OtoRhinoLaryngology News: 09/05/17

Τρίτη 5 Σεπτεμβρίου 2017

Local relapse of nasopharyngeal cancer and Voxel-based analysis of FMISO uptake using PET with semiconductor detectors

Abstract

Background

Hypoxic cancer cells are thought to be radioresistant and could impact local recurrence after radiotherapy (RT). One of the major hypoxic imaging modalities is [¹⁸F]fluoromisonidazole positron emission tomography (FMISO-PET). High FMISO uptake before RT could indicate radioresistant sites and might be associated with future local recurrence. The predictive value of FMISO-PET for intra-tumoral recurrence regions was evaluated using high-resolution semiconductor detectors in patients with nasopharyngeal carcinoma after intensity-modulated radiotherapy (IMRT).

Methods

Nine patients with local recurrence and 12 patients without local recurrence for more than 3 years were included in this study. These patients received homogeneous and standard doses of radiation to the primary tumor irrespective of FMISO uptake. The FMISO-PET image before RT was examined via a voxel-based analysis, which focused on the relationship between the degree of FMISO uptake and recurrence region.

Results

In the pretreatment FMISO-PET images, the tumor-to-muscle ratio (TMR) of FMISO in the voxels of the tumor recurrence region was significantly higher than that of the non-recurrence region (p < 0.0001). In the recurrent patient group, a TMR value of 1.37 (95% CI: 1.36–1.39) corresponded to a recurrence rate of 30%, the odds ratio was 5.18 (4.87–5.51), and the area under the curve (AUC) of the receiver operating characteristic curve was 0.613. In all 21 patients, a TMR value of 2.42 (2.36–2.49) corresponded to an estimated recurrence rate of 30%, and the AUC was only 0.591.

Conclusions

The uptake of FMISO in the recurrent region was significantly higher than that in the non-recurrent region. However, the predictive value of FMISO-PET before IMRT is not sufficient for up-front dose escalation for the intra-tumoral high-uptake region of FMISO. Because of the higher mean TMR of the recurrence region, a new hypoxic imaging method is needed to improve the sensitivity and specificity for hypoxia.

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Long-term neurologic and cardiac correction by intrathecal gene therapy in Pompe disease

Pompe disease is a lysosomal storage disorder caused by acid-α-glucosidase (GAA) deficiency, leading to glycogen storage. The disease manifests as a fatal cardiomyopathy in infantile form. Enzyme replacement t...

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Age-dependent changes in synaptic plasticity enhance tau oligomerization in the mouse hippocampus

The aggregation mechanism of phosphorylated tau is an important therapeutic target for tauopathies, including Alzheimer's disease, although the mechanism by which aggregation occurs is still unknown. Because t...

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A case of pure red cell aplasia during nivolumab therapy for cardiac metastatic melanoma.

Nivolumab is an antibody against programmed cell death 1 and functions as an immune checkpoint inhibitor for various malignancies, including unresectable melanomas. Nivolumab causes several immune-related adverse events, which typically include skin rash, pneumonitis, thyroid dysfunction, hepatitis, and colitis; in rare cases, anemia may be present. There are several reports of autoimmune hemolytic anemia that has developed in response to nivolumab; however, there are few reports of pure red cell aplasia (PRCA). We describe a patient who developed PRCA during nivolumab administration. A 70-year-old Japanese woman received nivolumab for cardiac metastasis from malignant melanoma from an unknown site. Twenty-one months after nivolumab administration (31 courses), treatment was discontinued because she developed severe anemia. Blood test results indicated normocytic, normochromic anemia, and reticulocytopenia, but all other components were normal. Bone marrow aspiration showed increased megakaryocytes and decreased erythroblasts; these findings were consistent with PRCA. Anemia improved without recurrence after treatment with corticosteroids and blood transfusions. The steroid dosage was reduced gradually, and to date, the patient has not experienced recurrence of anemia. The tumor decreased in size and the patient has shown a continued response to treatment with decrease in disease for 3 years. Although it is unclear how nivolumab causes PRCA, hematological toxicities have been reported in patients treated with immunotherapy drugs. PRCA might be an unrecognized immune-mediated adverse event that did not manifest during the clinical trial phase. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Acute motor and sensory axonal neuropathy related to treatment with MEK inhibitors in a patient with advanced melanoma.

Approximately one-half of advanced cutaneous melanomas have a V600 mutation in the BRAF gene that activates the mitogen-activated protein kinase pathway. The combination of BRAF plus MEK inhibitors is one of the most effective treatments for these patients. Severe neurological toxicities have been reported in the literature. However, these toxicities are very rare. Here, we present one patient with acute motor and sensory axonal neuropathy, which is a subtype of Guillain-Barre syndrome, secondary to treatment with MEK inhibitors. This side effect had never been described as related to these agents. However, the mitogen-activated protein kinase pathway can be involved in Guillain-Barre syndrome, and awareness of early neurological injury signs is important in patients treated with MEK inhibitors. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Clinical grade manufacturing of genetically modified, CAR-expressing NK-92 cells for the treatment of ErbB2-positive malignancies

Abstract

Background

The NK-92/5.28.z cell line (also referred to as HER2.taNK) represents a stable, lentiviral-transduced clone of ErbB2 (HER2)-specific, second-generation CAR-expressing derivative of clinically applicable NK-92 cells. This study addresses manufacturing-related issues and aimed to develop a GMP-compliant protocol for the generation of NK-92/5.28.z therapeutic doses starting from a well-characterized GMP-compliant master cell bank.

Materials and methods

Commercially available GMP-grade culture media and supplements (fresh frozen plasma, platelet lysate) were evaluated for their ability to support expansion of NK-92/5.28.z. Irradiation sensitivity and cytokine release were also investigated.

Results

NK-92/5.28.z cells can be grown to clinically applicable cell doses of 5 × 10⁸ cells/L in a 5-day batch culture without loss of viability and potency. X-Vivo 10 containing recombinant transferrin supplemented with 5% FFP and 500 IU/mL IL-2 in VueLife 750-C1 bags showed the best results. Platelet lysate was less suited to support NK-92/5.28.z proliferation. Irradiation with 10 Gy completely abrogated NK-92/5.28.z proliferation and preserved viability and potency for at least 24 h. NK-92/5.28.z showed higher baseline cytokine release compared to NK-92, which was significantly increased upon encountering ErbB2(+) targets [GZMB (twofold), IFN-γ (fourfold), IL-8 (24-fold) and IL-10 (fivefold)]. IL-6 was not released by NK cells, but was observed in some stimulated targets. Irradiation resulted in upregulation of IL-8 and downregulation of sFasL, while other cytokines were not impacted.

Conclusion

Our concept suggests NK-92/5.28.z maintenance culture from which therapeutic doses up to 5 × 10⁹ cells can be expanded in 10 L within 5 days. This established process is feasible to analyze NK-92/5.28.z in phase I/II trials.

