing a combination of poor patient compliance, possible ineffectiveness of treatment and a lack of familiarity with current guidelines amongst general practitioners and some ENT specialists. Work is needed to disseminate guidelines to all practitioners involved and reduce unnecessary burden on existing healthcare resources for this common condition by ensuring timely referral and definitive management.

This article is protected by copyright. All rights reserved.



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Levels of {alpha}- and {beta}-synuclein regulate cellular susceptibility to toxicity from {alpha}-synuclein oligomers [Research]

α-Synuclein (α-syn) is associated with a range of diseases, including Parkinson disease. In disease, α-syn is known to aggregate and has the potential to be neurotoxic. The association between copper and α-syn results in the formation of stellate toxic oligomers that are highly toxic to cultured neurons. We further investigated the mechanism of toxicity of α-syn oligomers. Cells that overexpress α-syn showed increased susceptibility to the toxicity of the oligomers, while those that overexpressed β-syn showed increased resistance to the toxic oligomers. Elevated α-syn expression caused an increase in expression of the transcription factor Forkhead box O3a (FoxO3a). Inhibition of FoxO3a activity by the overexpression of DNA binding domain of FoxO3a resulted in significant protection from α-syn oligomer toxicity. Increased FoxO3a expression in cells was shown to be caused by increased ferrireductase activity and Fe(II) levels. These results suggest that α-syn increases FoxO3a expression as a result of its intrinsic ferrireductase activity. The results also suggest that FoxO3a plays a pivotal role in the toxicity of both Fe(II) and toxic α-syn species to neuronal cells.—Angelova, D. M., Jones, H. B. L., Brown, D. R. Levels of α- and β-synuclein regulate cellular susceptibility to toxicity from α-synuclein oligomers.



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H-ras deletion protects against angiotensin II-induced arterial hypertension and cardiac remodeling through protein kinase G-I{beta} pathway activation [Research]

Ras proteins regulate cell survival, growth, differentiation, blood pressure, and fibrosis in some organs. We have demonstrated that H-ras gene deletion produces mice hypotension via a soluble guanylate cyclase-protein kinase G (PKG)–dependent mechanism. In this study, we analyzed the consequences of H-ras deletion on cardiac remodeling induced by continuous angiotensin II (AngII) infusion and the molecular mechanisms implied. Left ventricular posterior wall thickness and mass and cardiomyocyte cross-sectional area were similar between AngII-treated H-Ras knockout (H-ras–/–) and control wild-type (H-ras+/+) mice, as were extracellular matrix protein expression. Increased cardiac PKG-Iβ protein expression in H-ras–/– mice suggests the involvement of this protein in heart protection. Ex vivo experiments on cardiac explants could support this mechanism, as PKG blockade blunted protection against AngII-induced cardiac hypertrophy and fibrosis markers in H-ras–/– mice. Genetic modulation studies in cardiomyocytes and cardiac and embryonic fibroblasts revealed that the lack of H-Ras down-regulates the B-RAF/MEK/ERK pathway, which induces the glycogen synthase kinase-3β-dependent activation of the transcription factor, cAMP response element-binding protein, which is responsible for PKG-Iβ overexpression in H-ras–/– mouse embryonic fibroblasts. This study demonstrates that H-ras deletion protects against AngII-induced cardiac remodeling, possibly via a mechanism in which PKG-Iβ overexpression could play a partial role, and points to H-Ras and/or downstream proteins as potential therapeutic targets in cardiovascular disease.—Martín-Sánchez, P., Luengo, A., Griera, M., Orea, M. J., López-Olañeta, M., Chiloeches, A., Lara-Pezzi, E., de Frutos, S., Rodríguez-Puyol, M., Calleros, L., Rodríguez-Puyol, D. H-ras deletion protects against angiotensin II–induced arterial hypertension and cardiac remodeling through protein kinase G-Iβ pathway activation.



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Strategic Directions in Immunoresponsive Biomaterials in Tissue Engineering

Tissue Engineering Part A Oct 2017, Vol. 23, No. 19-20: 1042-1043.


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Bioengineered Submucosal Organoids for In Vitro Modeling of Colorectal Cancer

Tissue Engineering Part A Oct 2017, Vol. 23, No. 19-20: 1026-1041.


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Diagnostic relevance of IgE sensitization profiles to eight recombinant Phleum pratense molecules

Abstract

Background

Grass pollen–related seasonal allergic rhinoconjunctivitis (SARg) is clinically heterogeneous in severity, comorbidities and response to treatment. The component-resolved diagnostics disclosed also a high heterogeneity at molecular level. Our study aimed at analyzing the characteristics of the IgE sensitization to Phleum pratense molecules and investigating the diagnostic relevance of such molecules in childhood.

Methods

We examined 1120 children (age 4–18y) with SARg. Standardized questionnaires on atopy were acquired through informatics platform (AllergyCARD). Skin prick tests were performed with pollen extracts. Serum IgE to airborne allergens and eight Phleum pratense molecules (rPhl p 1, rPhl p 2, rPhl p 4, rPhl p 5b, rPhl p 6, rPhl p 7, rPhl p 11, rPhl p 12) were tested by ImmunoCAP FEIA.

Results

The analysis of IgE responses against eight Phleum pratense molecules showed 87profiles. According to the number of molecules recognized by IgE, the more complex profiles were characterized by higher serum total IgE, higher grass-specific serum IgE and higher number and degree of sensitization to pollens. The most frequent IgE sensitization profile was the monomolecular Phl p 1. Sensitization to Phl p 7 was a reliable biomarker of asthma, whereas Phl p 12 of oral allergy syndrome. Sensitization to Phl p 7 was associated with a higher severity of SAR, and complex profiles were associated with longer disease duration.

Conclusions

In a large pediatric population, the complexity of IgE sensitization profiles against Phleum pratense molecules is related to high atopic features although useless for predicting the clinical severity. The detection of serum IgE to Phl p 1, Phl p 7 and Phl p 12 can be used as clinical biomarkers of SARg and comorbidities. Further studies in different areas are required to test the impact of different IgE molecular profiles on AIT response.

This article is protected by copyright. All rights reserved.



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Effect of V –Y plasty on lip lengthening and treatment of gummy smile

The aim of this study was to assess the effect of isolated V –Y plasty on lip lengthening and the treatment of gummy smile. An isolated V–Y plasty was performed on 14 patients with a gummy smile. In each case, measurements of upper lip length and gingival display were recorded from posed-smile photographs taken preoperatively and at 1, 3, and 6 months pos toperatively. Gingival display decreased significantly and lip length increased significantly over all intervals investigated. Applying this technique after Le Fort I surgery may be beneficial; however, as with other injection or surgical lip lengthening methods, its stand-alone application should b e questioned. (Source: International Journal of Oral and Maxillofacial Surgery)

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Ability of polymer-bound P-glycoprotein inhibitor ritonavir to overcome multidrug resistance in various resistant neuroblastoma cell lines

imagePolymer prodrugs can considerably improve the treatment of tumors with multidrug resistance, often caused by overexpression of P-glycoprotein (P-gp). Here, we present the effect of the N-(2-hydroxypropyl) methacrylamide-based polymer conjugate with P-gp inhibitor ritonavir (RIT) on the increase of free doxorubicin (DOX) and polymer-bound DOX cytotoxicity in the human neuroblastoma 4 cell line and its resistant clones to different cytostatics. The increase in cytotoxicity after polymer–RIT conjugate pretreatment was higher for the lines overexpressing P-gp and less pronounced for those with decreased P-gp levels. Moreover, the effect of polymer conjugate containing inhibitor and DOX on the same polymer chain was lower than that of two individual polymer conjugates used sequentially. In conclusion, the polymer–RIT conjugate can significantly increase the cytotoxicity of free DOX and polymer–DOX conjugates in cells with various multidrug resistance origins and can thus be considered a suitable therapeutic enhancer of polymer prodrugs.

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A noninterventional, multicenter, prospective phase IV study of trabectedin in patients with advanced soft tissue sarcoma

imageThis prospective, noninterventional study is the first phase IV trial designed to evaluate trabectedin in patients with advanced soft tissue sarcoma in real-life clinical practice across Europe. To be included in the study, patients must have received more than or equal to one cycle of trabectedin and be currently on treatment. The primary endpoint was progression-free survival as defined by investigators. The secondary endpoints included objective response rate, disease control rate, time to progression and the growth modulation index (GMI), overall survival, and an assessment of the cancer-related symptoms and safety. A total of 218 patients from 41 European centers were evaluated. Patients received a median of six cycles per patient, mostly on an outpatient basis (n=132; 60.6%). The median progression-free survival was 5.9 months, with 70 and 49% of patients free from progression at 3 and 6 months after treatment, respectively. Three (1.4%) patients achieved a complete response and 55 (25.2%) patients achieved a partial response for an objective response rate of 26.6%. A total of 85 (39.0%) patients had disease stabilization for a disease control rate of 65.6%. The median GMI was 0.8, with 5.1 and 38.8% of patients with a GMI of greater than 1.1 to less than 1.33 and greater than or equal to 1.33, respectively. The median overall survival was 21.3 months. Febrile neutropenia (2.3% of patients), neutropenia, nausea, and pneumonia (1.4% each) were the most common trabectedin-related grade 3/4 serious adverse drug reactions. Trabectedin confers clinically meaningful long-term benefits to patients with multiple soft tissue sarcoma histotypes, being either comparable or better than those observed previously in clinical trials, and with a manageable safety profile.

