Head and Neck Diseases by Alexandros G.Sfakianakis: 09/06/18

Πέμπτη 6 Σεπτεμβρίου 2018

The effect of antioxidants on Helicobacter pylori eradication: A systematic review with meta‐analysis

Helicobacter, EarlyView.

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The effect of antioxidants on Helicobacter pylori eradication: A systematic review with meta‐analysis

Helicobacter, EarlyView.

https://ift.tt/2MRBna6

Oral Hedgehog Pathway Inhibition as a Means for Ocular Salvage in Locally Advanced Intraorbital Basal Cell Carcinoma

BACKGROUND Basal cell cancer is the most common cutaneous malignancy. It rarely presents with locally advanced or metastatic disease. Rare presentations such as intraorbital invasion remain a difficult clinical problem with significant potential morbidity. There is no review of sonic hedgehog pathway inhibitors (HPIs) for intraorbital basal cell cancer, and evidence regarding optimal management is limited. OBJECTIVE To evaluate the evidence for the management of intraorbital basal cell cancer with HPIs. METHODS A search to identify evidence for treatment intraorbital basal cell cancers with HPIs to date was performed in PubMed database and OVID using the phrases "basal cell cancer/carcinoma/BCC," "intraorbital," "orbital," "ocular," "periocular," "vismodegib," "GDC-0449," "sonidegib," and "LDE224," in various combinations with Boolean operators "AND" and "OR." RESULTS Rigorous clinical trials have previously reported the use of vismodegib and sonidegib in locally advanced and metastatic basal cell carcinoma (BCC). However, specific descriptions of treatment of intraorbital tumors are rarely presented in detail adequate for analysis. Twenty-two cases of intraorbital BCC treated with vismodegib have been described in the literature, and no cases using sonidegib were identified. These vary in quality, but highlight important questions regarding optimal treatment duration, follow-up, and adjunctive therapies. Reports describing locally advanced BCC in various facial and periocular locations, but without specific mention of intraorbital invasion, were excluded. CONCLUSION Vismodegib is an attractive eye and vision-sparing option in patients with locally advanced intraorbital basal cell cancer whose other options often include exenteration, radiation, or other radical surgery. Address correspondence and reprint requests to: Jason Mathis, Department of Dermatology, University of Utah, 30 North 1800 East 4A330, Salt Lake City, Utah 84132, or e-mail: jason.mathis@hsc.utah.edu The authors have indicated no significant interest with commercial supporters. © 2018 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.

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Novel Fasciotomy Technique for the Keystone Flap

No abstract available

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Repair of Apical Triangle Defects Using Melolabial Rotation Flaps

BACKGROUND The apical triangle of the upper cutaneous lip, also known as the alar-facial sulcus, is an anatomical structure bound medially by the nasal ala, laterally by the medial cheek, and inferiorly by the remainder of the upper cutaneous lip. During reconstruction, retaining the central concavity and the convex lateral and medial outlines of this location is required to maintain midfacial symmetry. OBJECTIVE This is a retrospective study of our use of the melolabial rotation flap for reconstruction of surgical defects of the apical triangle. METHODS AND MATERIALS Eighty-six surgical defects involving the apical triangle that were repaired with melolabial rotation flaps were included. All tumors were treated with Mohs micrographic surgery before reconstruction. Preoperative, intraoperative, and postoperative details of each case were analyzed. RESULTS Of the 86 defects included in the study, 68 (79%) were evaluated postoperatively. The apical triangle was preserved in all cases. Clinical asymmetry was noted in 3 patients (3.4%). No major complications were noted, and no patient required surgical revision. CONCLUSION Melolabial rotation flaps may be considered for single-stage reconstruction of surgical defects involving the apical triangle. Address correspondence and reprint requests to: Arash Kimyai-Asadi, MD, 7515 Main Street, Suite 240, Houston, TX 77030, or e-mail: akimyai@yahoo.com The authors have indicated no significant interest with commercial supporters. © 2018 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2O19E32

Correction to: Facile synthesis of carbon-coated layered double hydroxide and its comparative characterisation with Zn–Al LDH: application on crystal violet and malachite green dye adsorption—isotherm, kinetics and Box-Behnken design

The original publication of this paper contains an error. The correct Figure 8 is shown in this paper.

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Synthesis of mesoporous core-shell TiO 2 microstructures with coexposed {001}/{101} facets: enhanced intrinsic photocatalytic performance

Abstract

TiO₂ microstructures were synthesized via a facile one-step route for enhanced intrinsic photocatalytic performance. The prepared TiO₂ microstructures are featured by both mesoporous core-shell structures and coexposed {001}/{101} facets. Their intrinsic photocatalytic performance were remarkably enhanced due to their high specific surface area, coexposed {001}/{101} facets, and promoted separation of photogenerated carriers. Furthermore, the origin and detailed mechanism for diethylenetriamine (DETA) that served as a high efficient stabilizer of TiO₂ {001} facet have been theoretically investigated. Finally, a new DETA-modified Ostwald ripening mechanism was originally proposed when studying the growth mechanism of the mesoporous core-shell TiO₂ spherical microstructures with coexposed {001}/{101} facets.

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Pemphigus vulgaris as the first manifestation of multiple myeloma: a case report

The association between pemphigus and malignancy has been well documented for decades but an association between pemphigus vulgaris and multiple myeloma is unusual. We report a case of pemphigus vulgaris revea...

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Minimal Increase in Survival Throughout the Years in Patients with Soft Tissue Sarcoma with Synchronous Metastases: Results of a Population‐Based Study

AbstractBackground.Treatment options for patients with metastatic soft tissue sarcoma (STS) have increased in the last decade. We aimed to examine whether this is associated with improved overall survival (OS) in patients with STS with synchronous metastases.Patients and Methods.Patients diagnosed with STS and synchronous metastases from 1989 to 2014 were queried from The Netherlands Cancer Registry. Trends in OS were assessed by the Kaplan‐Meier method and log‐rank test in time intervals of 5 years, for the whole study population and in subgroups for liposarcomas, leiomyosarcoma, and other STS subtypes. A multivariable Cox regression analysis was performed to identify characteristics prognostic for OS.Results.Median OS of the 1,393 identified patients did not improve significantly over the years from 5.8 months in 1989–1994 to 8.1 months in 2010–2014, but there was an evident trend. Median OS was prolonged in the subgroups of liposarcomas (3.6 to 9.3 months), leiomyosarcomas (11.3 to 14.6 months), and other STS subtypes (5.7 to 6.3 months), although there were no significant improvements in OS over the years. Primary tumor site in one of the extremities and surgery in an academic center had a favorable effect on OS, whereas significant negative predictors were no treatment, elderly age, STS subtype other than liposarcoma or leiomyosarcoma, high or unknown grade, and nodal involvement.Conclusion.Although overall survival of patients with STS with synchronous metastases in this nationwide and "real‐life" population has improved over the years, the improvement was not statistically significant, despite new treatment options.Implications for Practice.Treatment of patients with metastatic soft tissue sarcoma (STS) has changed in the past years, with new drugs such as trabectedin (2007) and pazopanib (2012) becoming available. By using data from the nationwide Netherlands Cancer Registry, the impact of these changes in treatment policies on survival is analyzed in a "real‐life" population of patients with STS with synchronous metastases, rather than in a strictly selected trial population. Unfortunately, overall survival improved only minimally and not significantly for these patients diagnosed from 1989 to 2014. Hopefully, the advent of novel treatment options, such as eribulin and olaratumab, will further improve the outcome of this patient group.

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An Open Label Phase Ib Dose Escalation Study of TRC105 (Anti‐Endoglin Antibody) with Axitinib in Patients with Metastatic Renal Cell Carcinoma

AbstractBackground.TRC105 is an IgG1 endoglin monoclonal antibody that potentiates VEGF inhibitors in preclinical models. We assessed safety, pharmacokinetics, and antitumor activity of TRC105 in combination with axitinib in patients with metastatic renal cell carcinoma (mRCC).Subjects, Materials, and Methods.Heavily pretreated mRCC patients were treated with TRC105 weekly (8 mg/kg and then 10 mg/kg) in combination with axitinib (initially at 5 mg b.i.d. and then escalated per patient tolerance to a maximum of 10 mg b.i.d.) until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design.Results.Eighteen patients (median number of prior therapies = 3) were treated. TRC105 dose escalation proceeded to 10 mg/kg weekly without dose‐limiting toxicity. Adverse event characteristics of each drug were not increased in frequency or severity when the two drugs were administered concurrently. TRC105 and axitinib demonstrated preliminary evidence of activity, including partial responses (PR) by RECIST in 29% of patients, and median progression‐free survival (11.3 months). None of the patients with PR had PR to prior first‐line treatment. Lower baseline levels of osteopontin and higher baseline levels of TGF‐β receptor 3 correlated with overall response rate.Conclusion.TRC105 at 8 and 10 mg/kg weekly was well tolerated in combination with axitinib, with encouraging evidence of activity in patients with mRCC. A multicenter, randomized phase II trial of TRC105 and axitinib has recently completed enrollment (NCT01806064).Implications for Practice.TRC105 is a monoclonal antibody to endoglin (CD105), a receptor densely expressed on proliferating endothelial cells and also on renal cancer stem cells that is implicated as a mediator of resistance to inhibitors of the VEGF pathway. In this Phase I trial, TRC105 combined safely with axitinib at the recommended single agent doses of each drug in patients with renal cell carcinoma. The combination demonstrated durable activity in a VEGF inhibitor‐refractory population and modulated several angiogenic biomarkers. A randomized Phase II trial testing TRC105 in combination with axitinib in clear cell renal cell carcinoma has completed accrual.