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High mobility group box 1 enhances hyperthermia-induced seizures and secondary epilepsy associated with prolonged hyperthermia-induced seizures in developing rats

Abstract

Levels of high mobility group box 1 (HMGB1), an important inflammatory mediator, are high in the serum of febrile seizure (FS) patients. However, its roles in FS and secondary epilepsy after prolonged FS are poorly understood. We demonstrate HMGB1's role in the pathogenesis of hyperthermia-induced seizures (HS) and secondary epilepsy after prolonged hyperthermia-induced seizures (pHS). In the first experiment, 14–15-day-old male rats were divided into four groups: high-dose HMGB1 (100 μg), moderate-dose (10 μg), low-dose (1 μg), and control. Each rat was administered HMGB1 intranasally 1 h before inducing HS. Temperature was measured at seizure onset with electroencephalography (EEG). In the second experiment, 10–11-day-old rats were divided into four groups: pHS + HMGB1 (10 μg), pHS, HMGB1, and control. HMGB1 was administered 24 h after pHS. Video-EEGs were recorded for 24 h at 90 and 120 days old; histological analysis was performed at 150 days old. In the first experiment, the temperature at seizure onset was significantly lower in the high- and moderate-dose HMGB1 groups than in the control group. In the second experiment, the incidence of spontaneous epileptic seizure was significantly higher in the pHS + HMGB1 group than in the other groups. Comparison between pHS + HMGB1 groups with and without epilepsy revealed that epileptic rats had significantly enhanced astrocytosis in the hippocampus and corpus callosum. In developing rats, HMGB1 enhanced HS and secondary epilepsy after pHS. Our findings suggest that HMGB1 contributes to FS pathogenesis and plays an important role in the acquired epileptogenesis of secondary epilepsy associated with prolonged FS.

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Mucus plugging in allergic bronchopulmonary aspergillosis: Implication of the eosinophil DNA traps

Publication date: Available online 5 September 2017
Source:Allergology International
Author(s): Ayumi Omokawa, Shigeharu Ueki, Yuta Kikuchi, Masahide Takeda, Mariko Asano, Kazuhiro Sato, Masaaki Sano, Hiroshi Ito, Makoto Hirokawa

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Multiple Myeloma Presenting as Massive Amyloid Deposition in a Parathyroid Gland Associated with Amyloid Goiter: A Medullary Thyroid Carcinoma Mimic on Intra-operative Frozen Section

Abstract

Clinical examples of amyloid deposition in parathyroid glands are exceedingly rare and usually present as an incidental finding in a patient with amyloid goiter. Here, we present the first histologically documented case of parathyroid amyloid deposition that presented as a mass. The patient did not have hyperparathyroidism. The parathyroid gland was submitted for intra-operative frozen section and concern for medullary thyroid carcinoma was raised. An important histologic clue arguing against medullary thyroid carcinoma was the evenly dispersed nature of the amyloid. Histologic perinuclear clearing and parathyroid hormone immunohistochemistry confirmed parathyroid origin on permanent sections. The patient was also found to have associated amyloid goiter. Mass spectrometry of the amyloid showed it to be composed of kappa light chains. On further work-up, the patient was diagnosed with multiple myeloma. Awareness of parathyroid amyloid deposition is important as it is a histologic mimic of medullary thyroid carcinoma, especially on frozen section. Amyloid typing with evaluation for multiple myeloma in any patient with kappa or lambda light chain restriction is also important.

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Disease-stabilizing treatment based on all-trans retinoic acid and valproic acid in acute myeloid leukemia – identification of responders by gene expression profiling of pretreatment leukemic cells

Abstract

Background

Acute myeloid leukemia (AML) is an aggressive malignancy only cured by intensive therapy. However, many elderly and unfit patients cannot receive such treatment due to an unacceptable risk of treatment-related morbidity and mortality. Disease-stabilizing therapy is then the only possible strategy, one alternative being treatment based on all-trans retinoic acid (ATRA) combined with the histone deacetylase inhibitor valproic acid and possibly low-toxicity conventional chemotherapy.

Methods

Primary AML cells were derived from 43 patients included in two clinical studies of treatment based on ATRA, valproic acid and theophyllamine; low toxicity chemotherapy (low-dose cytarabine, hydroxyurea, 6-mercaptopurin) was also allowed. Pretreatment leukemic cells were analyzed by mutation profiling of 54 genes frequently mutated in myeloid malignancies and by global gene expression profiling before and during in vivo treatment.

Results

Patients were classified as responders and non-responders to the treatment, however response to treatment showed no significant associations with karyotype or mutational profiles. Significance analysis of microarray (SAM) showed that responders and non-responders significantly differed with regard to the expression of 179 different genes. The differentially expressed genes encoding proteins with a known function were further classified based on the PANTHER (protein annotation through evolutionary relationship) classification system. The identified genes encoded proteins that are involved in several important biological functions, but a main subset of the genes were important for transcriptional regulation. These pretherapy differences in gene expression were largely maintained during treatment. Our analyses of primary AML cells during in vivo treatment suggest that ATRA modulates HOX activity (i.e. decreased expression of HOXA3, HOXA4 and HOXA5 and their regulator PBX3), but altered function of DNA methyl transferase 3A (DNMT3A) and G-protein coupled receptor signaling may also contribute to the effect of the overall treatment.

Conclusions

Responders and non-responders to AML stabilizing treatment based on ATRA and valproic acid differ in the pretreatment transcriptional regulation of their leukemic cells, and these differences may be important for the clinical effect of this treatment.

Trial registrations

ClinicalTrials.gov no. NCT00175812; EudraCT no. 2004–001663-22, registered September 9, 2005 and ClinicalTrials.gov no. NCT00995332; EudraCT no. 2007–2007–001995-36, registered October 14, 2009.

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Structure and diversity of human dendritic spines evidenced by a new three-dimensional reconstruction procedure for Golgi staining and light microscopy

Publication date: Available online 5 September 2017
Source:Journal of Neuroscience Methods
Author(s): Roman Reberger, Aline Dall'Oglio, Claudio R. Jung, Alberto A. Rasia-Filho
BackgroundDifferent approaches aim to unravel detailed morphological features of neural cells. Dendritic spines are multifunctional units that reflect cellular connectivity, synaptic strength and plasticity.New MethodA novel three-dimensional (3D) reconstruction procedure is introduced for visualization of dendritic spines from human postmortem brain tissue using brightfield microscopy. The segmentation model was based on thresholding the intensity values of the dendrite spine image along 'z' stacks. We used median filtering and removed false positives. Fine adjustments during image processing confirmed that the reconstructed image of the spines corresponded to the actual original data.ResultsExamples are shown for the cortical amygdaloid nucleus and the CA3 hippocampal area. Structure of spine heads and necks was evaluated at different angles. Our 3D reconstruction images display dendritic spines either isolated or in clusters, in a continuum of shapes and sizes, from simple to more elaborated forms, including the presence of spinule and complex 'thorny excrescences'.Comparison with Existing MethodsThe procedure has the advantages already described for the adapted "single-section" Golgi method, since it provides suitable results using human brains fixed in formalin for long time, is relatively easy, requires minimal equipment, and uses an algorithm for 3D reconstruction that provides high quality images and more precise morphological data.ConclusionThe procedure described here allows the reliable visualization and study of human dendritic spines with broad applications for normal controls and pathological studies.