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Two faces of Hippo: activate or suppress the Hippo pathway in cancer

imageThe Hippo pathway has generated considerable interest in recent years because of its involvement in several key hallmarks of cancer progression and metastasis. Research on the Hippo signaling pathway in cancer has been used to determine the activity of yes-associated protein (YAP) in tumorigenesis and disease progression. Previous studies have shown that the Hippo pathway can be used as a target to inhibit YAP activity and is a viable treatment for cancer. However, more studies are required to further advance our understanding of the Hippo signaling pathway in cancer. It has been shown that knockout of serine/threonine-kinases LATS1/2 in the Hippo pathway suppresses cancer immunity in mice. In addition, suppression of the oncogene YAP could contribute toward cancer immune therapy. Therefore, regulation of Hippo signaling can be an attractive alternative strategy for cancer treatment. This review will provide a summary of currently known compounds that activate or suppress the Hippo pathway.

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Bcl-2 and Bcl-xL mediate resistance to receptor tyrosine kinase-targeted therapy in lung and gastric cancer

imagePromising clinical efficacy has been observed with receptor tyrosine kinase inhibitors (TKIs) particularly in lung and gastric cancers with mutations or amplifications in the targeted receptor tyrosine kinases (RTKs). However, the efficacy and the duration of the response to these inhibitors are limited by the emergence of drug resistance. Here, we report treatment of RTK-dependent lung and gastric cancer cell lines with TKIs increased protein levels of Bcl-2 and Bcl-xL. The combination of the Bcl-2 and Bcl-xL inhibitor ABT-263 and TKIs was superior to TKIs alone in reducing cell viability and capacity of resistant colony formation. Furthermore, resistant cells established with exposure of RTK-dependent cells to increasing concentrations of TKIs also express higher levels of Bcl-2 or Bcl-xL compared with their parental cells. The combination of inhibitors of PI3K/AKT, MEK/ERK, and Bcl-2/Bcl-xL effectively reduced the viability of resistant cells and inhibited tumor size in a xenograft model derived from resistant cells by inducing apoptosis. Our results define a generalizable resistance mechanism to TKIs and rationalize inhibition of Bcl-2 and Bcl-xL as a strategy to augment responses and blunt acquired resistance to TKIs in lung and gastric cancer.

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Extended topoisomerase 1 inhibition through liposomal irinotecan results in improved efficacy over topotecan and irinotecan in models of small-cell lung cancer

imageLiposomal irinotecan (irinotecan liposome injection, nal-IRI), a liposomal formulation of irinotecan, is designed for extended circulation relative to irinotecan and for exploiting discontinuous tumor vasculature for enhanced drug delivery to tumors. Following tumor deposition, nal-IRI is taken up by phagocytic cells followed by irinotecan release and conversion to its active metabolite, SN-38. Sustained inhibition of topoisomerase 1 by extended SN-38 exposure as a result of delivery by nal-IRI is hypothesized to enable superior antitumor activity compared with traditional topoisomerase 1 inhibitors such as conventional irinotecan and topotecan. We evaluated the antitumor activity of nal-IRI compared with irinotecan and topotecan in preclinical models of small-cell lung cancer (SCLC) including in a model pretreated with carboplatin and etoposide, a first-line regimen used in SCLC. Nal-IRI demonstrated antitumor activity in xenograft models of SCLC at clinically relevant dose levels, and resulted in complete or partial responses in DMS-53, DMS-114, and NCI-H1048 cell line-derived models as well as in three patient-derived xenograft models. The antitumor activity of nal-IRI was superior to that of topotecan in all models tested, which generally exhibited limited control of tumor growth and was superior to irinotecan in four out of five models. Further, nal-IRI demonstrated antitumor activity in tumors that progressed following treatment with topotecan or irinotecan, and demonstrated significantly greater antitumor activity than both topotecan and irinotecan in NCI-H1048 tumors that had progressed on previous carboplatin plus etoposide treatment. These results support the clinical development of nal-IRI in patients with SCLC.

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miR-449a: a potential therapeutic agent for cancer

imageMicroRNAs (miRNAs) have been reported to be associated with cancer progression and carcinogenesis. They are small, highly conserved, noncoding RNA molecules consisting of 19–25 nucleotides. By binding to complementary binding sites within the 3′-untranslated region of target mRNAs, miRNAs inhibit the translation of mRNAs or promote their degradation. miRNAs play critical roles in cancer initiation and development by functioning either as oncogenes or as tumor suppressors. Similarly, several studies have shown that miRNAs are involved in regulating various biological processes, including apoptosis, proliferation, cellular differentiation, signal transduction, and carcinogenesis. Among miRNAs, one that may be of particular interest in cancer biology is miR-449a, which has been reported to inhibit tumor growth, invasion, and metastasis, and to promote apoptosis and differentiation through the transforming growth factor-β activated kinase 1, NOTCH, nuclear factor-κB/P65/vascular endothelial growth factor, retinoblastoma-E2F, mitogen-activated protein kinase signaling pathways, WNT–β-catenin signaling, tumor protein P53, and androgen receptor signaling pathways. The miR-449 cluster is located in the second intron of CDC20B on chromosome 5q11.2, a region that has been identified as a susceptibility locus in cancer, and the abnormal expression of miR-449a may be related to the occurrence and development of tumors. As one example, miR-449a has been reported to be involved in the development of carcinoma and may be a potential prognostic indicator. On the basis of the putative pathogenetic relationships between cancer and miR-449a, we consider that miR-449a has the potential to serve as a therapeutic agent for the treatment of some types of cancer. In this review, the role of miR-449a in tumorigenesis and its mechanism of action are explored. Furthermore, its potential as a therapeutic agent in cancer treatment is considered.

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N1-guanyl-1,7-diaminoheptane enhances the chemosensitivity of acute lymphoblastic leukemia cells to vincristine through inhibition of eif5a-2 activation

imageN1-guanyl-1,7-diaminoheptane (GC7), a deoxyhypusine synthase inhibitor, has been shown to exert antiproliferation effects in many solid tumors by regulating eukaryotic translation initiation factor 5a2 (eif5a-2). However, little is known about the role of GC7 and eif5a-2 in drug resistance in acute lymphoblastic leukemia (ALL). In the present study, we investigated the effect of GC7 on drug-resistant ALL and its potential mechanism. We found that using the CCK-8 assay that combined treatment with GC7 and vincristine (VCR) significantly inhibited the cell viability of two ALL cell lines. Using EdU incorporation assays and flow cytometry, we also showed that GC7 could markedly enhance the VCR sensitivity of ALL cells by suppressing cell proliferation and promoting apoptosis. Furthermore, we showed that GC7 could downregulate eif5a-2 and myeloid cell leukemia-1 (Mcl-1) expression. Knockdown of eif5a-2 inhibited the expression of Mcl-1 and significantly enhanced the VCR sensitivity. Moreover, eif5a-2 knockdown decreased the regulatory role of GC7 in increasing VCR sensitivity. Thus, our findings indicate that combined treatment with GC7 could enhance VCR sensitivity of ALL cells by regulating the eif5a-2/Mcl-1 axis. Together, our results highlight the potential clinical application of GC7 in VCR-based chemotherapy for the treatment of ALL.

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A novel hydroxyphenyl hydrazone derivate YCL0426 inhibits cancer cell proliferation through sequestering iron

imageCancer cells have an increased requirement for iron than normal cells, and iron chelators are under active consideration for cancer treatment. The metal-sequestering potential and antiproliferative mechanisms of a novel hydroxyphenyl hydrazone derivate YCL0426 were investigated here. Antiproliferative activity of YCL0426 was detected by MTT assay. The iron-sequestering potential was evaluated by ferrozine–Fe(II) sequestering assay and Fe(II) titration assay. Cell-cycle-arresting profile was checked by flow cytometry and the DNA synthesis status was evaluated by BrdU incorporation assay. SW480 cells stably expressing Rad51-EGFP fusion protein were used to evaluate the DNA damaging potential of the compound. The impact of extra Fe(II) supplement on compound activities was also examined. YCL0426 shows significant antiproliferative activity on 15 cancer cell lines with mean IC50 values of 5.25 μmol/l. YCL0426 displayed concentration-dependent Fe(II) sequestering ability in ferrozine–Fe(II) sequestering assay, and induced upregulation of transferrin receptor 1 and divalent metal transporter 1 expression in HepG2 cells, which are genes responsible for Fe(II) uptake. YCL0426 blocked DNA synthesis in BrdU incorporation assay, and arrested cell cycle at S or G1 phase. Besides, YCL0426 induced Rad51 foci formation and histone H2AX phosphorylation with EC50 values of 1.35 and 2.29 μmol/l, respectively, indicating the emergence of DNA damage. All these cellular responses, and even the growth-inhibiting activity of YCL0426, can be readily reversed by Fe(II) repletion, indicating that iron sequestering is responsible, at least in part, for the antiproliferative activity of YCL0426. YCL0426 is a potent iron chelator that exerts significant antiproliferative activities by inducing G1/S arrest and DNA damage.