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“I need to know what makes somebody tick …”: Challenges and Strategies of Implementing Shared Decision‐Making in Individualized Oncology

AbstractBackground.Shared decision‐making (SDM) has been advocated as an ethical framework for decision‐making in cancer care. According to SDM, patients make decisions in light of their values and based on the available evidence. However, SDM is difficult to implement in cancer care. A lack of applicability in practice is often reported. This empirical‐ethical study explores factors potentially relevant to current difficulties in translating the concept of SDM into clinical practice.Methods.This study was conducted with nonparticipant observation of the decision‐making process in patients with gastrointestinal cancers for whom the benefit of adjuvant chemotherapy was uncertain according to clinical guidelines. Triangulation of qualitative data analysis was conducted by means of semistructured interviews subsequent to the observation. Observation notes and interview transcripts were analyzed according to the principles of grounded theory.Results.Deviating from the concept of SDM, oncologists initiated a process of eliciting values and medical information prior to conveying information. The purpose of this approach was to select and individualize information relevant to the treatment decision. In doing so, the oncologists observed used two strategies: "biographical communication" and a "metacommunicative approach." Both strategies could be shown to be effective or to fail depending on patients' characteristics such as their view of the physicians' role and the relevance of value‐related information for medical decision‐making.Conclusion.In contrast to the conceptual account of SDM, oncologists are in need of patient‐related information prior to conveying information. Both strategies observed to elicit such information are in principle justifiable but need to be adapted in accordance with patient preferences and decision‐making styles.Implications for Practice.This study showed that knowledge of patients' values and preferences is very important to properly adapt the giving of medical information and to further the process of shared decision‐making. Shared decision‐making (SDM) trainings should consider different strategies of talking about values. The right strategy depends largely on the patient's preferences in communication. To be aware of the role of values in SDM and to be able to switch communicative strategies might prove to be of particular value. A more systematic evaluation of the patient's decision‐making preferences as part of routine procedures in hospitals might help to reduce value‐related barriers in communication.

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Regorafenib for Patients with Metastatic Colorectal Cancer Who Progressed After Standard Therapy: Results of the Large, Single‐Arm, Open‐Label Phase IIIb CONSIGN Study

AbstractBackground.In the phase III CORRECT trial, regorafenib significantly improved survival in treatment‐refractory metastatic colorectal cancer (mCRC). The CONSIGN study was designed to further characterize regorafenib safety and allow patients access to regorafenib before market authorization.Methods.This prospective, single‐arm study enrolled patients in 25 countries at 186 sites. Patients with treatment‐refractory mCRC and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1 received regorafenib 160 mg once daily for the first 3 weeks of each 4‐week cycle. The primary endpoint was safety. Progression‐free survival (PFS) per investigator assessment was the only efficacy evaluation.Results.In total, 2,872 patients were assigned to treatment and 2,864 were treated. Median age was 62 years, ECOG PS 0/1 was 47%/53%, and 74% had received at least three prior regimens for metastatic disease. Median treatment duration was three cycles. Treatment‐emergent adverse events (TEAEs) led to dose reduction in 46% of patients. Regorafenib‐related TEAEs led to treatment discontinuation in 9%. Grade 5 regorafenib‐related TEAEs occurred in <1%. The most common grade ≥3 regorafenib‐related TEAEs were hypertension (15%), hand–foot skin reaction (14%), fatigue (13%), diarrhea (5%), and hypophosphatemia (5%). Treatment‐emergent grade 3–4 laboratory toxicities included alanine aminotransferase (6%), aspartate aminotransferase (7%), and bilirubin (13%). Ongoing monitoring identified one nonfatal case of regorafenib‐related severe drug‐induced liver injury per DILI Working Group criteria. Median PFS (95% confidence interval [CI]) was 2.7 months (2.6–2.7).Conclusion.In CONSIGN, the frequency and severity of TEAEs were consistent with the known safety profile of regorafenib. PFS was similar to reports of phase III trials. ClinicalTrials.gov: NCT01538680.Implications for Practice.Patients with metastatic colorectal cancer (mCRC) who fail treatment with standard therapies, including chemotherapy and monoclonal antibodies targeting vascular endothelial growth factor or epidermal growth factor receptor, have few treatment options. The multikinase inhibitor regorafenib was shown to improve survival in patients with treatment‐refractory mCRC in the phase III CORRECT (N = 760) and CONCUR (N = 204) trials. However, safety data on regorafenib for mCRC in a larger number of patients were not available. The CONSIGN trial, carried out prospectively in more than 2,800 patients across 25 countries, confirmed the safety profile of regorafenib from the phase III trials and reinforced the importance of using treatment modifications to manage adverse events.

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A Pioneer in Neuroendocrinology

Exp Clin Endocrinol Diabetes 2018; 126: 534-535
DOI: 10.1055/a-0658-1185

Article in Thieme eJournals:
Table of contents | Full text

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Most Innovative Paper Award

Exp Clin Endocrinol Diabetes 2018; 126: 471-471
DOI: 10.1055/a-0696-9405

Dear Readers,It is our – and the publisher's – conviction that a scientific journal's mission is not only to provide its readers with the most relevant and interesting papers available, but also to further scientific research and to reward and honour those whose contributions to the advancement of science are truly remarkable. We are thus especially delighted to announce that from this year onward, we – the Editors-in-Chief together with the publisher Georg Thieme Verlag- will again officially award the most innovative paper published in Experimental and Clinical Endocrinology & Diabetes. Eligible are all original papers within the fields of endocrinology and diabetes published the two years previously, i. e. the prize awarded in 2019 will consider papers published in 2017 and 2018.Of course, true to the title of the journal, the prize – worth € 4,000 – will alternate between endocrinology and diabetes and will be awarded either during the DGE or the DDG conference. Endocrinology will make a start in 2019 and we are looking forward to our first winners on stage during the DGE conference 20–22 March 2019.
[...]

Article in Thieme eJournals:
Table of contents | Abstract | Full text

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Untersuchung der Qualität der Hörgeräteversorgung bei Senioren unter Berücksichtigung kognitiver Einflussfaktoren

Laryngo-Rhino-Otol
DOI: 10.1055/a-0671-2295

In der Gruppe der über 65-Jährigen ist die Hörminderung eines der häufigsten gesundheitlichen Probleme. Um die Kommunikationsfähigkeit in dieser Population aufrecht zu erhalten, ist eine adäquate Hörgeräteversorgung essentiell. Das Ziel der vorliegenden Studie war die Überprüfung der Qualität der Hörgeräteversorgung bei Senioren in Bezug auf die Wiederherstellung der Sprachdiskrimination. Weiterhin sollte der Einfluss des Alters und einiger kognitiver Parameter auf das Sprachverstehen betrachtet werden. Es wurden 40 Probanden im Alter von 66 bis 88 Jahren mit ein- oder beidseitiger Hörgeräteversorgung untersucht. Es wurde der gemittelte Hörverlust der Frequenzen 0,5–1-2–4 kHz und der gemittelte Hochton-Hörverlust bei den Frequenzen 2–4-6 kHz sowie das maximale Einsilberverstehen (mEV) und das hörgeräteversorgte Sprachverstehen bei 65 dB betrachtet. Um mögliche kognitive Einflussfaktoren zu ermitteln, wurden ein Demenzscreening-Verfahren (DemTect-Test) und ein Test zur Prüfung des Arbeitsgedächtnisses angewendet. Zwar zeigte sich ein Gewinn durch die Hörgeräteversorgung in 82 % der untersuchten Fälle, die nach Hilfsmittelrichtlinie geforderte Verbesserung von mindestens 20 % gegenüber der unversorgten Situation wurde jedoch in 56 % der Fälle nicht erreicht. Weiterhin wurde das individuelle mEV mit Abweichung von höchstens zehn Prozentpunkten von 81 % aller Fälle nicht erreicht. Signifikante Korrelationen zwischen Zahlenfolgen-Merkspanne bzw. DemTect-Ergebnis und mEV konnten nicht festgestellt werden. Im untersuchten Probandenkollektiv ergaben sich auch keine Hinweise für eine Abhängigkeit des Ergebnisses der Hörgeräteversorgung vom Lebensalter oder von (milder) kognitiver Beeinträchtigung sowie reduzierter Arbeitsgedächtnisleistung.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents | Abstract | Full text

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“The validity of the EQ-5D-5L in measuring quality of life benefits of breast reconstruction”

The EuroQol EQ-5D-5L instrument is the most widely-used quality of life measure in health economic evaluations. It is unclear whether such a generic instrument is valid enough to estimate the benefits of breast reconstruction (BR), given the specific changes observed in quality of life after BR. Hence, we aimed to evaluate the validity of EQ-5D-5L in patients who had undergone postmastectomy BR.

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Reply to MS#JAAD-D-18-01527

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Ruxolitinib for the treatment of severe alopecia areata

https://ift.tt/2wMx8Sr

Lightening Becker’s nevus: Role of topical therapies

https://ift.tt/2NpP6Ev

Trichloroacetic acid as a treatment for persistent oral mucosal lesions in pemphigus vulgaris

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Previously undiagnosed Darier disease complicated by bilateral ecthyma gangrenosum masquerading as a vasculopathy with retiform eschar formation

We present the case of a 57-year-old incarcerated man with a history of hepatitis C and life-long presumed atopic dermatitis who presented with a two month history of painful, progressive, ulcerations with overlying eschars on his bilateral lower extremities. He had been treated unsuccessfully with oral trimethoprim-sulfamethoxazole and clindamycin before admission. Upon admission, he was found to have leukocytosis but was otherwise hemodynamically stable and afebrile. On exam, he had erythematous hyperkeratotic papules coalescing into plaques on the neck, chest, abdomen, back, and extremities, with a flexural predominance, and retiform ulcerations with overlying eschars on the bilateral lower legs.

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Onychogryphosis: A case report and review of the literature

Patient history: A 67-year-old man presented with a 30-year history of severe thickening, curving, and yellow discoloration of his left great toenail. He stated that the nail broke off midway and regrew every six months. It had become more painful recently and was impinging on his second toe, making it difficult to walk and put on socks. There is no history of trauma, tinea pedis or family history of onychomycosis. Physical examination was notable for thickening and lateral deviation of the left first toenail.

https://ift.tt/2M5aTNa

Pruritus in patients under targeted anticancer therapy: Multidimensional analysis using the 5-D itch scale

Background: Pruritus is very common symptom in patients under anticancer therapy. However, the characteristics of pruritus according to anticancer agents have not been known well.