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Histochemical features of aluminum chloride histiocytic reaction and the use of PAS stain to provide a clue to prior subtle biopsy sites

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Clinical grade manufacturing of genetically modified, CAR-expressing NK-92 cells for the treatment of ErbB2-positive malignancies

Abstract

Background

Materials and methods

Results

Conclusion

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Predictors of Hearing Outcomes Following Low-dose Stereotactic Radiosurgery in Patients with Vestibular Schwannomas: A Retrospective Cohort Review

Publication date: Available online 5 September 2017
Source:Clinical Neurology and Neurosurgery
Author(s): Ryh-Hsin Lin, Tang-Chuan Wang, Chia-Der Lin, Hung-Lin Lin, Hsiung-Kwang Chung, Ching-Yuang Wang, Yung-An Tsou, Ming-Hsui Tsai
ObjectivesHearing deterioration is a major concern for hearing-preserved patients with vestibular schwannomas who are treated with stereotactic radiosurgery (SRS). Thus, determining which patients are more likely to have worse hearing outcomes following SRS may facilitate clinicians in deciding whether conservative policy should be applied in the interest of hearing preservation. This study aimed to define the predictors of hearing outcomes following SRS.Patients and MethodsThis retrospective study included 100 patients who underwent low-dose SRS (12- to 13-Gy marginal dose) for vestibular schwannomas between January 2004 and January 2014. Clinical factors and hearing outcomes following radiosurgery were reviewed.ResultsAll patients had serviceable hearing at diagnosis and prior to SRS. The median follow-up period was 6.5 years (range, 3–10 years). The hearing preservation rate in the first, third, and fifth year after radiosurgery was 89%, 68%, and 63%, respectively. A mean cochlear dose lower than 4Gy was a favorable predictor of hearing outcome. Maximal cochlear dose, patient age, pre-treatment pure-tone average, and imaging characteristics were not associated with post-treatment hearing preservation. Our study showed an accelerated rate of deterioration of serial pure-tone average in the first 3years, followed by a more gradual decline after radiosurgery.ConclusionOur results suggest that cochlear dose constraint is the most crucial factor for hearing preservation. This study provides insight into the rate of hearing preservation and the pattern of hearing deterioration following radiosurgery and can help clinicians advise patients of hearing outcomes following SRS.

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Progressive halo-vest traction preceding posterior occipitocervical instrumented fusion for irreducible atlantoaxial dislocation and basilar invagination

Publication date: Available online 5 September 2017
Source:Clinical Neurology and Neurosurgery
Author(s): Peng Li, Deming Bao, Huijuan Cheng, Fanshuai Meng, Junwei Li
ObjectivesSurgical treatment of irreducible atlantoaxial dislocation (IAAD) with basilar invagination (BI) is associated with high rates of severe complications, including mortality. This retrospective study investigated the safety and efficacy of progressive halo-vest traction for IAAD with BI prior to posterior occipitocervical instrumented fusion.Patients and methodsBetween 2009 and 2013, 39 patients with IAAD with BI underwent preoperative reduction by progressive halo-vest traction for 20.82±4.21 days. Instrumented fusion was then performed through a posterior approach. Clinical outcomes were based on pain scale and Japanese Orthopedic Association (JOA) scores. Radiographic analysis evaluated changes in atlantodental distance, McGregor's line violation, spinal canal width at the craniocervical junction, cervicomedullary angle, C2-C7 lordosis angle, and the occiput-C2 angle.ResultsFollow-ups ranged from 48 to 96 months. Both atlantodental distance and BI significantly improved in all patients. The rates of complete anatomical reduction were 85% for IAAD, and 95% for BI. Most of the patients reported satisfactory pain relief and improvement in daily activity; the mean JOA scores at baseline and last follow-up were 9.10 and 15.92, respectively. Although complications occurred in 10 patients (25.64%), all of which healed uneventfully. The bony fusion rate was 100%.ConclusionProgressive halo-vest traction before surgery is safe and effective for reduction of IAAD with BI. The technique we describe is a promising method for treatment of complex craniocervical junction deformity.

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Neuroscience Step-down Unit Admission Criteria for Patients with Intracerebral Hemorrhage

Publication date: Available online 5 September 2017
Source:Clinical Neurology and Neurosurgery
Author(s): Ayham M. Alkhachroum, Oladi Bentho, Neel Chari, Ashish Kulhari, Wei Xiong
ObjectivesThe goal of our study is to determine optimal criteria which can be used to avoid admission to neuroscience intensive care units for patients with intracerebral hemorrhage (ICH).Patients and MethodsThis is a retrospective cohort study of 431 patients with primary ICH from January 2013 to the end of December 2015 and reviewed multiple admitting characteristics. Based on these needs, we tested the following step-down unit admission criteria: Supratentorial ICH, ICH volume <20 cc, no Intraventricular hemorrhage (IVH), systolic BP <200mmHg, no respiratory failure, GCS≥12. We classified 431 patients into two groups; 1- Patients who met step-down unit admission Criteria (71 patients). 2-Patients who didn't meet the criteria (360 patients).ResultsIn our patients, 16.5% fulfilled the criteria. Length of stay in the ICU was 1.43days in step-down unit admission criteria patients. None of the patients who fulfilled the criteria were readmitted to the ICU, compared to 3 readmissions among the group of patients who did not fulfill the criteria (P=0.82). None of these patients required a neurosurgical procedure vs 47 patients (10.9%) in the other group (P=0.04). Among patients who met the criteria, 83.1% were discharged home or rehab RR 0.33 CI (0.19-0.55), (P < 0.0001).ConclusionWe propose that patients who fulfill step-down unit admission criteria can be safely monitored in stroke unit and they have no need for ICU admission. Further studies are needed to validate these criteria in a prospective manner.

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Multiple Myeloma Presenting as Massive Amyloid Deposition in a Parathyroid Gland Associated with Amyloid Goiter: A Medullary Thyroid Carcinoma Mimic on Intra-operative Frozen Section

Abstract

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Editorial Board (p/u from previous issue)

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Cover 2 - Masthead (p/u from previous issue)

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Information for authors (p/u from previous issue)

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Future and recent issues (p/u from previous issue and update)

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Non-uraemic calciphylaxis: a diagnostic and management challenge for the burns team

Abstract

Calciphylaxis is a rare systemic condition usually seen in patients with end-stage renal disease. It is characterised by pathological calcification of dermal blood vessels, causing ischaemia and necrosis in the skin and subcutaneous fat. The lesions are usually small but, in extreme cases, may be very extensive and may mimic necrotising fasciitis, prompting extensive surgical debridement. We describe the challenges faced in managing such a case. A 38-year-old female patient was admitted to another hospital with widespread progressive truncal skin necrosis. A provisional diagnosis of necrotising fasciitis was made, and she underwent debridement of 32% of her total body surface area (TBSA). However, her condition rapidly deteriorated and she was transferred to our burn centre for further management. Diagnosis of calciphylaxis was based on clinical features and confirmed by tissue biopsy. Characteristic findings of progressive skin and fat necrosis at the wound margins with healthy underlying fascia and muscle were recognised from previously treated cases of calciphylaxis; however, the absence of renal disease proved misleading. Non-uraemic calciphylaxis is very rare but can, as in this case, be associated with alcoholic liver disease. At our centre, the patient required prolonged ventilation and supportive treatment in burns critical care, combined with intensive wound management, repeated episodes of debridement, temporary wound cover using human skin allografts and reconstruction using split-thickness autograft. We report this case to alert others to this rare condition as a possible diagnosis in patients presenting with extensive panniculitis. We discuss associations, diagnostic difficulties, novel therapies and the importance of multidisciplinary care in managing these complex cases.

Level of evidence: Level V, diagnostic study.