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Anticancer drugs and the regulation of Hedgehog genes GLI1 and PTCH1, a comparative study in nonmelanoma skin cancer cell lines

imageNonmelanoma skin cancer is the most common cancer in humans, comprising mainly basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). BCC proliferation is highly dependent on the Hedgehog signaling pathway. We aimed to investigate a panel of anticancer drugs with known activity against skin cancer for their therapeutic potential in localized, enhanced topical treatment of SCC and BCC. Cytotoxicity profiles for vismodegib, 5-fluorouracil (5-FU), methotrexate (MTX), cisplatin, bleomycin, and vorinostat were established in terms of half maximal inhibitory concentration values in a panel of immortalized keratinocytes (HaCaT), BCC (UWBCC1 and BCC77015), and SCC (A431 and SCC25) cell lines. The impact of treatment on the regulation of Hedgehog pathway target genes (GLI1 and PTCH1), measured by real-time PCR, was compared between UWBCC1 and HaCaT. Varying cell line sensitivity profiles to the examined anticancer drugs were observed. Generally, 24-h drug exposure was sufficient to reduce cell viability. We found that 5-FU, MTX, and cisplatin significantly downregulated the expression of two genes controlled by the Hedgehog pathway (≤25-, 2.9-, and 12.5-fold, respectively, for GLI1 in UWBCC1 cells at 48 h, P

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Gallic acid induces G1 phase arrest and apoptosis of triple-negative breast cancer cell MDA-MB-231 via p38 mitogen-activated protein kinase/p21/p27 axis

imageGallic acid (GA) possesses potential antitumoral activity on different types of malignancies. In this study, we aimed to explore the antitumoral effects of GA on triple-negative breast cancer (TNBC) cells, the breast cancer cells showing resistance to hormonal therapy or HER2 receptor targeting therapy. We observed that GA treatment significantly decreased the cell viability of human TNBC cell line MDA-MB-231 and HS578T in a dose-dependent manner. In addition, GA exerted a relative lower cytotoxicity on noncancer breast fibroblast MCF-10F. Next, we analyzed the changes of cell-cycle distribution in response to GA treatment and found that GA led to an increase of G0/G1 and sub-G1 phase ratio in MDA-MB-231 cells. We further explored the crucial mediators controlling cell cycle and inducing apoptotic signaling, and the findings showed that GA downregulated cyclin D1/CDK4 and cyclin E/CDK2, upregulated p21Cip1and p27Kip1, and induced activation of caspase-9 and caspase-3. In addition, we demonstrated that p38 mitogen-activated protein kinase was involved in the GA-mediated cell-cycle arrest and apoptosis. Collectively, our findings indicate that GA inhibits the cell viability of TNBC cells, which may attribute to the G1 phase arrest and cellular apoptosis via p38 mitogen-activated protein kinase/p21/p27 axis. Thus, we suggest that GA could be beneficial to TNBC treatment.

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Rhabdomyosarcoma cells are susceptible to cell death by LDK378 alone or in combination with sorafenib independently of anaplastic lymphoma kinase status

imageAnaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is often overexpressed in rhabdomyosarcoma (RMS). However, its oncogenic and functional role in RMS remains unclear. Therefore, we investigated the antitumor activity of LDK378 (ceritinib), a new second-generation ALK inhibitor approved for patients with ALK-positive non-small-cell lung cancers. Here, we report that LDK378 reduces cell viability and induces cell death in RMS cell lines at low micromolar IC50 concentrations irrespective of ALK expression levels or phosphorylation status. Compared with Karpas 299 non-Hodgkin's lymphoma cells carrying the NPM–ALK fusion gene, RMS cell lines proved to be far less sensitive to LDK378. The broad-range caspase inhibitor zVAD.fmk significantly protects RMS cells from LDK378-mediated cell death, indicating that LDK378 induces caspase-dependent apoptotic cell death. Before the onset of apoptosis, LDK378 reduces phosphorylation of AKT, S6 ribosomal protein, STAT3 and – to a lesser extent – phosphorylation of ERK, showing that it suppresses key survival pathways. Importantly, we identify a synergistic induction of cell death by combining subtoxic concentrations of LDK378 with the multitargeting kinase inhibitor sorafenib. Calculation of the combination index confirmed that this interaction is synergistic. Also, LDK378 cooperates with sorafenib to significantly reduce colony formation of RMS cells, showing that this combination affects long-term clonogenic growth. In conclusion, LDK378 induces caspase-dependent apoptotic cell death in RMS cells independent of their ALK status and synergizes at subtoxic concentrations with sorafenib to induce cell death. These findings have important implications for the use of LDK378 in RMS.

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Early tumor shrinkage indicates a favorable response to bevacizumab-based first-line chemotherapy for metastatic colorectal cancer

imageA close correlation between early tumor shrinkage (ETS) and overall survival (OS) has been shown in antiepidermal growth factor receptor antibody-based chemotherapies for metastatic colorectal cancer (mCRC), but the clinical impact of ETS in bevacizumab-based chemotherapy has not been adequately clarified. Clinical data of mCRC patients who started initial chemotherapy without antiepidermal growth factor receptor antibody from 2005 to 2010 were retrospectively evaluated. The relative change in tumor size after 8 weeks of chemotherapy expected from the first image assessment [estimated ETS (EETS)] and the relative change in the tumor size at the nadir compared with the baseline [depth of response (DPR)] were examined. Seventy-three patients were enrolled and 61 patients were evaluable for survival by simple regression analysis. Bevacizumab-based chemotherapies were administered to 40 (66%) patients. The median EETS, DPR, progression-free survival, and OS were 16.1%, 27.2%, 8.0 months, and 19.5 months, respectively. Progression-free survival showed a positive correlation with OS (R2=0.429), whereas EETS and DPR were less correlated with OS (R2=0.0682, 0.186). EETS was well correlated with DPR (R2=0.659). Patients with EETS greater than 16.12% were predicted to achieve tumor shrinkage of more than 30% at the maximum response. EETS in bevacizumab-treated mCRC showed a close correlation with DPR, which suggested that EETS might be useful, indicating a favorable response in treatment with bevacizumab-based chemotherapy.

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IJERPH, Vol. 14, Pages 1255: Direct Effects of the Home, School, and Consumer Food Environments on the Association between Food Purchasing Patterns and Dietary Intake among Rural Adolescents in Kentucky and North Carolina, 2017

IJERPH, Vol. 14, Pages 1255: Direct Effects of the Home, School, and Consumer Food Environments on the Association between Food Purchasing Patterns and Dietary Intake among Rural Adolescents in Kentucky and North Carolina, 2017

International Journal of Environmental Research and Public Health doi: 10.3390/ijerph14101255

Authors: Alison Gustafson Stephanie Jilcott Pitts Jordan McDonald Hannah Ford Paige Connelly Rachel Gillespie Emily Liu Heather Bush Candace Brancato Toyin Babatande Janet Mullins

Background: Obesity rates are higher among rural versus urban adolescents. To examine possible mechanisms for the rural-urban adolescent obesity disparity, we examined the direct and indirect effects of food purchasing patterns, and the home, school, and consumer food environments on dietary intake among rural adolescents. Methods: A baseline survey was conducted among adolescents in eight rural high schools (four in Eastern Kentucky, and four in Eastern North Carolina). Participants answered questions about food purchasing patterns, dietary intake, home food availability, and demographics. The school and consumer food environments were assessed using validated measures from the School Meals Cost Study (United States Department of Agriculture-Mathematica) and the Nutrition Environment Measurement Survey for Stores, Restaurants, and Corner Stores. Results: Of 432 adolescents, 55% were normal weight, 24% were overweight, and 21% were obese. There was a direct association between unhealthy food purchasing patterns (shopping frequently at gas stations, fast food, and dollar stores) and consuming more added sugars, when compared to those with a healthy shopping pattern (shopping less frequently at gas stations, fast food, and dollar stores) [Odds Ratio = 2.41 (95% CI (confidence interval) 0.99, 3.82)]. Those who reported always having fruits and vegetables in the home consumed more servings of fruits and vegetables [OR = 0.31 cups (95% CI 0.22, 0.44)] compared to those who reported never having fruits and vegetables in the home. Adolescents attending a school with a low healthy food availability score consumed fewer servings of fruits and vegetables [−0.001 (95% CI −0.001, 0.0001)] compared to those attending a school with a high healthy food availability score. Conclusions: There are direct associations between food purchasing patterns, the home and school food environments, and dietary intake among rural adolescents. These cross-sectional results informed the development of the "Go Big and Bring it Home" program, a text messaging intervention to improve adolescents' fruit, vegetable, and healthy beverage intake.



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IJMS, Vol. 18, Pages 2196: Towards Better Understanding of Pea Seed Dormancy Using Laser Desorption/Ionization Mass Spectrometry

IJMS, Vol. 18, Pages 2196: Towards Better Understanding of Pea Seed Dormancy Using Laser Desorption/Ionization Mass Spectrometry

International Journal of Molecular Sciences doi: 10.3390/ijms18102196

Authors: Monika Cechová Markéta Válková Iveta Hradilová Anna Janská Aleš Soukup Petr Smýkal Petr Bednář

Seed coats of six pea genotypes contrasting in dormancy were studied by laser desorption/ionization mass spectrometry (LDI-MS). Multivariate statistical analysis discriminated dormant and non-dormant seeds in mature dry state. Separation between dormant and non-dormant types was observed despite important markers of particular dormant genotypes differ from each other. Normalized signals of long-chain hydroxylated fatty acids (HLFA) in dormant JI64 genotype seed coats were significantly higher than in other genotypes. These compounds seem to be important markers likely influencing JI64 seed imbibition and germination. HLFA importance was supported by study of recombinant inbred lines (JI64xJI92) contrasting in dormancy but similar in other seed properties. Furthemore HLFA distribution in seed coat was studied by mass spectrometry imaging. HLFA contents in strophiole and hilum are significantly lower compared to other parts indicating their role in water uptake. Results from LDI-MS experiments are useful in understanding (physical) dormancy (first phases of germination) mechanism and properties related to food processing technologies (e.g., seed treatment by cooking).