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Patient experience of the “two-week wait” cancer referral pathway in a large secondary care department in England

Background: The 2-week wait (2WW) system has been implemented across the NHS in England to enable rapid referral of patients with squamous cell carcinoma and malignant melanoma from primary to secondary care. Patients are told that the referral is to exclude skin cancer. In our secondary care dermatology department, a 2-week lag between referral and dermatology consultation represents a 19-week reduction in wait time (WT) from a standard referral. Little is currently known about the patients' perception of this streamlining, how WT impacts patient quality of life, and how appropriate patients consider this WT when being referred for suspected malignancy.

https://ift.tt/2MUBKki

Process of standardized postoperative telephone follow-up implementation for Mohs micrographic surgery

Mohs micrographic surgery (MMS) is an effective outpatient procedure for skin cancer removal with low reported complication rates. Identifying both major and minor postoperative complications is necessary to improve the quality of Mohs-based surgical care. There are currently no established standards for regular patient follow-up after MMS. Therefore, there exists a need to determine standardized, cost-effective, and reproducible follow-up strategies. The objective of this study was to determine whether routine telephone follow-up is an effective tool to capture postoperative complications and other patient-reported concerns.

https://ift.tt/2NovQXW

Predicting therapy outcome by HLA-Cw6 genotyping in psoriasis patients treated with secukinumab

Introduction: A possible correlation of genetic markers and response to treatment has been proclaimed. The strongest association has been shown between HLA-Cw6 and ustekinumab. So far it is unclear whether this effect can be also found in IL-17.

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Pigmented eccrine poroma: A clinical dermoscopy challenge

Eccrine poroma is a benign neoplasia originated from the intraepidermal portion of the sweat gland duct. It is characterized by a papule, plaque or nodule, normochromic or erythematous, exophytic or hyperkeratotic. Although its pathogenesis is still unknown, it seems to be related to radiation, trauma or scars. The pigmented variant, more frequent in blacks and affecting mainly nonacral areas, is responsible for 17% of the cases. Various clinical-dermatoscopic features have been described, directing its differential diagnosis to other benign and malignant neoplasia, such as seborrheic keratosis, epithelized pyogenic granuloma, basal-cell and squamous-cell carcinoma, angiofibroma, and melanoma.

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Pediatric melanoma immunotherapy: A retrospective examination of a decade of clinical experience at a tertiary care center

Background: Pediatric or adolescent melanoma, defined as melanoma in patients below age 20, is an infrequent occurrence that represents 0.4% of the approximately 87,110 new cases of melanoma diagnosed in the United States annually. As a result, few data exist to guide therapy that prolong survival, in particular with more recently developed immune therapies, such as immune checkpoint inhibitors. This lack of data is especially important as there is growing evidence that pediatric melanoma differs in its presentation, gene expression, and behavior from adult melanoma, and that response to therapy may vary by age.

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Painful subcutaneous lesions in a patient with metastatic melanoma

Introduction: We present the case of a patient with metastatic melanoma (MM) treated with combined therapy (vemurafenib + cobimetinib), who develops painful subcutaneous lesions compatible with secondary panniculitis.

https://ift.tt/2MUwAos

Old is gold—Revisiting the efficacy of topical psoralen–ultraviolet A phototherapy for palmoplantar dermatoses

Palmoplantar involvement of dermatoses such as atopic dermatitis and psoriasis has significant impact on quality of life. While systemic treatment options have increased in recent years, topical psoralen ultraviolet A (tPUVA) therapy remains a viable option when topical treatments have failed and potential systemic adverse events outweigh benefits. Literature on tPUVA efficacy is sparse. Our objectives were to report the efficacy of tPUVA after an initial treatment course and to identify associated clinical factors.

https://ift.tt/2M7nnDK

Nicolau syndrome appears after filling hyaluronic acid with the use of blanching technique

A 34-year-old woman was treated in our clinic for mild acne and scars. Two years before, oral isotretinoin was given to the patient with a complete healing of the acne but numerous 2–3-mm scars remained in both cheeks. Two sessions of a nonablative CO2 laser was performed one year after the termination of the isotretinoin treatment with partial improvement of the scars. After that, a blanching technique with hyaluronic acid was offered to the patient. She was injected with a low reticulated hyaluronic acid with lidocaine using a 30 Gy needle doing a blanching technique to fill the scars presented in her cheeks.

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Aggregation, sedimentation, and dissolution of CuO and ZnO nanoparticles in five waters

Abstract

With the accelerated application of copper oxide (CuO) and zinc oxide (ZnO) nanoparticles (NPs) in commercial products, concerns about the potential impacts on the environment have been growing. Environmental behaviors of NPs are expected to significantly influence their fate and ecological risk in the aquatic environment. In this study, the environmental behaviors of two metallic NPs (CuO and ZnO NPs), including aggregation, sedimentation, and dissolution, were systematically evaluated in five representative waters (pool water, lake water, rainwater, tap water, and wastewater) with varying properties. Remarkable aggregation, sedimentation, and dissolution were observed for both metallic NPs, among which ZnO NPs exhibited greater influence. CuO (ZnO) NPs aggregated to 400 (500) nm, 500 (900) nm, and 800 (1500) nm in lake water, wastewater, and tap water, respectively. The sedimentation rates of CuO and ZnO NPs in the five waters were ranked as tap water > wastewater > lake water > pool water > rainwater. The dissolution of CuO and ZnO NPs in waters follows a first-order reaction rate model and is affected by ionic type, ionic strength (IS), and NOM (natural organic matter) concentrations. Redundancy analysis (RDA) indicated that the aggregation and sedimentation of NPs have a strong correlation, insofar as the sedimentation rates increase with increasing aggregation rates. The aggregation and dissolution of NPs have a negative correlation, insofar as the dissolution rates reduce with increasing aggregation rates. The aggregation, sedimentation, and dissolution of NPs can be influenced by ionic types, IS, and TOC in waters, among which, TOC may the dominant factor.

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Noise-Induced Hypersensitization of the Acoustic Startle Response in Larval Zebrafish

ABSTRACT

Overexposure to loud noise is known to lead to deficits in auditory sensitivity and perception. We studied the effects of noise exposure on sensorimotor behaviors of larval (5–7 days post-fertilization) zebrafish (Danio rerio), particularly the auditory-evoked startle response and hearing sensitivity to acoustic startle stimuli. We observed a temporary 10–15 dB decrease in startle response threshold after 18 h of flat-spectrum noise exposure at 20 dB re·1 ms⁻². Larval zebrafish also exhibited decreased habituation to startle-inducing stimuli following noise exposure. The noise-induced sensitization was not due to changes in absolute hearing thresholds, but was specific to the auditory-evoked escape responses. The observed noise-induced sensitization was disrupted by AMPA receptor blockade using DNQX, but not NMDA receptor blockade. Together, these experiments suggest a complex effect of noise exposure on the neural circuits mediating auditory-evoked behaviors in larval zebrafish.

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The Stress Response in the Non-sensory Cells of the Cochlea Under Pathological Conditions—Possible Role in Mediating Noise Vulnerability

Abstract

Various stressors, such as loud sounds and the effects of aging, impair the function and viability of the cochlear sensory cells, the hair cells. Stressors trigger pathophysiological changes in the cochlear non-sensory cells as well. We have here studied the stress response mounted in the lateral wall of the cochlea during acute noise stress and during age-related chronic stress. We have used the activation of JNK/c-Jun, ERK, and NF-κB pathways as a readout of the stress response, and the expression of the FoxO3 transcription factor as a possible additional player in cellular stress. In the aging cochlea, NF-κB transcriptional activity was strongly induced in the stria vascularis of the lateral wall. This induction was linked with the atrophy of the stria vascularis, suggesting a role for NF-κB signaling in mediating age-related strial degeneration. Acutely following noise exposure, the JNK/c-Jun, ERK, and NF-κB pathways were activated in the spiral ligament of the lateral wall of CBA/Ca mice. This activation was concomitant with the morphological transformation of macrophages, suggesting that the upregulation of stress signaling leads to macrophage activation. In contrast, C57BL/6J mice lacked these responses. Only the combination of noise exposure and a systemic stressor, lipopolysaccharide, exceeded the threshold for the activation of stress signaling in the lateral wall of C57BL/6J mice. In addition, we found that, at the young adult age, outer hair cells of CBA/Ca mice are much more vulnerable to loud sounds compared to these cells of C57BL/6J mice. These results suggest that the differential stress response in the lateral wall of the two mouse strains underlies, in part, the differential noise vulnerability of their outer hair cells. Together, we propose that the molecular stress response in the lateral wall modulates the outcome of the stressed cochlea.

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The RNA-Specific Adenosine Deaminase ADAR1 Inhibits Human Protein Kinase R Activation

Viral Immunology, Volume 31, Issue 7, Page 537-538, September 2018.

https://ift.tt/2CtLlcQ

Interaction of S17 Antibody with the Functional Binding Region of the Hepatitis B Virus Pre-S2 Epitope

Viral Immunology, Volume 31, Issue 7, Page 492-499, September 2018.

https://ift.tt/2wQOf6d

Interactions between hypothalamic pituitary thyroid axis and other pituitary dysfunctions

Abstract

Central hypothyroidism is defined as low circulating free thyroxine (free T4) with inappropriately low circulating thyrotropin (TSH), in context of a hypothalamic pituitary pathology. Rare cases of idiopathic central hypothyroidism caused by a functional defect may occur, and the condition is often overlooked due to difficulty in achieving the correct diagnosis, sparse symptomatology of the condition and a high risk of misinterpretion of the biochemical changes in central hypothyroidism. Central hypothyroidism is mainly seen in patients with hypothalamic–pituitary pathology due to one of many possible aetiologies, where other hormone deficiencies often co-exist, and both the presence of other deficiencies and their replacement have a strong influence on the measurement of the thyroid-related hormones and thereby interpretation of the thyroid function variables in relation to the clinical impact of thyroid hormone substitution therapy. Conversely, lack of thyroid hormone has a similar strong influence on the interpretation of other pituitary hormone axes, as well as their replacement. Undertreating patients with central hypothyroidism may have serious metabolic consequences with a potentially increased risk of cardiovascular morbidity. The present review thus aims at describing central hypothyroidism, by an overview of interactions of hypothyroidism with other pituitary hormones, diagnosing/testing for central hypothyroidism, and focusing on consequences of undertreatment. Finally, it is mentioned how to deal with new diagnostic settings with lower a priori likelihood of hypopituitarism, particularly in view of the importance of stringent diagnostic testing in order to avoid overdiagnosing central hypothyroidism.