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Vocal Tract Morphology in Inhaling Singing: Characteristics During Vowel Production—A Case Study in a Professional Singer

Publication date: Available online 5 September 2017
Source:Journal of Voice
Author(s): Mieke Moerman, Françoise Vanhecke, Lieven Van Assche, Johan Vercruysse
BackgroundA professional singer produced various vowels on a comfortable loudness and pitch in an inspiratory and expiratory phonation manner. The present study investigates the morphological differences and tries to find a link with the acoustical characteristics.Objectives/HypothesisWe hypothesize that features, constantly present over all vowels, characterize inhaling phonation and that the formant frequencies reflect the morphological findings.Study designA prospective case study was carried out.MethodsA female singer uttered the vowels /a/, /e/, /i/, /o/, and /u/ in a supine position under magnetic resonance imaging, on a comfortable loudness and pitch, in both inhaling and exhaling manner. The exact same parameters as in previous reports were measured (1–3). Acoustical analysis was performed with Praat.ResultsWilcoxon directional testing demonstrates a statistically significant difference in (1) the distance between the lips, (2) the antero-posterior tongue diameter, (3) the distance between the lips and the tip of the tongue, (4) the distance between the epiglottis and the posterior pharyngeal wall, (5) the narrowing of the subglottic space, and (6) the oropharyngeal and the hypopharyngeal areas. Acoustical analysis reveals slightly more noise and irregularity during reverse phonation. The central frequency of F0 and F1 is identical, whereas that of F2 and F3 increases, and that of F4 varies.ConclusionsA smaller mouth opening, a narrowing of the subglottic space, a larger supralaryngeal inlet, and a smaller antero-posterior tongue diameter can be considered as morphological characteristics for reverse phonation. Acoustically, reverse phonation discretely contains more noise and perturbation. The formant frequency distribution concurs with a mouth narrowing and pharyngeal widening during inhaling.

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Clinical Features of a Family with Multiple Endocrine Neoplasia Type 2A Caused by the D631Y RET Mutation

Thyroid , Vol. 0, No. 0.

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Vocal Tract Morphology in Inhaling Singing: Characteristics During Vowel Production—A Case Study in a Professional Singer

Target volume delineation of anal cancer based on magnetic resonance imaging or positron emission tomography

Abstract

Purpose

To compare target volume delineation of anal cancer using positron emission tomography (PET) and magnetic resonance imaging (MRI) with respect to inter-observer and inter-modality variability.

Methods

Nineteen patients with anal cancer undergoing chemoradiotherapy were prospectively included. Planning computed tomography (CT) images were co-registered with 18F–fluorodexocyglucose (FDG) PET/CT images and T2 and diffusion weighted (DW) MR images. Three oncologists delineated the Gross Tumor Volume (GTV) according to national guidelines and the visible tumor tissue (GTV_T). MRI and PET based delineations were evaluated by absolute volumes and Dice similarity coefficients.

Results

The median volume of the GTVs was 27 and 31 cm³ for PET and MRI, respectively, while it was 6 and 11 cm³ for GTV_T. Both GTV and GTV_T volumes were highly correlated between delineators (r = 0.90 and r = 0.96, respectively). The median Dice similarity coefficient was 0.75 when comparing the GTVs based on PET/CT (GTV_PET) with the GTVs based on MRI and CT (GTV_MRI). The median Dice coefficient was 0.56 when comparing the visible tumor volume evaluated by PET (GTV_{T_PET}) with the same volume evaluated by MRI (GTV_{T_MRI}). Margins of 1–2 mm in the axial plane and 7–8 mm in superoinferior direction were required for coverage of the individual observer's GTVs.

Conclusions

The rather good agreement between PET- and MRI-based GTVs indicates that either modality may be used for standard target delineation of anal cancer. However, larger deviations were found for GTV_T, which may impact future tumor boost strategies.

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Expanded access to cancer treatments from conversion to neutropenia prophylaxis with biosimilar filgrastim-sndz

Future Oncology, Ahead of Print.

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Ternary cocktail nanoparticles for sequential chemo-photodynamic therapy

Abstract

Background

Previous clinical trials have already demonstrated that combinations of two or more drugs were more effective in the cancer treatment, especially sequential photodynamic design combing with sequential chemotherapy. In our study, we propose a ternary cocktail NP delivery system based on self-decomposable NPs, which could realize synergistic chemo-photodynamic therapy through double loading chemo-drugs and multi-level programmable PDT treatment.

Methods

PS drug methylene blue (MB) was encapsulated into the center of the NP_small, NP_big&thin, and NP_big&thick carriers through "grown-in" loading mechanism, which was released based on the drug concentration difference of the drug release environment. NP_small, NP_big&thin, and NP_big&thick carriers have three different drug release profiles, which could realize multi-level programmable PDT treatment. At the same time, antitumor drug gemcitabine hydrochloride (GM) and Docetaxel (DTX), were chosen as the double loading chemo-drugs that absorbed onto the NP_big&thin and NP_big&thick surface, respectively. In specific, various particle configurations were used for modulating the inner MB sequential release with three pulse T_max. Also, by adjusting the NP_big&thin and NP_big&thick configuration, the release interval lag time between absorbed GM and DTX can be successfully modulated to achieve maximized chemotherapeutic efficacy.

Results

In vitro and in vivo results demonstrated that these three pulses T_max and the sustained release of MB could maximize the multi-level programmable PDT treatment. And the absorbed GM and DTX also have a release time lag of 12 h, which has been proved as the most effectiveness synergistic interval lag time in the cancer treatment.

Conclusion

Such a precise sequential release manner ternary cocktail NPs provided a promising platform for efficient and safe chemo-photodynamic therapy, which serves as a promising drug delivery system to cure cancer in the future.

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The Absence of HCV RNA and NS5A Protein in Peripheral Blood Mononuclear Cells Is a Prognostic Tool for Sustained Virological Response

Viral Immunology , Vol. 0, No. 0.

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Expanded access to cancer treatments from conversion to neutropenia prophylaxis with biosimilar filgrastim-sndz

Future Oncology, Ahead of Print.

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ERp29 controls invasion and metastasis of gastric carcinoma by inhibition of epithelial-mesenchymal transition via PI3K/Aktsignaling pathway

Abstract

Background

Gastric cancer (GC) accounts for the fourth most occurring malignancy and the third major cause of cancer death. Identifying novel molecular signaling pathways participating in gastric tumorigenesis and progression is pivotal for rational design of targeted therapies to improve advanced GC outcome. Recently, the endoplasmic reticulum (ER) protein 29 (ERp29) has been shown to inversely associate with primary tumor development and function as a tumor suppressor in breast cancer. However, the role of ERp29 in GC patients' prognosis and its function in GC progression is unknown.

Methods

Clinical importance of ERp29 in the prognosis of GC patients was assessed by examining its expression in 148 GC tumor samples and correlation with clinicopathological characteristics and survival of the patients. The function and underlying mechanisms of ERp29 in GC growth, invasion and metastasis were explored both in vitro and in vivo.

Results

Downregulation of ERp29 was commonly found in GC tissues and highly correlated with more aggressive phenotypes and poorer prognosis. Functional assays demonstrated that knockdown of ERp29 increased GC cell migration and invasion and promoted metastasis. Conversely, ectopic overexpression of ERp29 produced opposite effects. Mechanistic studies revealed that loss of ERp29 induced an epithelial-to-mesenchymal transition (EMT) in the GC cells through activation of PI3K/Akt pathway signaling.