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IJMS, Vol. 18, Pages 2198: The Roles of Matricellular Proteins in Oncogenic Virus-Induced Cancers and Their Potential Utilities as Therapeutic Targets

IJMS, Vol. 18, Pages 2198: The Roles of Matricellular Proteins in Oncogenic Virus-Induced Cancers and Their Potential Utilities as Therapeutic Targets

International Journal of Molecular Sciences doi: 10.3390/ijms18102198

Authors: Naoyoshi Maeda Katsumi Maenaka

Matricellular proteins differ from other classical extracellular matrix proteins; for instance, they are transiently expressed as soluble proteins rather than being constitutively expressed in pathological conditions, such as acute viral infections. Accumulating studies have revealed that matricellular proteins, including osteopontin and tenascin-C, both of which interact with integrin heterodimers, are involved in inflammatory diseases, autoimmune disorders, and cancers. The concentrations of these matricellular proteins are elevated in the plasma of patients with certain types of cancers, indicating that they play important roles in oncogenesis. Chronic viral infections are associated with certain cancers, which are distinct from non-viral cancers. Viral oncogenes play critical roles in the development and progression of such cancers. It is vital to investigate the mechanisms of tumorigenesis and, particularly, the mechanism by which viral proteins induce tumor progression. Viral proteins have been shown to influence not only the viral-infected cancer cells, but also the stromal cells and matricellular proteins that constitute the extracellular matrix that surrounds tumor tissues. In this review, we summarize the recent progress on the involvement of matricellular proteins in oncogenic virus-induced cancers to elucidate the mechanism of oncogenesis and consider the possible role of matricellular proteins as therapeutic targets in virus-induced cancers.



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[18F]fluorothymidine positron emission tomography informs the synergistic efficacy of capecitabine and trifluridine/tipiracil in colon cancer

In cancer therapy, enhanced thymidine uptake by the salvage pathway can bypass dTMP depletion, thereby conferring resistance to thymidylate synthase inhibition. We investigated whether sequential combination therapy of capecitabine and trifluridine/tipiracil (TAS-102) could synergistically enhance antitumor efficacy in colon cancer xenograft models. We also examined 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) positron emission tomography (PET) as a means to predict therapeutic response to a sequential combination of capecitabine and trifluridine/tipiracil. [3H]FLT uptake after 5-fluorouracil treatment in vitro and [18F]FLT uptake after capecitabine (360 mg/kg/day) in athymic nude mice (Balb/c-nu) with xenografts (n = 10-12 per group) were measured using eight human colon cancer cell lines. We determined the synergistic effects of sequential combinations of 5-fluorouracil and trifluridine in vitro as well as the sequential combination of oral capecitabine (30-360 mg/kg) and trifluridine/tipiracil (trifluridine 75 or 150 mg/kg with tipiracil) in six xenograft models (n = 6-10 per group). We observed significant increases in [3H]FLT uptake in all cell lines and [18F]FLT uptake in five xenograft models after 5-fluorouracil and capecitabine treatment, respectively. Increased [18F]FLT uptake after capecitabine followed by extinction of uptake correlated strongly with tumor growth inhibition (ρ = −0.81, P = 0.02). The effects of these combinations were synergistic in vitro. A synergy for sequential capecitabine and trifluridine/tipiracil was found only in mouse xenograft models showing increased [18F]FLT uptake after capecitabine. Our results suggest that the sequential combination of capecitabine and trifluridine/tipiracil is synergistic in tumors with an activated salvage pathway after capecitabine treatment in mice, and [18F]FLT PET imaging may predict the response to capecitabine and the synergistic antitumor efficacy of a sequential combination of capecitabine and trifluridine/tipiracil.

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Subtype-specific cancer-associated fibroblasts contribute to the pathogenesis of uterine leiomyoma.

Recent genomic studies have identified subtypes of uterine leiomyoma (LM) with distinctive genetic alterations. Here we report the elucidation of the biological characteristics of the two most prevalent LM subtypes, MED12 mutant (MED12-LM) and HMGA2-overexpressing (HMGA2-LM) LM. Since each tumor carries only one genetic alteration, both subtypes are considered to be monoclonal. Approximately 90% of cells in HMGA2-LM were smooth muscle cells (SMC) with HMGA2 overexpression. In contrast, MED12-LM consisted of similar numbers of SMC and non-SMC, which were mostly tumor-associated fibroblasts (TAF). Paradoxically, TAF carried no mutations in MED12, suggesting an interaction between SMC and TAF to coordinate their growth. The higher amount of ECM in MED12-LM than HMGA2-LM was partially due to the high concentration of collagen-producing TAF. SMC growth in a xenograft assay was driven by progesterone in both LM subtypes. In contrast, TAF in MED12-LM proliferated in response to estradiol, whereas progesterone had no effect. The high concentration of estrogen-responsive TAF in MED12-LM explains the inconsistent discoveries between in vivo and in vitro studies on the mitogenic effect of estrogen and raises questions regarding the accuracy of previous studies utilizing MED12-LM cell culture. In addition, the differential effects of estradiol and progesterone on these LM subtypes emphasize the importance of subtypes and genotypes in designing non-surgical therapeutic strategies for LM.

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RUNX1 upregulation by cytotoxic drugs promotes apoptosis

Mutations in the RUNX1 gene have been associated with chemotherapy resistance and poor prognosis in patients with acute myeloid leukemia (AML), T cell acute lymphoblastic leukemia (T-ALL) and myelodysplastic syndromes (MDS). However, the underlying mechanisms connecting RUNX1 to the success of therapy remain elusive. Here we explore the hypothesis that RUNX1 is directly involved in the response of hematopoietic cells to cytotoxic agents. RUNX1 was upregulated post-transcriptionally by cytotoxic agents in C57BL/6 mice in vivo and hematopoietic cell lines. Upregulation was also seen in primary human AML cells after treatment with cytarabine in vitro. Upon overexpression, RUNX1 restricted proliferation, promoted apoptosis, and augmented the DNA damage response. This unknown activity of RUNX1 required an intact runt homology domain (RHD), a domain where most leukemia-associated point mutations cluster. Consistent with this, two RHD-defective RUNX1 proteins lacked any anti-proliferative or apoptotic activity, and RHD-defective (K83N, N109D) mutant RUNX1 conferred resistance to ionizing radiation when overexpressed in Ba/F3 cells under certain conditions. Our experiments reveal a novel function of RUNX1 and offer an explanation for the link between RUNX1 mutations and chemotherapy and radiation resistance. Moreover, these data suggest that pharmacological modulation of RUNX1 might be an attractive new approach to treat hematological malignancies.

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New generation nanomedicines constructed from self-assembling small molecule prodrugs alleviate cancer drug toxicity

The therapeutic index for chemotherapeutic drugs is determined in part by systemic toxicity, so strategies for dose intensification to improve efficacy must also address tolerability. In addressing this issue, we have investigated a novel combinatorial strategy of reconstructing a drug molecule and using sequential drug-induced nanoassembly to fabricate supramolecular nanomedicines (SNM). Using cabazitaxel (CTX) as a target agent, we established that individual synthetic prodrugs tethered with polyunsaturated fatty acids were capable of recapitulating self-assembly behavior independent of exogenous excipients. The resulting SNM could be further refined by PEGylation with amphiphilic copolymers suitable for preclinical studies. Among these CTX derivatives, docosahexaenoic acid-derived compound 1 retained high anti-proliferative activity. SNM assembled with compound 1 displayed an unexpected enhancement of tolerability in animals along with effective therapeutic efficacy in a mouse xenograft model of human cancer, compared to free drug administered in its clinical formulation. Overall, our studies showed how attaching flexible lipid chains to a hydrophobic and highly toxic anticancer drug can convert it to a systemic self-deliverable nanotherapy, preserving its pharmacological efficacy while improving its safety profile.

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SGK1 is a critical component of an AKT-independent pathway essential for PI3K-mediated tumor development and maintenance

Activation of the PI3K-AKT signaling cascade is a common critical event during malignant transformation. In this study, we used thyroid gland epithelial cells and a series of genetically engineered mouse strains as model systems to demonstrate that, while necessary, AKT activation is not sufficient for PI3K-driven transformation. Instead, transformation requires the activity of the PDK1-regulated AGC family of protein kinases. In particular, SGK1 was found to be essential for proliferation and survival of thyroid cancer cells harboring PI3K-activating mutations. Notably, co-targeting SGK1 and AKT resulted in significantly higher growth suppression than inhibiting either PI3K or AKT alone. Overall, these findings underscore the clinical relevance of AKT-independent pathways in tumors driven by genetic lesions targeting the PI3K cascade.

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A synthetic CD8{alpha}:MyD88 co-receptor enhances CD8+ T cell responses to weakly immunogenic and lowly expressed tumor antigens

T cell-based immunotherapies are a promising approach for patients with advanced cancers. However, various obstacles limit T cell efficacy, including suboptimal T cell receptor (TCR) activation and an immunosuppressive tumor environment. Here we developed a fusion protein by linking CD8α and MyD88 (CD8α:MyD88) to enhance CD8+ T cell responses to weakly immunogenic and poorly expressed tumor antigens. CD8α:MyD88-engineered T cells exhibited increased proliferation and expression of effector and co-stimulatory molecules in a tumor antigen-dependent manner. These effects were accompanied by elevated activation of TCR and Toll-like receptor (TLR) signaling-related proteins. CD8α:MyD88-expressing T cells improved anti-tumor responses in mice. Enhanced anti-tumor activity was associated with a unique tumor cytokine/chemokine signature, improved T cell infiltration, reduced markers of T cell exhaustion, elevated levels of proteins associated with antigen presentation, and fewer macrophages with an immunosuppressive phenotype in tumors. Given these observations, CD8α:MyD88 represents a unique and versatile approach to help overcome immunosuppression and enhance T cell responses to tumor antigens.

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Protein acyltransferase DHHC3 regulates breast tumor growth, oxidative stress and senescence

DHHC-type protein acyltransferases may regulate the localization, stability and/or activity of their substrates. In this study, we show that the protein palmitoyltransferase DHHC3 is upregulated in malignant and metastatic human breast cancer. Elevated expression of DHHC3 correlated with diminished patient survival in breast cancer and six other human cancer types. ZDHHC3 ablation in human MDA-MB-231 mammary tumor cell xenografts reduced the sizes of both the primary tumor and metastatic lung colonies. Gene array data and fluorescence dye assays documented increased oxidative stress and senescence in ZDHHC3-ablated cells. ZDHHC3-ablated tumors also showed enhanced recruitment of innate immune cells (anti-tumor macrophages, natural killer cells) associated with clearance of senescent tumors. These anti-tumor effects were reversed upon reconstitution with wildtype, but not enzyme-active site-deficient DHHC3. Concomitant ablation of the upregulated oxidative stress protein TXNIP substantially negated the effects of ZDHHC3 depletion on oxidative stress and senescence. Diminished DHHC3-dependent palmitoylation of ERGIC3 protein likely played a key role in TXNIP upregulation. In conclusion, DHHC3-mediated protein palmitoylation supports breast tumor growth by modulating cellular oxidative stress and senescence.