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Interactions between hypothalamic pituitary thyroid axis and other pituitary dysfunctions

Abstract

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Transcriptome analysis to identify the Ras and Rap1 signal pathway genes involved in the response of TM3 Leydig cells exposed to zearalenone

Abstract

The mechanism of action of zearalenone (ZEA) in inducing germ cell tumors is unclear, and little is known about the change in the transcriptome of germ cells after ZEA exposure. To explore the molecular basis of the ZEA oncogene, we examined the median lethal concentration (50 μmol/L) and pro-apoptotic effect of ZEA on TM3 Leydig cells by MTT and TUNEL assay. Subsequently, we investigated the genetic changes in the transcriptome of TM3 Leydig cells exposed to 50 μmol/L ZEA. The transcriptome sequencing results show that 772 genes are significantly down-regulated, while 204 genes are significantly up-regulated. Gene ontology (GO) enrichment analysis shows that ZEA has a major effect on the connective function, cell composition, cell cycle, and energy metabolism of the TM3 Leydig cells. Using the results of the GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, we select the Ras and Rap1 signaling pathways that are closely related to the occurrence of cancer. The differentially expressed genes visualized in the KEGG pathway were selected for RT-qPCR differential gene expression validation. The results show that the gene expression results are consistent with the transcriptome sequencing results. This study thus provides a theoretical molecular basis for the mechanism of ZEA carcinogenesis.

https://ift.tt/2M57tcZ

Comparison of relative and absolute rectal dose–volume parameters and clinical correlation with acute and late radiation proctitis in prostate cancer patients

Abstract

Purpose

To compare relative and absolute dose–volume parameters (DV) of the rectum and their clinical correlation with acute and late radiation proctitis (RP) after radiotherapy (RT) for prostate cancer (PCa).

Patients and methods

366 patients received RT for PCa. In total, 49.2% received definitive RT, 20.2% received postoperative RT and 30.6% received salvage RT for biochemical recurrence. In 77.9% of patients, RT was delivered to the prostate or prostate bed, and additional whole pelvic RT was performed in 22.1%. 33.9% received 3D-RT, and 66.1% received IMRT. The median follow-up was 59.5 months (18.0–84.0 months). The relative (in %) and absolute (in ccm) rectal doses from 20–75 Gy including the receiver operating characteristics curves (rAUC) from 30–65 Gy (in % and ccm) and several other clinical parameters were analyzed in univariate and multivariate analyses. We performed the statistical analyses separately for the entire cohort (n = 366), patients with (n = 81) and without (n = 285) pelvic RT, comparing RP vs. RP ≥ grade I.

Results

With the exception of the V50_Gyccm (p = 0.02) in the univariate analyses for acute RP in the entire patient cohort, no absolute DV parameter (in ccm) was statistically significant associated with either acute or late RP. In the multivariate analyses, 3D-RT (p < 0.008) and rAUC_V30–50 _Gy% (p = 0.006) were significant parameters for acute RP for the entire cohort, and the V50_Gy% (p = 0.01) was the significant parameter for patients with pelvic RT. The rAUC_V40–50 _Gy% (p = 0.004) was significant for RT to the prostate/prostate bed. Regarding the statistical analysis for late RP, the rAUC_V30–65 _Gy% (p = 0.001) was significant for the entire cohort, and rAUC_V30–50 _Gy% (p = 0.001) was significant for RT of the prostate/prostate bed. No parameter was significant in patients with pelvic RT.

Conclusion

Absolute DV parameters in ccm are not required for RT in PCa patients.

https://ift.tt/2M6FR7m

Noise-Induced Hypersensitization of the Acoustic Startle Response in Larval Zebrafish

ABSTRACT

https://ift.tt/2NSJ1O1

Improved Neural Coding of ITD with Bilateral Cochlear Implants by Introducing Short Inter-pulse Intervals

Abstract

Bilateral cochlear implant (CI) users have poor perceptual sensitivity to interaural time differences (ITDs), which limits their ability to localize sounds and understand speech in noisy environments. This is especially true for high-rate (> 300 pps) periodic pulse trains, which are used as carriers in CI processors. Here, we investigate a novel stimulation strategy in which extra pulses are added to high-rate periodic pulse trains to introduce short inter-pulse intervals (SIPIs). We hypothesized that SIPIs can improve neural ITD sensitivity similarly to the effect observed by randomly jittering IPIs (Hancock et al., J. Neurophysiol. 108:714–28, 2012). To test this hypothesis, we measured ITD sensitivity of single units in the inferior colliculus (IC) of unanesthetized rabbits with bilateral CIs. Introducing SIPIs into high-rate pulse trains significantly increased firing rates for ~ 60 % of IC neurons, and the extra spikes tended to be synchronized to the SIPIs. The additional firings produced by SIPIs uncovered latent ITD sensitivity that was comparable to that observed with low-rate pulse trains. In some neurons, high spontaneous firing rates masked the ITD sensitivity introduced by SIPIs. ITD sensitivity in these neurons could be revealed by emphasizing stimulus-synchronized spikes with a coincidence detection analysis. Overall, these results with SIPIs are consistent with the effects observed previously with jittered pulse trains, with the added benefit of retaining control over the timing and number of SIPIs. A novel CI processing strategy could incorporate SIPIs by inserting them at selected times to high-rate pulse train carriers. Such a strategy could potentially improve ITD perception without degrading speech intelligibility and thereby improve outcomes for bilateral CI users.

https://ift.tt/2M0yX3G

The Stress Response in the Non-sensory Cells of the Cochlea Under Pathological Conditions—Possible Role in Mediating Noise Vulnerability

Abstract

https://ift.tt/2wQcoKm

Surface Motion of Tympanic Membrane in a Chinchilla Model of Acute Otitis Media

Abstract

The conductive hearing loss caused by acute otitis media (AOM) is commonly related to a reduction of the tympanic membrane (TM) mobility in response to sound stimuli. However, spatial alterations of the TM surface motion associated with AOM have rarely been addressed. In this study, the TM surface motion was determined using scanning laser Doppler vibrometry (SLDV) in a chinchilla model of AOM. The AOM was established by transbullar injection of nontypeable Haemophilus influenzae. The TM surface vibration was measured in control (uninfected) animals and two AOM groups of animals: 4 days (4D) and 8 days (8D) post inoculation. To quantify the effect of middle ear pressure in those infected ears, the SLDV measurement was first conducted in unopened AOM ears and then in middle ear pressure released ears. Results showed that middle ear infection generally reduced the TM displacement across the entire surface, but the reduction in the umbo displacement over the time course, from 4 to 8 days post inoculation, was less than the reduction in the displacement at the center of each quadrant. The presence of middle ear fluid shifted the occurrence of traveling-wave-like motion on the TM surface to lower frequencies. The observation of the spatial variations of TM surface motion from this study will help refine our understanding of the middle ear sound transmission characteristics in relation to AOM.

https://ift.tt/2MToV9X

Does the King Airway system signal the end of intubation skills?

Our co-hosts tackle the topic of supraglottic airways, and the best way to approach them in the field

https://ift.tt/2Ma8roI

Assessment of hair cortisol in euthyroid, hypothyroid, and subclinical hypothyroid subjects

Abstract

Purpose

Hypothyroidism is associated with an increase in serum cortisol level while the long-term activity of hypothalamic-pituitary-adrenal (HPA) axis in hypothyroid, and subclinical hypothyroid (SCH) subjects has not been studied. This study aimed to assess the hair cortisol levels as a long-term activity of HPA axis in hypothyroid, SCH and a group of healthy adult subjects. Also, it aimed to examine the correlation of hair cortisol levels with hypothalamic-pituitary-thyroid (HPT) axis and anthropometric measures.

Methods

We prospectively evaluated a group of normal, SCH and hypothyroid subjects. Serum TSH, FT4, and FT3 were measured as a component of the HPT axis. Hair samples were collected, prepared, followed by extraction of hair cortisol and measurement in pg/mg of hair. Hair cortisol levels were compared in normal, SCH and hypothyroid groups and correlated with HPT axis and anthropometric data.

Results

A total of 65 healthy volunteers were analyzed, and the mean hair cortisol level was reported to be 17.38 pg/mg of hair. Hair cortisol level was slightly higher in the SCH subjects, 18.19 pg/mg of hair; however the difference was not significant. Compared to the euthyroid subject, a significantly higher hair cortisol level was recorded in the hypothyroid subjects, 24.17 pg/mg hair, p < .05. Hair cortisol was significantly and positively associated with each of the serum TSH, age, weight and BMI (p < .05).

Conclusions

Overt hypothyroidism but not SCH is significantly associated with higher hair cortisol levels compared to normal subjects, and a significant relation between hair cortisol with HPT axis was found. Also, weight and BMI were positively correlated with hair cortisol level.

https://ift.tt/2CmhUtc

Assessment of hair cortisol in euthyroid, hypothyroid, and subclinical hypothyroid subjects

Abstract

Purpose

Methods

Results

Conclusions

https://ift.tt/2CmhUtc

Improved Neural Coding of ITD with Bilateral Cochlear Implants by Introducing Short Inter-pulse Intervals

Abstract

https://ift.tt/2M0yX3G

Surface Motion of Tympanic Membrane in a Chinchilla Model of Acute Otitis Media

Abstract

https://ift.tt/2MToV9X

Survival Among Patients With HER2-Positive Breast Cancer Treated With Sequential vs Concurrent Chemotherapy

This phase 3 randomized clinical trial compares disease-free and overall survival among patients with operable HER2-positive breast cancer who received concurrent vs sequential administration of neoadjuvant chemotherapy.

https://ift.tt/2M3Jqvi

Information Transparency in the Drug Approval Process—Reply

In Reply We read with interest the letter by Rini and colleagues in response to our Viewpoint, and we thank them for making us aware of the substantial information available at the US Food and Drug Administration's (FDA's) Oncologic Drugs Advisory Committee (ODAC) website. However, we still believe that there was excessive focus on disease-free survival (DFS) over overall survival (OS) at the committee meeting, for 2 main reasons.

https://ift.tt/2Qawqaf

Information Transparency in the Drug Approval Process

To the Editor Drs Gyawali and Goldstein recently published a Viewpoint in which they accuse the US Food and Drug Administration's (FDA's) Oncologic Drugs Advisory Committee (ODAC) of being ignorant of overall survival (OS) data from the S-TRAC adjuvant sunitinib trial, and that this ignorance led to a recommendation for approval from 6 ODAC members and subsequently the FDA. They further accuse the sponsor of hiding the OS data in the Supplement of the full publication.