Conclusion

These findings suggest that downregulation of ERp29 is probably one of the key molecular mechanisms responsible for the development and progression of GC.

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The association between smoking and breast cancer characteristics and outcome

Abstract

Background

Smoking is associated with an increased incidence of hormone receptor positive breast cancer. Data regarding worse breast cancer outcome in smokers are accumulating. Current literature regarding the impact of smoking on breast cancer characteristics is limited. We evaluated the impact of smoking on breast cancer characteristics and outcome.

Methods

This was a retrospective single center study. All women diagnosed from 4/2005 through 3/2012 and treated in our institute for early, estrogen receptor positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer, whose tumors were sent for Oncotype DX analysis were included. Medical records were reviewed for demographics, clinico-pathological parameters, treatment and outcome. Data regarding smoking were retrieved according to patients' history at the first visit in the oncology clinic. Patients were grouped and compared according to smoking history (ever smokers vs. never smokers), smoking status (current vs. former and never smokers) and smoking intensity (pack years ≥30 vs. the rest of the cohort). Outcomes were adjusted in multivariate analyses and included age, menopausal status, ethnicity, tumor size, nodal status and grade.

Results

A total of 662 women were included. 28.2% had a history of smoking, 16.6% were current smokers and 11.3% were heavy smokers. Smoking had no impact on tumor size, nodal involvement and Oncotype DX recurrence score. Angiolymphatic and perineural invasion rates were higher in current smokers than in the rest of the cohort (10.4% vs. 5.1%, p = 0.045, 8.3% vs. 3.5%, p = 0.031, respectively). Smoking had no other impact on histological characteristics. Five-year disease free survival and overall survival rates were 95.7% and 98.5%, respectively. Smoking had no impact on outcomes. Adjusted disease free survival and overall survival did not influence the results.

Conclusions

Smoking had no clinically significant influence on tumor characteristics and outcome among women with estrogen receptor positive, HER2 negative, early breast cancer. As the study was limited to a specific subgroup of the breast cancer population in this heterogeneous disease and since smoking is a modifiable risk factor for the disease, further research is required to clarify the possible impact of smoking on breast cancer.

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Development and external validation of nomograms to predict the risk of skeletal metastasis at the time of diagnosis and skeletal metastasis-free survival in nasopharyngeal carcinoma

Abstract

Background

The skeletal system is the most common site of distant metastasis in nasopharyngeal carcinoma (NPC); various prognostic factors have been reported for skeletal metastasis, though most studies have focused on a single factor. We aimed to establish nomograms to effectively predict skeletal metastasis at initial diagnosis (SMAD) and skeletal metastasis-free survival (SMFS) in NPC.

Methods

A total of 2685 patients with NPC who received bone scintigraphy (BS) and/or 18F–deoxyglucose positron emission tomography/computed tomography (18F–FDG PET/CT) and 2496 patients without skeletal metastasis were retrospectively assessed to develop individual nomograms for SMAD and SMFS. The models were validated externally using separate cohorts of 1329 and 1231 patients treated at two other institutions.

Results

Five independent prognostic factors were included in each nomogram. The SMAD nomogram had a significantly higher c-index than the TNM staging system (training cohort, P = 0.005; validation cohort, P < 0.001). The SMFS nomogram had significantly higher c-index values in the training and validation sets than the TNM staging system (P < 0.001 and P = 0.005, respectively). Three proposed risk stratification groups were created using the nomograms, and enabled significant discrimination of SMFS for each risk group.

Conclusion

The prognostic nomograms established in this study enable accurate stratification of distinct risk groups for skeletal metastasis, which may improve counseling and facilitate individualized management of patients with NPC.

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Circadian disruption promotes tumor growth by anabolic host metabolism; experimental evidence in a rat model

Abstract

Background

Light at night creates a conflicting signal to the biological clock and disrupts circadian physiology. In rodents, light at night increases the risk to develop mood disorders, overweight, disrupted energy metabolism, immune dysfunction and cancer. We hypothesized that constant light (LL) in rats may facilitate tumor growth via disrupted metabolism and increased inflammatory response in the host, inducing a propitious microenvironment for tumor cells.

Methods

Male Wistar rats were exposed to LL or a regular light-dark cycle (LD) for 5 weeks. Body weight gain, food consumption, triglycerides and glucose blood levels were evaluated; a glucose tolerance test was also performed. Inflammation and sickness behavior were evaluated after the administration of intravenous lipopolysaccharide. Tumors were induced by subcutaneous inoculation of glioma cells (C6). In tumor-bearing rats, the metabolic state and immune cells infiltration to the tumor was investigated by using immunohistochemistry and flow cytometry. The mRNA expression of genes involved metabolic, growth, angiogenes and inflammatory pathways was measured in the tumor microenvironment by qPCR. Tumor growth was also evaluated in animals fed with a high sugar diet.

Results

We found that LL induced overweight, high plasma triglycerides and glucose levels as well as reduced glucose clearance. In response to an LPS challenge, LL rats responded with higher pro-inflammatory cytokines and exacerbated sickness behavior. Tumor cell inoculation resulted in increased tumor volume in LL as compared with LD rats, associated with high blood glucose levels and decreased triglycerides levels in the host. More macrophages were recruited in the LL tumor and the microenvironment was characterized by upregulation of genes involved in lipogenesis (Acaca, Fasn, and Pparγ), glucose uptake (Glut-1), and tumor growth (Vegfα, Myc, Ir) suggesting that LL tumors rely on these processes in order to support their enhanced growth. Genes related with the inflammatory state in the tumor microenvironment were not different between LL and LD conditions. In rats fed a high caloric diet tumor growth was similar to LL conditions.

Conclusions

Data indicates that circadian disruption by LL provides a favorable condition for tumor growth by promoting an anabolic metabolism in the host.

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Prognostic consequences of implementing cancer patient pathways in Denmark: a comparative cohort study of symptomatic cancer patients in primary care

Abstract

Background

Cancer Patient Pathways (CPPs) were introduced in 2000–2015 in several European countries, including Denmark, to reduce the time to diagnosis and treatment initiation and ultimately improve patient survival. Yet, the prognostic consequences of implementing CPPs remain unknown for symptomatic cancer patients diagnosed through primary care.

We aimed to compare survival and mortality among symptomatic patients diagnosed through a primary care route before, during and after the CPP implementation in Denmark.

Methods

Based on data from the Danish Cancer in Primary Care (CaP) Cohort, we compared one- and three-year standardised relative survival (RS) and excess hazard ratios (EHRs) before, during and after CPP implementation for seven types of cancer and all combined (n = 7725) by using life-table estimation and Poisson regression. RS estimates were standardised according to the International Cancer Survival Standard (ICSS) weights. In addition, we compared RS and EHRs for CPP and non-CPP referred patients to consider potential issues of confounding by indication.

Results

In total, 7725 cases were analysed: 1202 before, 4187 during and 2336 after CPP implementation. For all cancers combined, the RS_3years rose from 45% (95% confidence interval (CI): 42;47) before to 54% (95% CI: 52;56) after CPP implementation. The excess mortality was higher before than after CPP implementation (EHR_3years before vs. after CPP = 1.35 (95% CI: 1.21;1.51)). When comparing CPP against non-CPP referred patients, we found no statistically significant differences in RS, but we found lower excess mortality among the CPP referred (EHR_1year CPP vs. non-CPP = 0.86 (95% CI: 0.73;1.01)).