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Small molecule inhibition of PD-1 transcription is an effective alternative to antibody blockade in cancer therapy

The impact of PD-1 immune checkpoint therapy prompts exploration of other strategies to downregulate PD-1 for cancer therapy. We previously showed that the serine/threonine kinase, glycogen synthase kinase GSK-3α/β, is a central regulator of PD-1 transcription in CD8+ T cells. Here, we show that the use of small molecule inhibitors of GSK-3α/β (GSK-3i) to reduce pcdc1 (PD-1) transcription and expression was as effective as anti-PD-1 and PDL-1 blocking antibodies in the control of B16 melanoma, or EL4 lymphoma, in primary tumor and metastatic settings. Further, the conditional genetic deletion of GSK-3α/β reduced PD-1 expression on CD8+ T cells, and limited B16 pulmonary metastasis to the same degree as PD-1 gene deficiency. In each model, GSK-3i inhibited PD-1 expression on tumor infiltrating lymphocytes (TILs), while increasing Tbx21 (T-bet) transcription, and the expression of CD107a+ (LAMP1) and granzyme B (GZMB) on CD8+ T-cells. Lastly, the adoptive transfer of T-cells treated ex vivo with a GSK-3 inhibitor delayed the onset of EL4 lymphoma growth to a similar extent as anti-PD-1 pre-treatment. Overall, our findings show how GSK-3 inhibitors that downregulate PD-1 expression can enhance CD8+ T-cell function in cancer therapy to a similar degree as PD-1 blocking antibodies.

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Polycomb group RING finger protein 3/5 activate transcription via an interaction with the pluripotency factor Tex10 in embryonic stem cells [Gene Regulation]

Polycomb group (PcG) proteins are epigenetic transcriptional repressors that orchestrate numerous developmental processes and have been implicated in the maintenance of embryonic stem (ES) cell state. More recent evidence suggests that a subset of PcG proteins engages in transcriptional activation in some cellular contexts. But how this property is exerted remains largely unknown. Here, we generated ES cells with single or combined disruption of Polycomb group RING finger protein 3 (Pcgf3) and Pcgf5 with the CRISPR-Cas9 technique. We report that although these mutant cells maintained their self-renewal and colony-forming capacity, they displayed severe defects in mesoderm differentiation in vitro and in vivo. Using RNA-Seq to analyze transcriptional profiles of ES cells with single or combined Pcgf3/5 deficiencies, we found that in contrast to the canonical role of the related polycomb repressive complex 1 (PRC1) in gene repression, Pcgf3/5 mainly function as transcriptional activators driving expression of many genes involved in mesoderm differentiation. Proteomic approaches and promoter occupancy analyses helped establish an extended Pcgf3/5 interactome and identified several novel Pcgf3/5 interactors. These included testis expressed 10 (Tex10), which may directly contribute to transcriptional activation via the transcriptional co-activator P300. Furthermore, Pcgf3/5 deletion in ES cells substantially reduced the occupancy of Tex10 and P300 at target genes. Finally, we demonstrated that Pcgf3/5 are essential for regulating global levels of the histone modifier H2AK119ub1 in ES cells. Our findings establish Pcgf3/5 as transcriptional activators that interact with Tex10 and P300 in ES cells and point to redundant activity of Pcgf3/5 in pluripotency maintenance.

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Mitogen and stress-activated protein kinase 1 is required for gonadotropin-releasing hormone-mediated activation of gonadotropin {alpha} subunit expression [Gene Regulation]

Pituitary gonadotropin hormones are regulated by gonadotropin-releasing hormone (GnRH) via MAPK signaling pathways which stimulate gene transcription of the common α-subunit (Cga) and the hormone-specific β-subunits of gonadotropin. We have reported previously that GnRH-induced activities at these genes include various histone modifications, but we did not examine histone phosphorylation. This modification adds a negative charge to residues of the histone tails that interact with the negatively charged DNA, is associated with closed chromatin during mitosis, but is increased at certain genes for transcriptional activation. Thus, the functions of this modification are unclear. We initially hypothesized that GnRH might induce phosphorylation of Ser-10 in histone 3 (H3S10p) as part of its regulation of gonadotropin gene expression, possibly involving cross-talk with H3K9 acetylation. We found that GnRH increases the levels of both modifications around the Cga gene transcriptional start site (TSS) and that JNK inhibition dramatically reduces H3S10p levels. However, this modification had only a minor effect on Cga expression and no effect on H3K9ac. GnRH also increased H3S28p and H3K27ac levels and also those of activated mitogen and stress-activated protein kinase 1 (MSK1). MSK1 inhibition dramatically reduced H3S28p levels in untreated and GnRH-treated cells and also affected H3K27ac levels. Although not affecting basal Cga expression, MSK1/2 inhibition prevented GnRH activation of Cga expression. Moreover, ChIP analysis revealed that GnRH-activated MSK1 targets the first nucleosome just downstream from the TSS. Given that the elongating RNA polymerase II (RNAPII) stalls at this well-positioned nucleosome, GnRH-induced H3S28p, possibly in association with H3K27ac, would facilitate the progression of RNAPII.

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The transcription factor MEF2A fine-tunes gene expression in the atrial and ventricular chambers of the adult heart [Developmental Biology]

The distinct morphological and functional properties of the cardiac chambers arise from an elaborate developmental program involving cell lineage determination, morphogenesis, and dynamic spatiotemporal gene expression patterns. While a number of transcription factors have been identified for proper gene regulation in the chambers, the complete transcriptional network that controls these patterns remains poorly defined. Previous studies have implicated the MEF2C transcription factor in the regulation of chamber-restricted enhancers. To better understand the mechanisms of MEF2-mediated regional gene regulation in the heart, we took advantage of MEF2A knockout (KO) mice, a model that displays a predominantly ventricular chamber phenotype. Transcriptomic analysis of atrial and ventricular tissue from adult MEF2A KO hearts revealed a striking difference in chamber gene expression, with a larger proportion of dysregulated genes in the atrial chambers. Canonical pathway analysis of genes preferentially dysregulated in the atria and ventricles revealed distinct MEF2A-dependent cellular processes in each cardiac chamber. In the atria, MEF2A regulated genes involved in fibrosis and adhesion, whereas in the ventricles, it controlled inflammation and endocytosis. Finally, analysis of transcription factor binding site motifs of differentially dysregulated genes uncovered distinct MEF2A coregulators for the atrial and ventricular gene sets, and a subset of these were found to cooperate with MEF2A. In conclusion, our results suggest a mechanism in which MEF2 transcriptional activity is differentially recruited to fine-tune gene expression levels in each cardiac chamber. This regulatory mechanism ensures optimal output of these gene products for proper physiological function of the atrial and ventricular chambers.

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The C-terminal region of A-kinase anchor protein 350 (AKAP350A) enables formation of microtubule-nucleation centers and interacts with pericentriolar proteins [Signal Transduction]

Microtubules in animal cells assemble (nucleate) from both the centrosome and the cis-Golgi cisternae. A-kinase anchoring protein 350 KDa (AKAP350A, also called AKAP450/CG-NAP/AKAP9) is a large scaffolding protein located at both the centrosome and Golgi apparatus. Previous findings have suggested that AKAP350 is important for microtubule dynamics at both locations, but how this scaffolding protein assembles microtubule nucleation machinery is unclear. Here, we found that overexpression of the C-terminal third of AKAP350A, EGFP-AKAP350A(2691-3907), induces the formation of multiple microtubule-nucleation centers (MTNCs). Nevertheless, these induced MTNCs lacked true centriole proteins, such as Cep135. Mapping analysis with AKAP350A truncations demonstrated that AKAP350A contains discrete regions responsible for promoting or inhibiting the formation of multiple MTNCs. Moreover, EGFP-AKAP350A(2691-3907) recruited several pericentriolar proteins to MTNCs, including gamma-tubulin, pericentrin, Cep68, Cep170, and Cdk5RAP2. Proteomic analysis indicated that Cdk5RAP2 and Cep170 both interact with the microtubule nucleation-promoting region of AKAP350A, while Cep68 interacts with the distal C-terminal AKAP350A region. Yeast 2-hybrid assays established a direct interaction of Cep170 with AKAP350A. Super-resolution and deconvolution microscopy analyses were performed to define the association of AKAP350A with centrosomes and these studies disclosed that AKAP350A spans the bridge between centrioles, co-localizing with rootletin and Cep68 in the linker region. siRNA-mediated depletion of AKAP350A caused displacement of both Cep68 and Cep170 from the centrosome. These results suggest that AKAP350A acts as a scaffold for factors involved in microtubule nucleation at the centrosome and coordinates the assembly of protein complexes associating with the intercentriolar bridge.