https://ift.tt/2wLZlIV

Clinical Trials, End Points, and Statistics—Measuring and Comparing Cancer Treatments in Practice

This Patient Page defines the some of the important terms and techniques that cancer researchers use to measure and report their findings.

https://ift.tt/2M3INlq

Terminal Cancer and Death—On Grief

This essay describes the process of coming to an understanding of grief following the death of a family member who had cancer.

https://ift.tt/2Q7uPSB

Trichloroacetic acid as a treatment for persistent oral mucosal lesions in pemphigus vulgaris

Publication date: Available online 6 September 2018

Source: Journal of the American Academy of Dermatology

Author(s): Hamidreza Mahmoudi, Kamran Balighi, Soheil Tavakolpour, Maryam Daneshpazhooh, Cheyda Chams-Davatchi

https://ift.tt/2wPfZHt

Lightening Becker’s nevus: Role of topical therapies

Publication date: Available online 6 September 2018

Source: Journal of the American Academy of Dermatology

Author(s): Naveen Kumar Kansal

https://ift.tt/2Q842pc

Reply to MS#JAAD-D-18-01527

Publication date: Available online 6 September 2018

Source: Journal of the American Academy of Dermatology

Author(s): Mao-Qiang Man

https://ift.tt/2M3o9lr

Ruxolitinib for the treatment of severe alopecia areata

Publication date: Available online 6 September 2018

Source: Journal of the American Academy of Dermatology

Author(s): Lucy Y. Liu, Brett A. King

https://ift.tt/2Qawmav

Inflammation cutanée de contiguïté : situations diverses et contours flous

Publication date: Available online 5 September 2018

Source: Annales de Dermatologie et de Vénéréologie

Author(s): P. del Giudice

https://ift.tt/2NNVd2m

Comparison of Opioid Utilization Patterns After Major Head and Neck Procedures

This observational study compares postoperative use of opioids between the United States and Hong Kong in patients undergoing head and neck surgery.

https://ift.tt/2wOZHiO

Validation of Haptic Properties of Materials for Endoscopic Sinus and Skull Base Surgery Simulation—Reply

In Reply In their analysis of our study, Dr Favier and colleagues suggest improvements in methodology to focus on haptic feedback fidelity through mechanical testing. We appreciate this thoughtful commentary and agree that both subjective and quantifiable measures are needed to optimally evaluate surgical simulators. As seen in their study evaluating mechanical characteristics of 3-dimensionally (3D)-printed material for skull base procedures, certain 3D-printed materials may differ in mechanical forces compared with human cadaver bone. Further, cadaver bone may not realistically represent in vivo sinus lamellae. Accordingly, although objective measurements of mechanical force are ideal, the intended audience of the simulator must also participate in the evaluation to assist in determining realism of the haptic feedback. Although we acknowledge that study participants were mostly resident physicians, surgical trainees are frequently the intended audience for surgical simulation and should be included in the development of such simulators. One method for evaluating the qualifications of study participants would be to choose a set number of live surgical experiences and statistically evaluate whether surgical experience affects participant rating of haptic feedback. Unfortunately, given the small sample size in our study, meaningful conclusions would be difficult to draw with these limited data.

https://ift.tt/2CqpEdD

Validation of Haptic Properties of Materials for Endoscopic Sinus and Skull Base Surgery Simulation

To the Editor In the field of rhinology and skull base surgery, many 3-dimensionally (3D)-printed simulators have been described. In their study, Hsieh and colleagues consider a material, VeroWhite, for endoscopic sinus and skull base surgical model 3D-printing. The aim was to study the anatomical accuracy and haptic feedback of the model to validate its use for surgical learning. Its anatomical accuracy was scientifically determined, thanks to a double comparison: segmentation of real patient anatomy compared with segmentation of the 3D-printed model; image-guided navigation on the model using the patient's original computed tomographic (CT) findings, to assess the accuracy of 13 important surgical landmarks. The authors concluded that VeroWhite was suitable to print accurate anatomical 3D models of the skull base and sinuses.

https://ift.tt/2oLDDBa

Association of Cognition and Age-Related Hearing Impairment

This cohort study investigates the link between age-related hearing impairment and cognitive decline and explores untreated hearing loss and social isolation as potential explanations in a cohort of individuals 50 years or older from the United Kingdom.

https://ift.tt/2wO2Sql

Symptom Burden Associated With Late Lower Cranial Neuropathy in Long-term Oropharyngeal Cancer Survivors

This cross-sectional survey study of oropharyngeal cancer survivors investigates the association of late lower cranial neuropathy with severity of cancer treatment–related symptoms and general functional impairment.

https://ift.tt/2oJj8VM

Preoperative Imaging in Primary Hyperparathyroidism

This narrative review describes the advantages and disadvantages of current and emerging preoperative imaging technologies for primary hyperparathyroidism.

https://ift.tt/2Cptwvv

Invisible Empire of Hate: Gender Differences in the Ku Klux Klan's Online Justifications for Violence

Violence and Gender, Ahead of Print.

https://ift.tt/2wNYMhX

New Perspectives on the Pathogenesis of PCOS: Neuroendocrine Origins

Publication date: Available online 5 September 2018

Source: Trends in Endocrinology & Metabolism

Author(s): Kirsty A. Walters, Robert B. Gilchrist, William L. Ledger, Helena J. Teede, David J. Handelsman, Rebecca E. Campbell

Polycystic ovary syndrome (PCOS) is the most common endocrine condition in reproductive-aged women. It is characterized by reproductive, endocrine, metabolic, and psychological features. The cause of PCOS is unknown, thus there is no cure and its management remains suboptimal because it relies on the ad hoc empirical management of symptoms only. We review here the strong support for PCOS having a neuroendocrine origin. In particular, we focus on the role of aberrant hypothalamic–pituitary function and associated hyperandrogenism, and their role as major drivers of the mechanisms underpinning the development of PCOS. This important information now provides a target site and a potential mechanism for the future development of novel, targeted, and mechanism-based effective therapies for the treatment of PCOS.

https://ift.tt/2wRQGW8

Regulatory T cell deficiency and autoimmune skin disease: beyond scurfy mouse and IPEX

Publication date: Available online 6 September 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Takashi Hashimoto, Hayato Takahashi, Shimon Sakaguchi

https://ift.tt/2NoWb8e

RhoA/ROCK Signaling Modulates Lineage Commitment of Mesenchymal Stem Cells in Asthma through Lef1

Publication date: Available online 5 September 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Xia Ke, Danh C. Do, Changjun Li, Yilin Zhao, Marian Kollarik, Qingling Fu, Mei Wan, Peisong Gao

ABSTRACT

Rationale

Mesenchymal stem cells (MSCs) are increased in the airways after allergen challenge. RhoA/ROCK signaling is critical in determining the lineage fate of MSCs in tissue repair/remodeling.

Objectives

To investigate the role of RhoA/ROCK signaling in lineage commitment of MSCs during allergen-induced airway remodeling and delineate the underlying mechanisms.

Methods

Active RhoA expression in asthmatic lung tissues and its role in cockroach allergen-induced airway inflammation and remodeling were investigated. The RhoA/ROCK signaling-mediated MSC lineage commitment was assessed in an asthma mouse model using MSC lineage tracing mice (nestin-Cre; ROSA26-EYFP). The role of RhoA/ROCK in MSC lineage commitment was also examined by MSCs expressing constitutively active RhoA (RhoA-L63) or dominant negative RhoA (RhoA-N19). Downstream RhoA-regulated genes were identified using the stem cell signaling array.

Results

Lung tissues from asthmatic mice showed increased expression of active RhoA when compared with those from controls. Inhibition of RhoA/ROCK signaling with fasudil, a RhoA/ROCK inhibitor, reversed established cockroach allergen-induced airway inflammation and remodeling as assessed by more collagen deposition/fibrosis. Furthermore, fasudil inhibited MSC differentiation into fibroblasts/myofibroblasts, but promoted MSC differentiation into epithelial cells in asthmatic nestin-Cre; ROSA26-EYFP mice. Consistently, expression of RhoA-L63 facilitated the differentiation of MSCs to fibroblasts/myofibroblasts, whereas expression of RhoA-19 switched the differentiation toward epithelial cells. Gene Array identified the Wnt signaling effector Lef1 as the most up-regulated gene in RhoA-L63-transfected MSCs. Knockdown of Lef1 induced MSC differentiation away from fibroblasts/myofibroblasts but towards epithelial cells.

Conclusions

These findings uncover a previously unrecognized role of RhoA/ROCK signaling in MSC-involved airway repair/remodeling in asthma.

https://ift.tt/2PGtMYM

Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency

Publication date: Available online 5 September 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Donald B. Kohn, Michael S. Hershfield, Jennifer M. Puck, Alessandro Aiuti, Annaliesse Blincoe, H. Bobby Gaspar, Luigi D. Notarangelo, Eyal Grunebaum

Abstract

Inherited defects in adenosine deaminase (ADA) cause a subtype of severe combined immunodeficiency (SCID), known as ADA-SCID. Most affected infants can be diagnosed while still asymptomatic by a SCID newborn screening test, allowing early initiation of therapy. We reviewed the evidence currently available and propose a consensus management strategy. In addition to the treatment of the immune deficiency of ADA-SCID, patients should be followed for specific non-infectious respiratory, neurological and biochemical complications associated with ADA deficiency. All patients should initially receive enzyme replacement therapy (ERT), followed by definitive treatment with either of two equal first line options. If an HLA matched sibling donor (MSD) or matched family donor (MFD) is available, allogeneic hematopoietic stem cell transplantation (HSCT) should be pursued. The excellent safety and efficacy observed in over 100 ADA-SCID patients who received gamma-retrovirus or lentivirus mediated autologous hematopoietic stem cell gene therapy (HSC-GT) since 2000 now positions HSC-GT as an equal alternative. If MSD/MFD HSCT or HSC-GT are not available or have failed, ERT can be continued or re-instituted, and HSCT using alternative donors should be considered. The outcomes of novel HSCT, ERT and HSC-GT strategies should be evaluated prospectively in "real life" conditions to further inform these management guidelines.

https://ift.tt/2MTPSdx

Dupilumab progressively improves systemic and cutaneous abnormalities in atopic dermatitis patients

Publication date: Available online 5 September 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Emma Guttman-Yassky, Robert Bissonnette, Benjamin Ungar, Mayte Suárez-Fariñas, Marius Ardeleanu, Hitokazu Esaki, Maria Suprun, Yeriel Estrada, Hui Xu, Xiangyu Peng, Jonathan I. Silverberg, Alan Menter, James G. Krueger, Rick Zhang, Usman Chaudhry, Brian Swanson, Neil M.H. Graham, Gianluca Pirozzi, George D. Yancopoulos, Jennifer D.D. Hamilton

ABSTRACT

Background

Dupilumab is an IL-4Rα monoclonal antibody inhibiting signaling of IL-4/IL-13, key drivers of Type 2-driven inflammation, as demonstrated by its efficacy in atopic/allergic diseases.