Conclusion

We found higher relative survival and lower mortality among symptomatic cancer patients diagnosed through primary care after the implementation of CPPs in Denmark. The observed changes in cancer prognosis could be the intended consequences of finding and treating cancer at an early stage, but they may also reflect lead-time bias and selection bias. The finding of a lower excess mortality among CPP referred compared to non-CPP referred patients indicates that CPPs may have improved the cancer prognosis independently.

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The values of neutrophil-lymphocyte ratio and/or prostate-specific antigen in discriminating real Gleason score ≥ 7 prostate cancer from group of biopsy-based Gleason score ≤ 6

Abstract

Background

The discrepant concordance between biopsy and radical prostatectomy (RP) specimen are well reported. To validate the clinical usefulness of neutrophil-lymphocyte ratio (NLR) in discriminating real GS ≥ 7 PCa from biopsy-based GS ≤ 6 PCa in comparison with serum total prostate-specific antigen (tPSA) and value of their combination.

Methods

One hundred one patients who underwent physical examinations incidentally found elevated tPSA and subsequently received biopsy with a conclusion of GS ≤ 6 and RP with an interval of 4-6 weeks after biopsy were enrolled. NLR and tPSA were obtained within 15 days prior to biopsy. Logistic regression model was applied appropriately; McNemar tests and AUC model were performed to evaluate differences among tPSA, NLR and their combination and corresponding diagnostic power respectively.

Results

The pathological results from RP specimen comprised 61 patients with GS ≤ 6 and 100 patients with GS ≥ 7. Higher tPSA and NLR were significantly associated with patients with actual GS ≥ 7 (All P < 0.05) concurrently. Multivariate logistic regression indicated that tPSA (OR = 1.088, 95% C.I. = 1.029-1.151, P = 0.003) and NLR (OR = 1.807, 95% C.I. = 1.021-3.200, P = 0.042) could be independent predictors for GS groupings. Under cutoff value of 14.09 ng/ml for tPSA and 2.25 for NLR, the sensitivity, specificity and accuracy were 60.0%, 80.3% and 67.7% for tPSA, 42%, 88.5% and 59.6% for NLR, and 71.0%, 75.4% and 72.7% for combination of tPSA and NLR (tPSA + NLR) respectively. The sensitivity of tPSA + NLR was significantly higher in comparison with tPSA (P = 0.001) and NLR (P < 0.001). Except for sensitivity, no significant difference was found between tPSA and NLR in specificity (P = 0.227) and accuracy (P = 0.132). tPSA got the largest AUC with 0.732 (p < 0.001, 95% C.I.: 0.651-0.813).

Conclusions

Serum tPSA and NLR were significantly elevated among GS ≥ 7 PCa concurrently. The combination of tPSA and NLR might have additional benefit to biopsy on discriminating real GS ≥ 7 Pca from biopsy-based GS ≤ 6 PCa. More stratification models and prospectively multicenter studies are necessary.

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Satisfaction with facial profile aesthetics: are norms overrated?

This study aimed to explore to what extent adults perceive deviations from the norm of a balanced profile with normal occlusion as reducing satisfaction with facial appearance and having a psychosocial impact. This cross-sectional study included 225 Caucasian subjects (64% women) aged 18–42 years. Their facial profiles were analyzed photogrammetrically and they were classified into three categories: within, below, or above the standard range for the Croatian population with a normal occlusion. Psychosocial issues were assessed by self-reported satisfaction with facial appearance and domains from the Orthognathic Quality of Life Questionnaire: social aspects of dentofacial aesthetics (SA), facial aesthetics concern (FA), and awareness of dentofacial aesthetics (AW).

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The action of anti-inflammatory agents in healthy temporomandibular joint synovial tissues is sex-dependent

This study evaluated the effects of dexamethasone, parecoxib, and glucosamine on cartilage thickness and cytokine levels in the temporomandibular joint (TMJ). Forty-eight rats (24 female, 24 male) were assigned to four treatments administered once daily for 7 days: control (saline intramuscularly), parecoxib (0.3mg/kg intramuscularly), dexamethasone (0.1mg/kg intramuscularly), and glucosamine (80mg/kg orally). The thickness of TMJ cartilage and levels of four cytokines were measured. Median cartilage thickness was higher in males than in females in the control (253.2 vs.

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Columnar metaplasia in the remnant esophagus is a long-term indicator for pneumonia after radical esophagectomy

Abstract

Background

This study investigated the long-term risk factors for pneumonia after esophageal reconstruction using a gastric tube via the posterior mediastinal route following esophagectomy for esophageal cancer. The influence of columnar metaplasia in the remnant esophagus was specifically assessed.

Methods

Among 225 patients who underwent esophagectomy between January 2004 and December 2010, the subjects were 54 patients who could be followed up for more than 5 years. Routine oncologic follow-up consisted of CT scanning of the abdomen and chest every 4–6 months and annual endoscopy. Data on the occurrence of pneumonia were collected by retrospective review of chest CT scans. Risk factors for pneumonia investigated by univariate and multivariate analyses included the age, gender, diameter of the stapler, length of the intrathoracic remnant esophagus, anastomotic stricture, and presence of columnar metaplasia in the remnant esophagus.

Results

The median age was 62.4 years (interquartile range: 55.8–68.0 years). Forty-three patients were men. Pneumonia was detected in 39 patients (72.2%). The incidence of columnar metaplasia in the remnant esophagus increases with time. Anastomotic stricture was significantly related to the absence of columnar metaplasia on endoscopy in the first year after esophagectomy (p = 0.013). Univariate analysis showed that the frequency of pneumonia was significantly related to the intrathoracic remnant esophagus length ≥4.4 cm (p = 0.014), age over 65 years (p = 0.014), and the presence of columnar metaplasia in the remnant esophagus in the fifth year after esophagectomy (p = 0.005). Among them, age over 65 years and the presence of columnar metaplasia in the remnant esophagus in the fifth year after esophagectomy were found to be independent indicators of the postoperative pneumonia by multivariate analysis.

Conclusion

Pneumonia occurred in 72.2% (39/54) of patients after esophagectomy for esophageal cancer. The presence of columnar metaplasia after esophagectomy is an indicator for pneumonia over the long term.

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Descriptive Rules for Achalasia of the Esophagus, June 2012: 4th Edition

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Is a slow-progression baked-milk protocol of oral immunotherapy always a safe option for children with cow's milk allergy? A randomized controlled trial

Abstract

Immunoglobulin-E mediated-cow's milk allergy (IgE-CMA) is the one of the most frequent IgE mediated-food allergy in children in industrialized countries and may cause life- threatening anaphylaxis. The natural history of CM IgE mediated food allergy is favorable for most children. However, the clinical outcome of CMA seems worse than previously described, with less chance of recovery after the age of 3¹.

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Non-uraemic calciphylaxis: a diagnostic and management challenge for the burns team

Abstract

Level of evidence: Level V, diagnostic study.

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UTHealth ORL & Hurricane Harvey

Learn more.

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UTHealth ORL & Hurricane Harvey

Hurricane Harvey brought catastrophic flooding to the 6 million inhabitants of the greater Houston region. We are happy to report... Read the full article...