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The type II transmembrane serine protease matriptase cleaves the amyloid precursor protein and reduces its processing to {beta} amyloid [Enzymology]

Recent studies have reported that many proteases, besides the canonical α-, β- and γ-secretases, cleave the amyloid precursor protein (APP) and modulate β amyloid (Aβ) peptide production. Moreover, specific APP isoforms contain Kunitz protease inhibitor (KPI) domains, which regulate the proteolytic activity of serine proteases. This prompted us to investigate the role of matriptase, a member of the type II transmembrane serine protease family, in APP processing. Using qRTPCR, we detected matriptase mRNA in several regions of the human brain, with an enrichment in neurons. RNA-seq data of human dorsolateral prefontal cortex revealed relatively high levels of matriptase RNA in young individuals while lower levels were detected in older individuals. We further demonstrate that matriptase and APP directly interact with each other and that matriptase cleaves APP at a specific arginine residue (Arg-102) both in vitro and in cells. Site-directed (Argto-Ala) mutagenesis of this cleavage site abolished matriptase-mediated APP processing. Moreover, we observed that a soluble, shed matriptase form cleaves endogenous APP in SH-SY5Y cells and that this cleavage significantly reduces APP processing to Aβ40. In summary, this study identifies matriptase as an APP cleaving enzyme, an activity that could have important consequences for the abundance of Aβ and in Alzheimer's disease pathology.

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ATA Announces Recipients of 2017 Special Awards

American Thyroid Association's 2017 Van Meter Award Lecture Delivered by Megan R. Haymart, MD

The post ATA Announces Recipients of 2017 Special Awards appeared first on American Thyroid Association.



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American Thyroid Association’s 2017 Van Meter Award Lecture Delivered by Megan R. Haymart, MD

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American Thyroid Association's 2017 Van Meter Award Lecture Delivered by Megan R. Haymart, MD

The ATA announced the Van Meter Award recipient

 October 19, 2017—The American Thyroid Association (ATA) is pleased to announce that the 2017 Van Meter Award recipient is Megan R. Haymart, MD, Megan R. Haymart, MDAssistant Professor of Medicine at the University of Michigan, Ann Arbor. The Van Meter Award recognizes outstanding contributions to research on the thyroid gland or related subjects by an investigator who is age 45 or under. At the ATA annual meeting in Victoria, British Columbia, Dr. Haymart will deliver the Van Meter Lecture at 8:05 am on October 19, 2017. Her lecture is titled "Implications of Diagnosing  Low-Risk Thyroid Cancer." The award winner is kept secret until the time of the lecture.

Dr. Haymart received her MD from the Johns Hopkins University School of Medicine. She completed an internship in Internal Medicine at Johns Hopkins Hospital and a fellowship in Endocrinology, Diabetes, and Metabolism at the University of Wisconsin.

Since joining the ATA in 2007, Dr. Haymart has donated a great deal of time and enthusiasm to the ATA, serving on the Public Health Committee (2010−12) and the Finance and Audit Committee (2012−18), which she now chairs.  She participated in Strategic Planning for the ATA in 2012; and has attended every annual meeting since 2006.   She serves on the editorial boards of Thyroid and Journal of Clinical Endocrinology and Metabolism (JCEM) and is an associate editor of VideoEndocrinology.  She is currently a candidate for the ATA Board of Directors.  In addition, she is a member of the Endocrine Society's Annual Meeting Steering Committee.

In the eight years since she began her independent career at the University of Michigan, Dr. Haymart has earned a reputation as one of the national leaders in thyroid clinical research. She has recently secured two major research grants, one to study the role of patient and physician perceptions in treatment decision-making in thyroid cancer care, and the other to study incidental thyroid cancer discovery and strategies to minimize over-diagnosis and over-treatment. Both are critical issues for the field.

She has published many important papers in high-profile journals. Dr. Haymart's CV lists 46 peer-reviewed publications, of which she is the first author of 17. These papers offer important new insights into thyroid cancer care and identify directions for future health services research.

Dr. Haymart's expertise also is recognized by frequent invitations to speak at national conferences—including the 2009, 2013, and 2016 ATA annual meetings and the 2011 and 2016 Endocrine Society annual meetings—and to give presentations, such as those at the University of Wisconsin (2012, 2014), the Washington Hospital Center (2014), and Johns Hopkins (2016).

Dr. Haymart's accomplishments, their impact on the field of thyroid cancer, and her contributions to thyroidology make her an ideal recipient of the Van Meter Award.  The Van Meter is supported by an endowment gift from the estate of long-time member, Dr. Jacob Robbins; and by an annual contribution from Mary Ann Liebert, Inc., publishers.

###

The American Thyroid Association (ATA) is the leading worldwide organization dedicated to the advancement, understanding, prevention, diagnosis, and treatment of thyroid disorders and thyroid cancer. ATA is an international membership medical society with over 1,700 members from 43 countries around the world. Celebrating its 94th anniversary, the ATA continues to deliver its mission of being devoted to thyroid biology and to the prevention and treatment of thyroid disease through excellence in research, clinical care, education, and public health.  These efforts are carried out via several key endeavors:

  • The publication of the highly regarded professional journals Thyroid, Clinical Thyroidology, and VideoEndocrinology
  • Annual scientific meetings
  • Biennial clinical and research symposia
  • Research grant programs for young investigators
  • Support of online professional, public, and patient educational programs
  • Development of guidelines for clinical management of thyroid disease and thyroid cancer

The ATA promotes thyroid awareness and information online through Clinical Thyroidology for the Public and extensive, authoritative explanations of thyroid disease and thyroid cancer in both English and Spanish. The ATA website serves as the clinical resource for patients and the public who look for reliable information on the Internet. Every fifth year, the American Thyroid Association joins with the Latin American Thyroid Society, the European Thyroid Association, and the Asia and Oceania Thyroid Association to cosponsor the International Thyroid Congress (ITC).

 

 

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Punctured Two-Dimensional Sheets for Harvesting Blue Energy

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b06657
ancac3?d=yIl2AUoC8zA


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Construction of Antithrombotic Tissue-Engineered Blood Vessel via Reduced Graphene Oxide Based Dual-Enzyme Biomimetic Cascade

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b04836
ancac3?d=yIl2AUoC8zA


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Sequential Dihydrogen Desorption from Hydride-Protected Atomically Precise Silver Clusters and the Formation of Naked Clusters in the Gas Phase

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b05406
ancac3?d=yIl2AUoC8zA


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Characterization of Melanosomes and Melanin in Japanese Patients with Hermansky-Pudlak Syndrome Types 1, 4, 6 and 9

Abstract

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism (OCA), a bleeding tendency and ceroid deposition. Most of the causative genes for HPS encode subunits of the biogenesis of lysosome-related organelles complex (BLOC). In this study, we identified one patient each with HPS4, HPS6 and HPS9 by whole-exome sequencing. Next, we analyzed hair samples from the three patients and representative patients with HPS1 and controls using electron microscopy and chemical methods. All HPS patients had fewer, smaller and more immature melanosomes than healthy controls. Further, all patients showed reduced total melanin content and increased levels of benzothiazine-type pheomelanin. The results of this study demonstrate the impact of the dysfunctions of BLOCs on the maturation of melanosomes and melanin levels and composition through analysis of their hair samples.

This article is protected by copyright. All rights reserved.



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Is Immunohistochemical Screening of Cutaneous Leiomyomas for the Early Detection of Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome Justified?.

No abstract available

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Painful Skin Nodule on the Finger of a 59 Year Old.

No abstract available

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Induction of Desmoplastic Trichoepithelioma in a Dermatofibroma.

Induction of follicular germinative structures above a dermatofibroma (DF) is a common finding. Rarely, induction of a trichoblastoma in a DF has been observed. Here, we report the case of a desmoplastic trichoepithelioma induced by a DF. The lesion with clinical and histological appearance of a DF situated on the left dorsal foot showed an associated adnexal proliferation that fulfilled histopathological criteria of desmoplastic trichoepithelioma. Immunohistochemistry (Ber-EP4, Bcl-2, CK17, CK20, CK7, EMA, and Ki67) helped to confirm the diagnosis and to exclude possible differential diagnoses. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Multisensory modulation of experimentally evoked perceptual distortion of the face

Abstract

Background

Chronic orofacial pain patients often perceive the painful face area as 'swollen' without clinical signs, i.e., a perceptual distortion (PD). Local anesthetic (LA) injections in healthy participants are also associated with PD

Objective

The aim was to explore whether PD evoked by LA into the infraorbital region of could be modulated by adding mechanical stimulation (MS) to the affected area

Methods

MS was given with a brush and a 128 mN von Frey filament. First, sixty healthy participants were randomly divided into three groups: 1) LA control, 2) LA with MS, 3) Isotonic solution (ISO) with MS as an additional control condition. To further examine the role of a multisensory modulation an additional experiment was conducted. Twenty participants received LA with MS (filament) in addition to visual feedback of their distorted face. The results of the two experiments are presented together

Results

All three LA groups experienced PD, per contra PD was not reported in the ISO group. MS alone did not change the magnitude of PD: brush (p = 0.089), filament (p = 0.203). However, when the filament stimulation was combined with additional visual information of a distorted face there was observable decrease in PD (p = 0.002)

Conclusion

The findings indicate the importance of multisensory integration for PD, and represent a significant step forward in the understanding of the factors that may influence this common condition. Future studies are encouraged to investigate further the cortical processing for possible implications for PD in pain management.

This article is protected by copyright. All rights reserved.



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World-Wide Immunoscore Task Force: meeting report from the “Melanoma Bridge”, Napoli, November 30th–December 3rd, 2016

The predictive accuracy of the traditional staging system is based on disease progression as a tumour cell-autonomous process, but it fails to incorporate the effects of the host immune response. A precise ana...

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Effect of Infla-Kine supplementation on the gene expression of inflammatory markers in peripheral mononuclear cells and on C-reactive protein in blood

Chronic inflammation is a predisposing factor to numerous degenerative diseases including cancer, heart failure and Alzheimer's disease. Infla-Kine is a natural supplement comprised of a proprietary blend of Lact...