Objective

This placebo-controlled, double-blind trial (NCT01979016) evaluated efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic Type 2 biomarkers of moderate-to-severe atopic dermatitis (AD) patients.

Methods

Skin biopsies and blood were evaluated from 54 patients randomized 1:1 to weekly subcutaneous 200 mg dupilumab or placebo for 16 weeks.

Results

Dupilumab (versus placebo) significantly improved AD clinical signs and symptoms, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4–16). Mean improvements in a meta-analysis-derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8% and 110.8% with dupilumab and −10.5% and 55.0% with placebo (weeks 4 and 16, respectively; P<0.001). Dupilumab significantly reduced expression of genes involved in Type 2 inflammation (IL-13/IL-31/CCL17/CCL18/CCL26), epidermal hyperplasia (K16/MKi67), T-cells, dendritic cells (ICOS/CD11c/CTLA4), and Th17/Th22 activity (IL-17A/IL-22/S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid-metabolism genes (FLG/LOR/claudins/ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P=0.001; week 16, P=0.0002). Improvements in clinical and histological measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed Type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen-specific IgEs.

Conclusion

Dupilumab-mediated inhibition of IL-4/IL-13 signaling via IL-4Rα blockade significantly and progressively improved disease activity, suppressed cellular/molecular cutaneous markers of inflammation and systemic measures of Type 2 inflammation, and reversed AD-associated epidermal abnormalities.

https://ift.tt/2PIpu34

Paraben exposures and asthma-related outcomes among children from the U.S. general population

Publication date: Available online 5 September 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Lesliam Quirós-Alcalá, Nadia N. Hansel, Meredith C. McCormack, Elizabeth C. Matsui

ABSTRACT

Background

Parabens are synthetic preservatives present in many consumer products. Their antimicrobial and endocrine disrupting properties have raised concerns that they may play a role in respiratory and allergic diseases; however, studies exploring these associations are scarce.

Objective

We examined the cross-sectional association between parabens and asthma morbidity among 450 children with asthma and with asthma prevalence among 4,023 children in the U.S. general population, participating in the National Health and Nutrition Examination Survey (2005-2014).

Methods

We conducted multivariable logistic regression to examine associations between urinary paraben biomarker concentrations (butyl-BP, ethyl-EP, methyl-MP, and propyl-PP) and asthma attacks and emergency department (ED) visits among children with asthma, and with current asthma diagnosis among all children. We also examined heterogeneity of associations by sex.

Results

We observed an increased prevalence odds of reporting ED visits for every 10-fold increase in MP and PP concentrations among boys with asthma (adjusted prevalence odds ratio, aPOR:2.61, 95% confidence interval, CI:1.40, 4.85 and aPOR:2.18, 95%CI:1.22, 3.89, respectively; p_{interaction-MP}=0.002; p_{interaction-PP}=0.003); associations remained after adjusting for other phenolic compounds previously linked to respiratory outcomes. No other dimorphic effects of exposure by sex were observed. Among children in the general population, no overall associations with current asthma were observed, although there was a positive trend with PP and current asthma diagnosis.

Conclusion

We identified differential effects of exposure to select parabens by sex on asthma morbidity. Further studies are needed to replicate these findings, and elucidate mechanisms by which parabens could impact respiratory health and elicit dimorphic effects by sex.

https://ift.tt/2MTPMmb

Midostaurin in patients with indolent systemic mastocytosis: An open-label phase 2 trial

Publication date: September 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 3

Author(s): Bjorn van Anrooij, Joanne N.G. Oude Elberink, Lambert F.R. Span, Jan G.R. de Monchy, Stefano Rosati, André B. Mulder, Johanna C. Kluin-Nelemans

https://ift.tt/2MP8fQN

Insulin decreases expression of the proinflammatory receptor proteinase-activated receptor-2 on human airway epithelial cells

Publication date: September 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 3

Author(s): Vivek D. Gandhi, Nami Shrestha Palikhe, Shereen M. Hamza, Jason R.B. Dyck, Jean Buteau, Harissios Vliagoftis

https://ift.tt/2NPl2ip

Deconstructive somatic cell nuclear transfer reveals novel regulatory T-cell subsets

Publication date: September 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 3

Author(s): Manching Ku, Eugene Ke, Mohsen Sabouri-Ghomi, Justin R. Abadejos, Brent Freeman, Amy Nham, Nathaniel Phillips, Kevin Y. Yang, Kathy O. Lui, Oktay Kirak

https://ift.tt/2PK8WI5

Aspergillosis, eosinophilic esophagitis, and allergic rhinitis in signal transducer and activator of transcription 3 haploinsufficiency

Publication date: September 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 3

Author(s): Mukil Natarajan, Amy P. Hsu, Michael A. Weinreich, Yuan Zhang, Julie E. Niemela, John A. Butman, Stefania Pittaluga, Janyce Sugui, Amanda L. Collar, Jean K. Lim, Tirdad Zangeneh, Tara Carr, Andrew J. Oler, Morgan Similuk, Lindsey B. Rosen, Jigar V. Desai, Alexandra F. Freeman, Steven M. Holland, Kyung J. Kwon-Chung, Joshua D. Milner

https://ift.tt/2MTzFVM

Association of ST2 polymorphisms with atopy, asthma, and leukemia

Publication date: September 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 3

Author(s): Melissa H. Bloodworth, Mark Rusznak, Lisa Bastarache, Janey Wang, Joshua C. Denny, R. Stokes Peebles

https://ift.tt/2PK2fps

Micro RNAs are required for Langerhans cell, skin- and lung-resident macrophage ontogeny

Publication date: September 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 3

Author(s): Yi Yao, Carly Martin, Congcong Yin, Chunyuan Guo, Zheng Dong, Li Zhou, Qing-Sheng Mi

https://ift.tt/2MRlYXf

AllergoOncology: Generating a canine anticancer IgE against the epidermal growth factor receptor

Publication date: September 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 3

Author(s): Judit Fazekas-Singer, Josef Singer, Kristina M. Ilieva, Miroslawa Matz, Ina Herrmann, Edzard Spillner, Sophia N. Karagiannis, Erika Jensen-Jarolim

https://ift.tt/2PK8Joh

Reference values for peripheral blood lymphocyte subsets of healthy children in China

Publication date: September 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 3

Author(s): Yuan Ding, Lina Zhou, Yu Xia, Wei Wang, Ying Wang, Li Li, Zhongxiang Qi, Linqing Zhong, Jinqiao Sun, Wenjing Tang, Fangfang Liang, Haijuan Xiao, Tao Qin, Ying Luo, Xuezhen Zhao, Zhou Shu, Ying Ru, Rongxin Dai, Hong Wang, Yanping Wang

https://ift.tt/2NnpE2j

Ozone exposure induces respiratory barrier biphasic injury and inflammation controlled by IL-33

Publication date: September 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 3

Author(s): Chloé Michaudel, Claire Mackowiak, Isabelle Maillet, Louis Fauconnier, Cezmi A. Akdis, Milena Sokolowska, Anita Dreher, Hern-Tze Tina Tan, Valérie F. Quesniaux, Bernhard Ryffel, Dieudonnée Togbe

Background

IL-33 plays a critical role in regulation of tissue homeostasis, injury, and repair. Whether IL-33 regulates neutrophil recruitment and functions independently of airways hyperresponsiveness (AHR) in the setting of ozone-induced lung injury and inflammation is unclear.

Objective

We sought to examine the role of the IL-33/ST2 axis in lung inflammation on acute ozone exposure in mice.

Methods

ST2- and Il33–deficient, IL-33 citrine reporter, and C57BL/6 (wild-type) mice underwent a single ozone exposure (1 ppm for 1 hour) in all studies. Cell recruitment in lung tissue and the bronchoalveolar space, inflammatory parameters, epithelial barrier damage, and airway hyperresponsiveness (AHR) were determined.

Results

We report that a single ozone exposure causes rapid disruption of the epithelial barrier within 1 hour, followed by a second phase of respiratory barrier injury with increased neutrophil recruitment, reactive oxygen species production, AHR, and IL-33 expression in epithelial and myeloid cells in wild-type mice. In the absence of IL-33 or IL-33 receptor/ST2, epithelial cell injury with protein leak and myeloid cell recruitment and inflammation are further increased, whereas the tight junction proteins E-cadherin and zonula occludens 1 and reactive oxygen species expression in neutrophils and AHR are diminished. ST2 neutralization recapitulated the enhanced ozone-induced neutrophilic inflammation. However, myeloid cell depletion using GR-1 antibody reduced ozone-induced lung inflammation, epithelial cell injury, and protein leak, whereas administration of recombinant mouse IL-33 reduced neutrophil recruitment in Il33–deficient mice.

Conclusion

Data demonstrate that ozone causes an immediate barrier injury that precedes myeloid cell–mediated inflammatory injury under the control of the IL-33/ST2 axis. Thus IL-33/ST2 signaling is critical for maintenance of intact epithelial barrier and inflammation.