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Endoscopy in inflammatory bowel disease: advances in disease management

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Alcohol consumption and bladder cancer risk with or without the flushing response: The Japan Public Health Center-based Prospective Study

ABSTRACT

The association between alcohol consumption and bladder cancer risk has been insufficiently investigated in East Asian populations, who frequently have the inactive enzyme for metabolizing acetaldehyde. Given that acetaldehyde associated with alcohol consumption is assessed as a carcinogen, consideration of differences in acetaldehyde exposure would aid accuracy in assessing the bladder cancer risk associated with alcohol consumption. Here, we conducted a population-based cohort study in Japan to examine this association, including information on the flushing response as a surrogate marker of the capacity of acetaldehyde metabolism. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariate Cox proportional hazard models. During follow up from 1990 through 2012 for the 95915 subjects (45649 men and 50266 women, aged 40-69 years), 354 men and 110 women were newly diagnosed with bladder cancer. No significant association between alcohol consumption and bladder cancer risk was observed in the overall analysis. Among male flushers, HRs were 1.04 (95% CI 0.70-1.54), 1.67 (1.16-2.42), 1.02 (0.62-1.67) and 0.63 (0.33-1.20) for alcohol consumption of 1-150, 151-300, 301-450, >450 g/week of pure ethanol compared with non- and occasional drinkers, respectively, indicating an inverted U-shaped association between alcohol consumption and bladder cancer risk. In contrast, no significant association was identified among male non-flushers. The marginally significant interaction between alcohol consumption and the flushing response (P for interaction = 0.083) may support our hypothesis that acetaldehyde derived from alcohol consumption is associated with bladder cancer risk. A prospective study considering polymorphisms of genes involved in acetaldehyde metabolism is warranted. This article is protected by copyright. All rights reserved.

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G protein-coupled receptor GPR55 promotes colorectal cancer and has opposing effects to cannabinoid receptor 1

Abstract

The putative cannabinoid receptor GPR55 has been shown to play a tumor-promoting role in various cancers, and is involved in many physiological and pathological processes of the gastrointestinal (GI) tract. While the cannabinoid receptor 1 (CB₁) has been reported to suppress intestinal tumor growth, the role of GPR55 in the development of GI cancers is unclear. We, therefore, aimed at elucidating the role of GPR55 in colorectal cancer (CRC), the third most common cancer worldwide.

Using azoxymethane (AOM)- and dextran sulfate sodium (DSS)-driven CRC mouse models, we found that GPR55 plays a tumor-promoting role that involves alterations of leukocyte populations, i.e. myeloid-derived suppressor cells and T lymphocytes, within the tumor tissues. Concomitantly, expression levels of COX-2 and STAT3 were reduced in tumor tissue of GPR55 knockout mice, indicating reduced presence of tumor-promoting factors. By employing the experimental CRC models to CB₁ knockout and CB₁/GPR55 double knockout mice, we can further show that GPR55 plays an opposing role to CB₁. We report that GPR55 and CB₁ mRNA expression are differentially regulated in the experimental models and in a cohort of 86 CRC patients. Epigenetic methylation of CNR1 and GPR55 was also differentially regulated in human CRC tissue compared to control samples.

Collectively, our data suggest that GPR55 and CB₁ play differential roles in colon carcinogenesis where the former seems to act as oncogene and the latter as tumor suppressor. This article is protected by copyright. All rights reserved.

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The Contribution of Toll-Like Receptor Signaling to the Development of Liver Fibrosis and Cancer in Hepatocyte-Specific TAK1-Deleted Mice

Abstract

Hepatocyte death is associated with liver inflammation, fibrosis, and hepatocellular carcinoma (HCC). Damaged cells trigger inflammation through activation of Toll-like receptor (TLR). Although the role of TLR4 in HCC development has been reported, the role of TLR9 in the development of HCC remains elusive. To investigate the role of TLR4 and TLR9 signaling in liver inflammation-fibrosis-cancer axis, we took advantage of mice with hepatic deletion of transforming growth factor-β-activated kinase 1 (Tak1ΔHep) that develop spontaneous liver injury, inflammation, fibrosis, and HCC, recapitulating the pathology of human HCC. We generated double knockout mice lacking genes of our interest with hepatic Tak1. Tak1ΔHep mice and Tlr4-deficient Tak1ΔHep mice had similar serum ALT levels, but Tlr4-deficient Tak1ΔHep mice exhibited significantly reduced macrophage infiltration, myofibroblast activation, and tumor formation. Ablation of TLR9 reduced spontaneous liver injury, inflammation, fibrosis, and cancer development in Tak1ΔHep mice. In addition, the common adaptor, myeloid differentiation factor 88 (MyD88)-deficient Tak1ΔHep mice also attenuated liver injury, macrophage recruitment, collagen deposition, and tumor growth compared with control Tak1ΔHep mice. Genetic ablation of TNF receptor type I (TNFR) in Tak1ΔHep mice remarkably reduced liver inflammation-fibrosis-cancer axis. Surprisingly, disruption of interleukin-1 receptor (IL-1R) had no effect on liver injury and tumor formation, although Il1r-deficient Tak1ΔHep showed attenuated macrophage infiltration and collagen deposition. In conclusion, TLR4- and TLR9-MyD88 are driving forces of progression to HCC accompanied by liver inflammation and fibrosis in Tak1ΔHep mice. Importantly, TLR4 and TLR9 downstream TNFR, but not IL-1R signaling is crucial for the development of HCC in Tak1ΔHep mice. This article is protected by copyright. All rights reserved.

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Apport de la volumétrie au rajeunissement facial. Partie 1 : greffe adipocytaire

Publication date: Available online 5 September 2017
Source:Annales de Chirurgie Plastique Esthétique
Author(s): P. Bui, C. Lepage
Depuis quelques années, une approche volumétrique par injections de graisse autologue vient compléter le lifting cervicofacial afin d'en améliorer le résultat esthétique et de pérenniser le rajeunissement facial. Si l'utilisation de graisse autologue comme tissu de comblement en chirurgie plastique date de la fin du 19^e siècle, son association avec le lifting cervicofacial ne s'est répandue que récemment. L'intérêt d'associer ces deux méthodes repose d'une part sur les caractéristiques physiopathologiques du vieillissement facial qui associe relâchement cutané et perte de volume, et d'autre part sur les propriétés d'induction tissulaire du greffon graisseux, source de « rajeunissement » des zones injectées. La méthodologie stricte qui consiste à prélever, traiter, puis injecter un greffon de graisse autologue porte le nom de LipoStructure^® ou lipofilling. Cette méthode est décrite dans sa globalité, puis région par région. Si cette méthode, aujourd'hui bien connue, semble simple, efficace, et reproductible, elle n'en demeure pas moins délicate. Elle exige de restituer à chaque patient un visage harmonieux aux volumes bien distribués. En associant la volumétrie au lifting, le chirurgien esthétique change de rôle, de tailleur, retirant l'excès de peau, il devient sculpteur, remodelant les visages avec pour objectif de restaurer l'harmonie propre aux visages jeunes.For a number of years, a volumetric approach using autologous fat injection has been implemented to improve cosmetic outcome in face-lift procedures and to achieve lasting rejuvenation. Autologous fat as filling tissue has been used in plastic surgery since the late 19th century, but has only recently been associated to face lift procedures. The interest of the association lies on the one hand in the pathophysiology of facial aging, involving skin sag and loss of volume, and on the other hand in the tissue induction properties of grafted fat, "rejuvenating" the injected area. The strict methodology consisting in harvesting, treating then injecting an autologous fat graft is known as LipoStructure^® or lipofilling. We here describe the technique overall, then region by region. It is now well known and seems simple, effective and reproducible, but is nevertheless delicate. For each individual, it is necessary to restore a harmonious face with well-distributed volumes. By associating volumetric to the face lift procedure, the plastic surgeon plays a new role: instead of being a tailor, cutting away excess skin, he or she becomes a sculptor, remodeling the face to restore the harmony of youth.