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MicroRNA-30a suppresses autophagy-mediated anoikis resistance and metastasis in hepatocellular carcinoma

MiRNA-30a (miR-30a) was previously reported as one of metastatic hepatocellular carcinoma (HCC)-related microRNAs. However, the function of miR-30a on enhancing our biological understanding of HCC metastasis is not clear. This study demonstrated that miR-30a was significantly down-regulated in HCC tissues and cell lines, and was associated with vascular invasion, metastasis potential and recurrent disease in HCC. Functional studies confirmed that miR-30a could inhibit the metastasis of HCC in a well-established nude mouse model of lung metastasis.

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Genomic Predictors of Chemotherapy Efficacy in Advanced or Recurrent Gastric Cancer in the GC0301/ TOP002 Phase III Clinical Trial

Recent gastric cancer clinical trials have aimed to establish the efficacy of combination therapy over monotherapy, however, the role for genomic biomarkers in these trials has remained largely unexplored. Here, using the NanoString expression platform, we analyzed 105 gastric tumors from a randomized phase III Japanese clinical trial (GC0301/TOP002) testing the efficacy of irinotecan plus S-1(IRI-S) versus S-1 therapy. We found that previously established proliferative subtype signatures, were associated with older patients (>65 years) and liver metastasis while mesenchymal subtype signatures were associated with younger patients (≤65 years) and peritoneal metastasis.

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Pancreatic stellate cells reorganize matrix components and lead pancreatic cancer invasion via the function of Endo180

Specific cell populations leading the local invasion of cancer are called "leading cells". However, the underlying mechanisms are unclear. Here, we identified leading cells in pancreatic cancer and determined how these cells lead and promote cancer cell invasion in the extracellular matrix (ECM). Using three-dimensional matrix remodeling assay, we found that pancreatic stellate cells (PSCs) frequently invaded the collagen matrix with pancreatic cancer cells (PCCs), which invaded behind the invading PSCs.

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“Is it Sjogren's syndrome or burning mouth syndrome? Distinct pathoses with similar oral symptoms”-a commentary

We write with regard to a recent article published by Aljonobi et al that compares clinical symptoms of Sjogren's syndrome (SS) and burning mouth syndrome (BMS).1 It is an interesting review about the clinical symptoms of SS and BMS and claims that these two syndromes have similar symptoms, thereby making the diagnosis challenging.

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Panaxynol, a natural Hsp90 inhibitor, effectively targets both lung cancer stem and non-stem cells

Cancer stem-like cells (CSCs) contribute to tumor recurrence and chemoresistance. Hence, strategies targeting CSCs are crucial for effective anticancer therapies. Here, we demonstrate the capacities of the non-saponin fraction of P. ginseng and its active principle panaxynol to inhibit Hsp90 function and viability of both non-CSC and CSC populations of NSCLC in vitro and in vivo. Panaxynol inhibited the sphere forming ability of NSCLC CSCs at nanomolar concentrations, and micromolar concentrations of panaxynol suppressed the viability of NSCLC cells (non-CSCs) and their sublines carrying acquired chemoresistance with minimal effect on normal cells derived from various organs.

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“Is it Sjögren's syndrome or burning mouth syndrome? Distinct pathoses with similar oral symptoms”- Response

We thank Drs. Mortazavi and Anbari for their thoughtful comments on our review1. We agree unequivocally that there are many distinguishing features between Sjögren's syndrome (SS) and burning mouth syndrome (BMS). Indeed, this was the focus our review as was nicely summarized in the commentary. However, our own clinical experience and the published literature demonstrate that the shared patient demographics and overlapping oral symptoms between the two conditions may cause confusion on the part of health care providers on initial presentation1-4.

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Nuances in component nasal hump reduction

Nasal hump reduction is a frequent manoeuver in rhinoplasty. Over the last years, composite hump reduction has been advocated in favour of component hump reduction. The latter allows a more controlled and stepwise approach in reducing the nasal dorsum by deprojecting the cartilaginous dorsum separately from the bony dorsum. This approach also preserves the upper lateral cartilages (ULCs) and their mucosa.

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Anthropometric growth study of the ear in a chinese population

A large number of anthropometric studies of the auricle have been reported in different nations, but little data are available in the Chinese population. The aim of this study was to analyze growth changes in the ear by measuring the width and length of ears in a Chinese population.

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Mammaplasty in patients with large areola: reducing the nipple-areola complex using intra-areolar incisions

Minimal incision breast reduction techniques resulting in periareolar scars are widely used. However, this technique is less suitable for patients with large areola diameters and relatively small breasts, requiring a modest reduction or lift only. As a result of the large nipple-areola-complex larger amounts of skin must be removed in order to resect the complete peripheral areola, increasing the risk of high-riding nipples, breast flattening and incomplete areola resection resulting in a rest on the vertical scar.

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Post-operative care of VRAM flaps for perineal reconstruction: results of a UK practice survey and literature review

The trans-pelvic vertical rectus abdominis myocutaneous (VRAM) flap has shown considerable utility in the reconstruction of pelvic defects following abdomino-perineal excision (APE) or total pelvic exenteration (TPE) for pelvic malignancy. These patients are often nursed post-operatively on colorectal wards, or even in outlying hospitals in those Plastics units operating on a hub-and-spoke basis. Protocols for the post-operative care of free flap reconstruction patients are well established and have been shown to reduce major complications1,2.

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The scrotal free flap: first successful clinical application of a free Super-Thin External Pudendal Artery (STEPA) flap for reconstruction of a foot defect

Dear Editor,

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American Thyroid Association: Charles H. Emerson, MD, Will Lead New Board of Directors

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American Thyroid Association: Charles H. Emerson, MD, Will Lead New Board of Directors

October 19, 2017—The American Thyroid Association (ATA) announces with pleasure the election of Charles H. Emerson, MD, as president of its Board of Directors. All terms begin at the close of the Annual Meeting, taking place October 18‒22 in Victoria, British Columbia.

Additional new board members include:

Elizabeth Pearce, MD, MSc, President-Elect
Julie Ann Sosa, MD, MA, FACS, Treasurer
Douglas Forrest, PhD, Research Director
Megan Haymart, MD, Clinician Director
Thomas Giordano, MD, PhD, Pathology Director

Charles H. Emerson, MD, President

Dr. Emerson is Professor Emeritus of Medicine at the University of Massachusetts Medical School (UMASSMED). He received his MD degree from the University of Virginia and completed his internship and residency in internal medicine at the Hospital of the University of Pennsylvania (Penn) in Philadelphia. After a year of endocrine fellowship at the same institution, he served as Chief of Endocrinology at the US Army Medical Center in Augusta, GA. Following military service, he returned to Penn and completed his endocrine fellowship, where he worked on purifying thyroid stimulating antigen, the kinetics of thyrotropin releasing hormone (TRH), inappropriate TSH secretion, and the effects of lithium and stable iodine on thyroid function.

After six years as Assistant Professor of Medicine at the University of Illinois, Dr. Emerson was recruited to UMASSMED by Lewis E. Braverman, MD. The two collaborated on a study of thyroid hormone metabolism in the chorion and placenta of various species, sparked by the finding that, in experimental models of hypothyroidism, reverse T3 in amniotic fluid was derived from the mother rather than the fetus. Among the other areas of Dr. Emerson's research are the effects of recombinant TSH in humans and rats, the relationship between age and the thyrotroph response to primary hypothyroidism and, working with Dr. Ronald Lechan, the mechanism of fasting-induced suppression of ProTRH mRNA in the hypothalamic paraventricular nucleus.

Dr. Emerson has served on the VA Merit Review Board and as an ad hoc member of NIH study sections. He is a member of the Endocrine Society, the American Association of Clinical Endocrinologists, the European Thyroid Association and, since 1976, the ATA. He has served on the ATA Program, Awards, and Development Committees, and as Chair of the Membership and Bylaws Committees. He was a member of the ATA Board from 2003 to 2007 and Treasurer from 2004 to 2007.

From 2008 through 2012 he was Editor-in-Chief of the journal Thyroid. He is currently Associate Editor of Clinical Thyroidology and Associated Editor of Endocrine Practice. Dr. Emerson was awarded the ATA's Distinguished Service Award in 2010.

He writes, "My vision of the ideal ATA is that it should be an intellectual home and voice for both individuals and groups, for original groundbreaking research and education of health care workers and the public, for scholarly work by one or two people and collective synthesis of the literature by groups. Revolutionary insights are generally formulated by individuals or close collaborations between two or three investigators. These in turn are integrated into the mainstream by groups, ideally in an erudite fashion. I will strive for an agenda and allocation of resources and time that is inclusive of these outwardly competing values."

Dr. Emerson has served a year on the board as President-Elect. He will now serve a one-year term as President, followed by a one-year term as Past-President.

Elizabeth Pearce, MD, MSc, President-Elect

Dr. Pearce is Associate Professor of Medicine in the Endocrinology, Diabetes, and Nutrition Section at Boston University School of Medicine. She received her undergraduate and medical degrees from Harvard and a masters' degree in epidemiology from the Boston University School of Public Health. She completed her residency in internal medicine at Beth Israel Deaconess Medical Center, and her fellowship in endocrinology at Boston University under the mentorship of Dr. Lewis Braverman. Her research interests include the sufficiency of dietary iodine in the U.S. and globally; thyroid function in pregnancy; thyroidal effects of exposure to environmental endocrine disruptors; and the cardiovascular effects of subclinical thyroid dysfunction. She has been part of the leadership of the Iodine Global Network (IGN; formerly ICCIDD) since 2009. She is a member of the AACE Thyroid Scientific Committee and serves as faculty for the Endocrine Society's annual board review course. She has served on multiple editorial boards, including those for Endocrine Practice, Journal of Clinical Endocrinology and Metabolism, Clinical Endocrinology, European Journal of Clinical Nutrition, and Lancet Diabetes & Endocrinology.