Graphical abstract

Graphical abstract for this article

https://ift.tt/2NTJSOk

Efficacy of lentivirus-mediated gene therapy in an Omenn syndrome recombination-activating gene 2 mouse model is not hindered by inflammation and immune dysregulation

Publication date: September 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 3

Author(s): Valentina Capo, Maria Carmina Castiello, Elena Fontana, Sara Penna, Marita Bosticardo, Elena Draghici, Luigi P. Poliani, Lucia Sergi Sergi, Rosita Rigoni, Barbara Cassani, Monica Zanussi, Paola Carrera, Paolo Uva, Kerry Dobbs, Nicolò Sacchetti, Luigi D. Notarangelo, Niek P. van Til, Gerard Wagemaker, Anna Villa

Background

Omenn syndrome (OS) is a rare severe combined immunodeficiency associated with autoimmunity and caused by defects in lymphoid-specific V(D)J recombination. Most patients carry hypomorphic mutations in recombination-activating gene (RAG) 1 or 2. Hematopoietic stem cell transplantation is the standard treatment; however, gene therapy (GT) might represent a valid alternative, especially for patients lacking a matched donor.

Objective

We sought to determine the efficacy of lentiviral vector (LV)–mediated GT in the murine model of OS (Rag2^R229Q/R229Q) in correcting immunodeficiency and autoimmunity.

Methods

Lineage-negative cells from mice with OS were transduced with an LV encoding the human RAG2 gene and injected into irradiated recipients with OS. Control mice underwent transplantation with wild-type or OS-untransduced lineage-negative cells. Immunophenotyping, T-dependent and T-independent antigen challenge, immune spectratyping, autoantibody detection, and detailed tissue immunohistochemical analyses were performed.

Results

LV-mediated GT allowed immunologic reconstitution, although it was suboptimal compared with that seen in wild-type bone marrow (BM)−transplanted OS mice in peripheral blood and hematopoietic organs, such as the BM, thymus, and spleen. We observed in vivo variability in the efficacy of GT correlating with the levels of transduction achieved. Immunoglobulin levels and T-cell repertoire normalized, and gene-corrected mice responded properly to challenges in vivo. Autoimmune manifestations, such as skin infiltration and autoantibodies, dramatically improved in GT mice with a vector copy number/genome higher than 1 in the BM and 2 in the thymus.

Conclusions

Our data show that LV-mediated GT for patients with OS significantly ameliorates the immunodeficiency, even in an inflammatory environment.

https://ift.tt/2NnpCHJ

An actin cytoskeletal barrier inhibits lytic granule release from natural killer cells in patients with Chediak-Higashi syndrome

Publication date: September 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 3

Author(s): Aleksandra Gil-Krzewska, Mezida B. Saeed, Anna Oszmiana, Elizabeth R. Fischer, Kathryn Lagrue, William A. Gahl, Wendy J. Introne, John E. Coligan, Daniel M. Davis, Konrad Krzewski

Background

Chediak-Higashi syndrome (CHS) is a rare disorder caused by biallelic mutations in the lysosomal trafficking regulator gene (LYST), resulting in formation of giant lysosomes or lysosome-related organelles in several cell types. The disease is characterized by immunodeficiency and a fatal hemophagocytic lymphohistiocytosis caused by impaired function of cytotoxic lymphocytes, including natural killer (NK) cells.

Objective

We sought to determine the underlying biochemical cause of the impaired cytotoxicity of NK cells in patients with CHS.

Methods

We generated a human cell model of CHS using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology. We used a combination of classical techniques to evaluate lysosomal function and cell activity in the model system and super-resolution microscopy to visualize F-actin and lytic granules in normal and LYST-deficient NK cells.

Results

Loss of LYST function in a human NK cell line, NK92mi, resulted in inhibition of NK cell cytotoxicity and reproduced other aspects of the CHS cellular phenotype, including the presence of significantly enlarged lytic granules with defective exocytosis and impaired integrity of endolysosomal compartments. The large granules had an acidic pH and normal activity of lysosomal enzymes and were positive for the proteins essential for lytic granule exocytosis. Visualization of the actin meshwork openings at the immunologic synapse revealed that the cortical actin acts as a barrier for secretion of such large granules at the cell-cell contact site. Decreasing the cortical actin density at the immunologic synapse or decreasing the lytic granule size restored the ability of LYST-deficient NK cells to degranulate and kill target cells.

Conclusion

The cortical actin and granule size play significant roles in NK cell cytotoxic function. We present evidence that the periodicity of subsynaptic actin is an important factor limiting the release of large lytic granules from NK cells from patients with CHS and could be a novel target for pharmaceutical intervention.

https://ift.tt/2NSvpCm

Metformin and blood cancers

Type 2 diabetes mellitus and cancer are correlated with changes in insulin signaling, a pathway that is frequently upregulated in neoplastic tissue but impaired in tissues that are classically targeted by insulin in type 2 diabetes mellitus. Many antidiabetes treatments, particularly metformin, enhance insulin signaling, but this pathway can be inhibited by specific cancer treatments. The modulation of cancer growth by metformin and of insulin sensitivity by anticancer drugs is so common that this phenomenon is being studied in hundreds of clinical trials on cancer. Many meta-analyses have consistently shown a moderate but direct effect of body mass index on the incidence of multiple myeloma and lymphoma and the elevated risk of leukemia in adults. Moreover, new epidemiological and preclinical studies indicate metformin as a therapeutic agent in patients with leukemia, lymphomas, and multiple myeloma. In this article, we review current findings on the anticancer activities of metformin and the underlying mechanisms from preclinical and ongoing studies in hematologic malignancies.

https://ift.tt/2M6E3eV

Revisiting the roles of VHR/DUSP3 phosphatase in human diseases

Protein tyrosine phosphatases have long been considered key regulators of biological processes and are therefore implicated in the origins of various human diseases. Heterozygosity, mutations, deletions, and the complete loss of some of these enzymes have been reported to cause neurodegenerative diseases, autoimmune syndromes, genetic disorders, metabolic diseases, cancers, and many other physiological imbalances. Vaccinia H1-related phosphatase, also known as dual-specificity phosphatase 3, is a protein tyrosine phosphatase enzyme that regulates the phosphorylation of the mitogen-activated protein kinase signaling pathway, a central mediator of a diversity of biological responses. It has been suggested that vaccinia H1-related phosphatase can act as a tumor suppressor or tumor-promoting phosphatase in different cancers. Furthermore, emerging evidence suggests that this enzyme has many other biological functions, such as roles in immune responses, thrombosis, hemostasis, angiogenesis, and genomic stability, and this broad spectrum of vaccinia H1-related phosphatase activity is likely the result of its diversity of substrates. Hence, fully identifying and characterizing these substrate-phosphatase interactions will facilitate the identification of pharmacological inhibitors of vaccinia H1-related phosphatase that can be evaluated in clinical trials. In this review, we describe the biological processes mediated by vaccinia H1-related phosphatase, especially those related to genomic stability. We also focus on validated substrates and signaling circuitry with clinical relevance in human diseases, particularly oncogenesis.

https://ift.tt/2Q7iL3L

The human adrenal cortex: growth control and disorders

This review summarizes key knowledge regarding the development, growth, and growth disorders of the adrenal cortex from a molecular perspective. The adrenal gland consists of two distinct regions: the cortex and the medulla. During embryological development and transition to the adult adrenal gland, the adrenal cortex acquires three different structural and functional zones. Significant progress has been made in understanding the signaling and molecules involved during adrenal cortex zonation. Equally significant is the knowledge obtained regarding the action of peptide factors involved in the maintenance of zonation of the adrenal cortex, such as peptides derived from proopiomelanocortin processing, adrenocorticotropin and N-terminal proopiomelanocortin. Findings regarding the development, maintenance and growth of the adrenal cortex and the molecular factors involved has improved the scientific understanding of disorders that affect adrenal cortex growth. Hypoplasia, hyperplasia and adrenocortical tumors, including adult and pediatric adrenocortical adenomas and carcinomas, are described together with findings regarding molecular and pathway alterations. Comprehensive genomic analyses of adrenocortical tumors have shown gene expression profiles associated with malignancy as well as methylation alterations and the involvement of miRNAs. These findings provide a new perspective on the diagnosis, therapeutic possibilities and prognosis of adrenocortical disorders.

https://ift.tt/2M3xREo

DNA repair pathways and cisplatin resistance: an intimate relationship

The main goal of chemotherapeutic drugs is to induce massive cell death in tumors. Cisplatin is an antitumor drug widely used to treat several types of cancer. Despite its remarkable efficiency, most tumors show intrinsic or acquired drug resistance. The primary biological target of cisplatin is genomic DNA, and it causes a plethora of DNA lesions that block transcription and replication. These cisplatin-induced DNA lesions strongly induce cell death if they are not properly repaired or processed. To counteract cisplatin-induced DNA damage, cells use an intricate network of mechanisms, including DNA damage repair and translesion synthesis. In this review, we describe how cisplatin-induced DNA lesions are repaired or tolerated by cells and focus on the pivotal role of DNA repair and tolerance mechanisms in tumor resistance to cisplatin. In fact, several recent clinical findings have correlated the tumor cell status of DNA repair/translesion synthesis with patient response to cisplatin treatment. Furthermore, these mechanisms provide interesting targets for pharmacological modulation that can increase the efficiency of cisplatin chemotherapy.

https://ift.tt/2Q7SYIG

Perspectives for cancer immunotherapy mediated by p19Arf plus interferon-beta gene transfer

While cancer immunotherapy has gained much deserved attention in recent years, many areas regarding the optimization of such modalities remain unexplored, including the development of novel approaches and the strategic combination of therapies that target multiple aspects of the cancer-immunity cycle. Our own work involves the use of gene transfer technology to promote cell death and immune stimulation. Such immunogenic cell death, mediated by the combined transfer of the alternate reading frame (p14ARF in humans and p19Arf in mice) and the interferon-β cDNA in our case, was shown to promote an antitumor immune response in mouse models of melanoma and lung carcinoma. With these encouraging results, we are now setting out on the road toward translational and preclinical development of our novel immunotherapeutic approach. Here, we outline the perspectives and challenges that we face, including the use of human tumor and immune cells to verify the response seen in mouse models and the incorporation of clinically relevant models, such as patient-derived xenografts and spontaneous tumors in animals. In addition, we seek to combine our immunotherapeutic approach with other treatments, such as chemotherapy or checkpoint blockade, with the goal of reducing dosage and increasing efficacy. The success of any translational research requires the cooperation of a multidisciplinary team of professionals involved in laboratory and clinical research, a relationship that is fostered at the Cancer Institute of Sao Paulo.

https://ift.tt/2M45V35

Interdisciplinary interventions in the perioperative rehabilitation of total laryngectomy: an integrative review