Dr. Pearce has been a member of the American Thyroid Association since 2000. She has chaired both the ATA's Publications and Public Health Committees. She co-chaired the 2012 Annual Meeting Program Committee and the 2009 and 2016 Spring Symposia, and was a member of the Program Committee for the 2015 International Thyroid Congress. She has served as a member of the ATA Finance Committee, and currently is a member of the Guidelines Policy Task Force. She was one of the leaders of the effort to establish the ATA's Braverman Lectureship and co-chaired the task force for the 2017 Pregnancy Guidelines. She is Associate Editor for both Thyroid and Clinical Thyroidology journals. She served as a member of the Board of Directors from 2009­ to 2013. Dr. Pearce was the 2011 recipient of the ATA Van Meter Award for outstanding contributions to research on the thyroid gland.

Julie Ann Sosa, MD, MA, FACS, Treasurer

After a year as Treasurer-Elect, Dr. Sosa will now become Treasurer. She is Professor of Surgery and Medicine in Oncology at Duke University, where she serves as Chief of Endocrine Surgery and Director of the Surgical Center for Outcomes Research, as well as Leader of the Endocrine Neoplasia Diseases Group at the Duke Cancer Institute and the Duke Clinical Research Institute, a large transdisciplinary group of clinicians and researchers. She received her AB at Princeton, her MA at Oxford, and her MD at Johns Hopkins, where she also completed the Halsted residency and a fellowship. Her clinical interest is in endocrine surgery, with a focus in thyroid cancer. She is an NIH-funded investigator and author of more than 230 peer-reviewed publications and 50 book chapters, largely focused on outcomes research and thyroid cancer, including clinical trials.

Dr. Sosa is also this year's Lewis E. Braverman Distinguished Award recipient. The Braverman Award recognizes an individual who: demonstrates excellence and passion for mentoring fellows, students, and junior faculty; has a long history of productive thyroid research; and is devoted to the ATA. At the Annual Meeting, she will present the Braverman lecture, titled "Retelling the Story of Thyroid Cancer—Rising Incidence, Mortality, and Maybe an Explanation."

In addition to Board liaison to the ATA Finance and Audit Committee and Internet Communications Committee, Dr. Sosa is a past Chair of the Program Committee and has served on the Nominating Committee and Patient Affairs and Education Committee, as well as guidelines committees for the management of thyroid nodules and differentiated thyroid cancer (2015) and hyperthyroidism/thyrotoxicosis (2011, 2016). She was vice president of the American Association of Endocrine Surgeons and serves on the Board of Directors of the International Thyroid Oncology Group as well as the Executive Council of the Society for Surgical Oncology. She is a member of the National Comprehensive Cancer Network (NCCN) Practice Guidelines Committee for Neuroendocrine Tumors. She is deputy editor of JAMA-Surgery and associate editor for World Journal of Surgery, Journal of Surgical Research, and Current Opinion in Oncology. She is on the editorial boards of the Annals of Surgical Oncology, Annals of Surgery, Hormones and Cancer, Endocrine, and Surgery. She has mentored more than 50 students, residents, and fellows.

Douglas Forrest, PhD, Research Director

Dr. Forrest is Senior Investigator in the Laboratory of Endocrinology and Receptor Biology at the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) at the National Institutes of Health (NIH). He received his PhD at Glasgow University for studies on feline leukemia virus. His life-long interest in thyroid hormone was first sparked during training at the European Molecular Biology Laboratory in Heidelberg and the Karolinska Institute in Stockholm.

In the United States, Dr. Forrest previously held faculty appointments as Assistant Professor, then Associate Professor at the Department of Human Genetics at Mount Sinai School of Medicine. His experience includes teaching and obtaining NIH and international grants. He has served on grant study sections and on the editorial boards of Thyroid, Endocrinology, Molecular Endocrinology, and Frontiers in Endocrinology. He has mentored trainees who have pursued careers in independent research, clinical practice, industry, and scientific administration.

Dr. Forrest's research interests concern thyroid hormone functions in mammalian development and disease with emphasis on basic and translational studies of thyroid hormone receptors and deiodinase enzymes. His contributions have been recognized with the ATA Van Meter Award and the Merck Prize of the European Thyroid Association. He has presented the Shizume Lecture of the Japanese Thyroid Association and the Pitt-Rivers Lecture of the British Endocrine Society.

A member of the ATA since 1999, Dr. Forrest has served on the Annual Meeting Program Committee, the Awards Committee, the Planning Committee for the Spring Summit on "The thyroid in pregnancy and development," and the Basic Research Guidelines Task Force. He co-authored the "ATA Guide to investigating thyroid hormone economy and action in rodent and cell models." He was co-chair with Elizabeth Pearce of the 82nd Annual Meeting in Quebec City. He currently serves on the Trainee Career and Advancement Committee as chair of the Basic Track and is a keen advocate for all trainees in the thyroid field.

Megan Haymart, MD, Clinician Director

Dr. Haymart is Associate Professor of Medicine in the Division of Metabolism, Endocrinology, and Diabetes and Hematology/Oncology at the University of Michigan. She received her MD degree from Johns Hopkins Medical School. She completed her internal medicine residency at Johns Hopkins Hospital and her endocrinology fellowship at the University of Wisconsin.

Dr. Haymart's clinical focus is thyroid cancer and thyroid nodules, working with a multidisciplinary endocrine oncology team at the University of Michigan. Her research focus is on variation in the management of thyroid disorders, with an emphasis on the role of patients, providers, and health systems in treatment decision-making. With R01 funding from the National Cancer Institute (NCI) of the National Institutes of Health (NIH), she is currently evaluating treatment decision-making in low-risk thyroid cancer. With R01 funding from the Agency for Healthcare Research and Quality (AHRQ), she is investigating the role of imaging in the over-diagnosis of low-risk thyroid cancer.

In addition to her clinical efforts and research endeavors, Dr. Haymart is involved in creating the National Comprehensive Cancer Network (NCCN) thyroid carcinoma guidelines. She is the recent recipient of the University of Michigan's Jerome Conn Award for Research Excellence. She currently serves as chair of the ATA Finance and Audit Committee and is on the Endocrine Society's Annual Meeting Steering Committee. She served on the editorial board of the Journal of Clinical Endocrinology and Metabolism (JCEM) from 2013 to 2016 and currently serves on the editorial boards of Thyroid (since 2013) and Endocrine Today (since 2017). She is also Associate Editor for VideoEndocrinology (2014‒present).

Thomas Giordano, MD, PhD, Pathology Director

Dr. Giordano is the Henry Clay Bryant Professor of Pathology in the Department of Pathology, University of Michigan Medical School, and holds a joint appointment in the Metabolism and Endocrinology Division of the school's Department of Internal Medicine. After receiving his BA from Johns Hopkins University, Dr. Giordano earned his MD and PhD in a combined program at the Rutgers University and UMDNJ's Robert Wood Johnson Medical School. His graduate studies in the Department of Microbiology involved the regulation of gene expression. He completed residency training in anatomic pathology at the National Cancer Institute (NCI) and fellowship training in oncologic pathology at Memorial Sloan-Kettering Cancer Center. Both residency and fellowship training permitted extensive exposure to endocrine pathology. He then joined the faculty at the University of Michigan Medical School.

Dr. Giordano is an endocrine and molecular pathologist with long-standing interests in thyroid and adrenocortical neoplasia. His specific academic interests in thyroid cancer include molecular and genomic profiling and tumor classification. He served as co-chair of The Cancer Genome Atlas's (TCGA's) Papillary Thyroid Carcinoma project, which he led from its initiation to publication in Cell in 2014. He also was instrumental in convincing the TCGA leadership to conduct their Adrenal Cortical Carcinoma project and served as co-chair of this study until its publication in Cancer Cell in 2016. He also served on the Analysis Working group for the TCGA Pheochromocytoma project, published in Cancer Cell in 2017. He currently serves on
the TCGA Steering Committee for the PanCancerAtlas project, the goal of which is to collectively evaluate the genomics of all tumors studied by TCGA.

Dr. Giordano regularly attends the ATA Annual Meeting and has participated on their Tumor Board for the last two years. He is a member of the ATA Laboratory Services Committee and ATA Anaplastic Thyroid Cancer (ATC) Guidelines Task Force.

Nominating Process

The ATA thanks this year's nominating committee, chaired by David Steward, and is extremely grateful to all who are willing to stand for election and to serve on the Board of Directors. Special thanks to those who will retire from the Board this year: Anthony Hollenberg, MD, Jacqueline Jonklaas, MD, outgoing Past-President Anthony Bianco, MD, PhD, and outgoing Treasurer David H. Sarne, who has served for six years in that position. Additional thanks to current President John Morris, MD, who now continues to serve as Past-President of the Board.

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The American Thyroid Association (ATA) is the leading worldwide organization dedicated to the advancement, understanding, prevention, diagnosis, and treatment of thyroid disorders and thyroid cancer. ATA is an international membership medical society with over 1,700 members from 43 countries around the world. Celebrating its 94th anniversary, the ATA continues to deliver its mission of being devoted to thyroid biology and to the prevention and treatment of thyroid disease through excellence in research, clinical care, education, and public health.  These efforts are carried out via several key endeavors:

 

  • The publication of the highly regarded professional journals Thyroid, Clinical Thyroidology, and VideoEndocrinology
  • Annual scientific meetings
  • Biennial clinical and research symposia
  • Research grant programs for young investigators
  • Support of online professional, public, and patient educational programs
  • Development of guidelines for clinical management of thyroid disease and thyroid cancer

 

The ATA promotes thyroid awareness and information online through Clinical Thyroidology for the Public and extensive, authoritative explanations of thyroid disease and thyroid cancer in both English and Spanish. The ATA website serves as the clinical resource for patients and the public who look for reliable information on the Internet. Every fifth year, the American Thyroid Association joins with the Latin American Thyroid Society, the European Thyroid Association, and the Asia and Oceania Thyroid Association to cosponsor the International Thyroid Congress (ITC).

 

 

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