The aim of this study was to use the scientific literature to identify interdisciplinary interventions for rehabilitation during the perioperative period for cancer patients who underwent total laryngectomy. We systematically researched controlled descriptors: laryngectomy, patient care team/education, patient care team/manpower, patient care team/methods, patient care team/utilization and rehabilitation. We performed a qualitative narrative synthesis and identified 549 articles. Of these, 113 were duplicates, 398 were excluded during the analysis of the title and abstract, 1 was excluded for unfeasibility of access, and 4 were excluded after reading the article in full, resulting in 33 included articles. The articles addressed different types of interdisciplinary actions, such as vocal, olfactory, pulmonary and alimentary rehabilitation; comparisons of prosthetic devices; and descriptions of practices for total laryngectomized patient rehabilitation. Although the interventions found in the literature were effective in the rehabilitation of the total laryngectomized patient, their interdisciplinarity was not evidenced but was highlighted in these studies as a factor for improvement in terms of practical assistance and quality of life.

https://ift.tt/2Q7Sp1w

Human papillomavirus and genome instability: from productive infection to cancer

Infection with high oncogenic risk human papillomavirus types is the etiological factor of cervical cancer and a major cause of other epithelial malignancies, including vulvar, vaginal, anal, penile and head and neck carcinomas. These agents affect epithelial homeostasis through the expression of specific proteins that deregulate important cellular signaling pathways to achieve efficient viral replication. Among the major targets of viral proteins are components of the DNA damage detection and repair machinery. The activation of many of these cellular factors is critical to process viral genome replication intermediates and, consequently, to sustain faithful viral progeny production. In addition to the important role of cellular DNA repair machinery in the infective human papillomavirus cycle, alterations in the expression and activity of many of its components are observed in human papillomavirus-related tumors. Several studies from different laboratories have reported the impact of the expression of human papillomavirus oncogenes, mainly E6 and E7, on proteins in almost all the main cellular DNA repair mechanisms. This has direct consequences on cellular transformation since it causes the accumulation of point mutations, insertions and deletions of short nucleotide stretches, as well as numerical and structural chromosomal alterations characteristic of tumor cells. On the other hand, it is clear that human papillomavirus-transformed cells depend on the preservation of a basal cellular DNA repair activity level to maintain tumor cell viability. In this review, we summarize the data concerning the effect of human papillomavirus infection on DNA repair mechanisms. In addition, we discuss the potential of exploiting human papillomavirus-transformed cell dependency on DNA repair pathways as effective antitumoral therapies.

https://ift.tt/2wPjq0X

Alterations in the expression and activity of extracellular matrix components in HPV-associated infections and diseases

Infection with human papillomaviruses is associated with a series of benign and malignant hyperproliferative diseases that impose a heavy burden on human populations. A subgroup of mucosal human papillomavirus types are associated with the majority of cervical cancers and a relevant fraction of vulvar, vaginal, anal, penile and head and neck carcinomas. Human papillomaviruses mediate cell transformation by the expression of two pleiotropic oncoproteins that alter major cellular regulatory pathways. However, these viruses are not complete carcinogens, and further alterations within the infected cells and in their microenvironment are necessary for tumor establishment and progression. Alterations in components of the extracellular matrix for instance, matrix metalloproteinases and some of their regulators such as tissue inhibitors of metalloproteinases, have been consistently reported in human papillomaviruses-associated diseases. Matrix metalloproteinases function by remodeling the extracellular matrix and alterations in their expression levels and/or activity are associated with pathological processes and clinical variables including local tumor invasion, metastasis, tumor relapse and overall patient prognosis and survival. In this review we present a summarized discussion on the current data concerning the impact of human papillomavirus infection on the activity and expression of extracellular matrix components. We further comment on the possibility of targeting extracellular matrix molecules in experimental treatment protocols.

https://ift.tt/2QbdckK

Heart-sparing volumetric modulated arc therapy for whole lung irradiation

Abstract

Purpose

Whole lung irradiation (WLI) is indicated for subgroups of patients with lung metastases from Wilms' tumor (nephroblastoma). WLI has traditionally been performed with an anterior/posterior field arrangement with poor potential for heart sparing; thus, new techniques are desirable to achieve a lower dose to the heart.

Materials and methods

We utilized volumetric modulated arc therapy (VMAT) for WLI with 18 Gy in a patient with metastatic nephroblastoma. The planning results were compared against a three-dimensional (3D) conformal plan.

Results

VMAT resulted in adequate target volume coverage with the prescribed dose. Mean heart dose was 10.2 Gy. The dose to organs at risk (OAR) was generally more favorable with VMAT when compared with a 3D-conformal radiotherapy plan.

Discussion

WLI with VMAT provides superior sparing of OARs and especially a considerably lower dose to the heart.

https://ift.tt/2MRnc51

Prognostic significance of cell cycle-associated proteins p16, pRB, cyclin D1 and p53 in resected oropharyngeal carcinoma

Abstract

Background

Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) has an improved outcome and may allow for treatment de-escalation. High-risk HPV (HR-HPV) infection is associated with deregulated expression of the cell cycle-associated proteins p16^INK4, pRB, cyclin D1 and p53. The objective of this study was to assess cell cycle proteins as potential surrogate markers for HR-HPV DNA testing to identify OPSCC with favorable prognosis after resection.

Methods

Tissue microarray cores of 313 surgically treated OPSCC were stained for p16^INK4a, pRB, cyclin D1 and p53 using immunohistochemistry. Protein expression was scored as high or low based on the proportion of positive carcinoma cells. Tumor samples were analysed for HR-HPV DNA with polymerase chain reaction-based testing. Associations between cell cycle protein expression and HR-HPV DNA status were evaluated by calculating sensitivity, specificity, predictive values, and diagnostic odds ratios (DOR). Kaplan-Meier and Cox regression analysis were applied to evaluate associations between cell cycle protein expression and patient outcome.

Results

High expression of p16^INK4a, cyclin D1, pRB and p53 in tumor cells were observed in 51.8%, 51.4%, 41.9% and 33.5% of OPSCC, respectively. HR-HPV DNA positive were 158/313 (50.5%) tumor samples (HPV16: 147, HPV18: 1, HPV33: 5, HPV35: 2, HPV56: 2, and HPV59: 1). P16^INK4a showed a higher DOR to predict HR-HPV DNA positivity than pRB, cyclin D1 and p53. Both the p16^INK4a/pRB and the p16^INK4a/pRB/cyclin D1/p53 signatures had lower DOR than p16^INK4a alone. Improved 5-year overall and disease-specific survival were associated with HR-HPV DNA positivity, high p16^INK4a, low pRB, low cyclin D1, and low p53 expression. Associations with improved outcome were also observed for the marker combinations high p16^INK4a/positive HR-HPV DNA, high p16^INK4a/low pRB and high p16^INK4a/low pRB/low cyclin D1/low p53. In a multivariate analysis adjusted for age, smoking history, pT and pN category, high p16^INK4a expression showed the lowest hazard ratio for death.

Conclusions

High p16^INK4a expression is a reliable marker for survival prognostication in surgically treated OPSCC patients. Protein signatures including the pRB, cyclin D1 and p53 proteins do not further increase the prognostic performance of p16^INK4a as a single marker.

https://ift.tt/2NTEn2j

Adsorption behavior of chloroform, carbon disulfide, and acetone on coconut shell-derived carbon: experimental investigation, simulation, and model study

Abstract

The adsorption performances of chloroform (TCM), carbon disulfide (CDS), and acetone (CP) were investigated and compared over self-prepared coconut shell-derived carbon (CDC) to study the adsorption behavior and mechanism of heteroatom (Cl, S, O)-containing volatile organic compounds (VOCs). The result indicates that the adsorption capacity of three typical VOCs obeys the sequence: TCM (361 mg/g) > CDS (194 mg/g) > CP (37 mg/g). However, desorption experiments show that adsorption intensity follows the order: CDS (165 °C) > TCM (147 °C) > CP (130 °C). The influence of surface oxygen-containing functional groups over CDC on adsorption performance was also studied by temperature programmed desorption (TPD) and in situ DRIFT spectra. It is implied that carbonyl in lactone and benzoquinonyl of CDC could affect VOC adsorption intensity by conjugation effect. Furthermore, adsorption isotherms of three VOCs were obtained through Grand Canonical Monte Carlo (GCMC) simulation and then fitted by classical isothermal models. Furthermore, the total adsorption potentials are calculated by potential theory, and the result follows the order: TCM (− 2.18 kJ/mol) > CDS (− 2.1 kJ/mol) > CP (− 1.5 kJ/mol). It is believed that the effect of magnetic susceptibility (χ) is more crucial than polarizability (∂) and the distance r between the interacting molecules for the potential difference.

https://ift.tt/2wQlF4R

Remediation potential of caffeine, oxybenzone, and triclosan by the salt marsh plants Spartina maritima and Halimione portulacoides

Abstract

Pharmaceuticals and personal care products (PPCPs) have attracted increasing concern during the last decade because of their widespread uses and continuous release to the aquatic environment. This work aimed to study the distribution of caffeine (CAF), oxybenzone (MBPh), and triclosan (TCS) when they arrive in salt marsh areas and to assess their remediation potential by two different species of salt marsh plants: Spartina maritima and Halimione portulacoides. Experiments were carried out in the laboratory either in hydroponics (sediment elutriate) or in sediment soaked in elutriate, for 10 days. Controls without plants were also carried out. CAF, MBPh, and TCS were added to the media. In unvegetated sediment soaked in elutriate, CAF was mainly in the liquid phase (83%), whereas MBPh and TCS were in the solid phase (90% and 56%, respectively); the highest remediation was achieved for TCS (40%) and mainly attributed to bioremediation. The presence of plants in sediment soaked in elutriate-enhanced PPCPs remediation, decreasing CAF and TCS levels between approximately 20-30% and MBPh by 40%.. Plant uptake, adsorption to plant roots/sediments, and bio/rhizoremediation are strong hypothesis to explain the decrease of contaminants either in water or sediment fractions, according to PPCPs characteristics.

https://ift.tt/2NUKtzc

Αρχειοθήκη ιστολογίου

! # Ola via Alexandros G.Sfakianakis on Inoreader

Η λίστα ιστολογίων μου

Πέμπτη 6 Σεπτεμβρίου 2018

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