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The Effects of Continuous Positive Airway Pressure Therapy on Troponin-T and N-Terminal Pro B-Type Natriuretic Peptide in Patients with Obstructive Sleep Apnoea: A Randomised Controlled Trial

Untreated obstructive sleep apnoea (OSA) is associated with increased risk of coronary artery disease (CAD) and heart failure. High-sensitivity cardiac troponin (hs Trop-T) and B-Type Natriuretic Peptide (NT-pro-BNP) are sensitive biomarkers for myocardial injury and heart failure respectively. No randomised controlled trials have examined the treatment effect of continuous positive airway pressure (CPAP) in patients with OSA on these biomarkers.

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Cardiac autonomic control during sleep in patients with myotonic dystrophy type 1: the effects of comorbid obstructive sleep apnea

Myotonic dystrophy type 1 (DM1) is a hereditary myopathy characterized by an autosomal dominant inheritance with important cardiovascular and autonomic deregulation. DM1 patients have a high prevalence of obstructive sleep apnea (OSA), but the effects of this comorbidity on cardiovascular autonomic control (CAC) are unknown. The present study aimed to investigate CAC during sleep-wake cycle in DM1 patients, taking into account the effects of OSA comorbidity.

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Comorbidity of narcolepsy and depressive disorders: a nationwide population-based study in Taiwan

Narcolepsy is a chronic sleep disorder that is likely to have neuropsychiatric comorbidities. Depression is a serious mood disorder that affects individuals' daily activities and functions. The current study aimed to investigate the relationship between narcolepsy and depressive disorders.

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Response to "Prognosis in patients with obstructive sleep apnea with special reference to comorbidities and treatment of positive airway pressure"

Thank you for Dr. Kawada for the interest into our paper.

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Newer Technologies in Breast Cancer Imaging: Dedicated Cone-Beam Breast CT

Dedicated breast computed tomography (CT) is the latest in a long history of breast imaging techniques dating back to the 1960s. Breast Imaging is performed both for cancer screening as well as for diagnostic evaluation of symptomatic patients. Dedicated breast CT received United States Food and Drug Administration (US FDA) approval for diagnostic use in 2015 and is slowly gaining recognition for its value in diagnostic 3D imaging of the breast, and also for injected contrast-enhanced imaging applications.

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The Associative Brain at Work: Evidence from Paired Associative Stimulation Studies in Humans

Donald Hebb's now-famous rule of synaptic plasticity states: "When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A's efficiency, as one of the cells firing B, is increased." Although not explicitly stated, the phrase "takes part in firing it" suggests very strongly that there is a close temporal connection between occurrence of the input (A) and the firing of cell B.

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Epileptic seizures in nonalcoholic Wernicke’s encephalopathy: a case report and literature review

Abstract

Wernicke encephalopathy (WE) is characterized by eye signs, cerebellar dysfunction, and confusion. Epileptic seizures are rare in nonalcoholic WE. We reviewed the clinical, laboratory, radiological, and prognostic characteristics of nonalcoholic WE accompanied by epileptic seizures. We reported 1 case and searched similar cases using PubMed, WoK, Ovid, and Embase. WE was diagnosed according to dietary deficiencies, clinical symptoms and brain magnetic resonance imaging (MRI). We reviewed 13 patients (median age, 27 years; 5 men) with clear histories of thiamine deficiency and symptoms of typical WE. The type of epileptic seizures reported in the 13 cases reviewed was generically reported as seizures or convulsions in 4 patients; 7 patients had generalized tonic-clonic seizures, 1 partial seizure, and 1 generalized convulsive status epileptics. Two patients had epileptic seizures as the first symptom of WE. Laboratory tests mainly indicated metabolic acidosis and electrolyte disturbances. Electroencephalography may present as normal patterns, increased slow waves or epileptic discharge. Six patients had cortical lesions on brain MRI. These lesions were usually diffuse and band-like, and sometimes involved all lobes either symmetrically or asymmetrically, with the frontal lobe as the most susceptible area. All cortical lesions were accompanied by non-cortical lesions typical of WE. Brain MRI abnormalities, after thiamine treatment, mostly disappeared on follow-up MRIs. The patients had good prognoses. Only 1 patient had repeated seizures, and there were no comas or deaths. Patients with nonalcoholic WE accompanied by seizures are young and generally have good prognoses. Most patients experienced generalized convulsive seizures, which may have been related to abnormal cerebral cortical metabolism due to subacute thiamine deficiency.

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Factors Associated with Contralateral Deep Venous Thrombosis after Iliocaval Venous Stenting

Publication date: Available online 5 September 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): S.A. Khairy, R.J. Neves, O. Hartung, G.J. O'Sullivan
BackgroundThe majority of iliac venous obstructions occur on the left side, and endovascular therapy has become the first line treatment for this condition. A left common iliac venous stent will protrude into the inferior vena cava (IVC) to some extent, thereby covering the contralateral common iliac vein (CIV) outflow. This may increase the risk of thrombosis of the contralateral iliac vein. The aim of this paper was to determine the rate of, and factors associated with, contralateral lower limb venous thrombosis after stenting, and to evaluate the results of salvage revascularisation.MethodsA total of 376 patients (102 from UCH, Galway, Ireland, 2008–16, and 274 from, CHU Nord, Marseille, France, 2000–15) with symptomatic acute or chronic left iliocaval venous obstruction were retrospectively evaluated. Either duplex ultrasound scanning (DUS) or computed tomographic venography (CTV) was used for pre- and post-operative imaging. Data were collected from the PACS system (IMPAX, Agfa, BE) of the Radiology Department, UCH, Galway, and from the electronic medical records of Vascular Surgery department, CHU Nord, Marseille.ResultsThe median age of stented patients was 46 (range 15–86 years), 80% were female (301/376). Following left CIV stent placement, 2.7% (10/376) later presented with a right (contralateral) iliac deep venous thrombosis (DVT). Acute DVT (p=.001), non-compliance with the prescribed 6 months anticoagulation (p = 0.05), pre-operative contralateral internal iliac vein (IIV) thrombosis (p = 0.001), and pre-existing IVC filter placement (p = 0.003) were all statistically significantly associated with contralateral DVT. All patients with symptomatic contralateral iliac DVT underwent clot removal in the acute phase. The primary patency of these limbs was 100% at 3 years.ConclusionStent placement across the iliocaval confluence from the left CIV is associated with a low but definite rate of contralateral iliac vein thrombosis. Acute DVT, pre-operative contralateral IIV thrombosis, pre-existing IVC filters, and anticoagulation non-compliance are significant risk factors.

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Probiotics for the prevention of atopic dermatitis and other allergic diseases: What are the real facts?

Publication date: Available online 5 September 2017
Source:Alergologia Polska - Polish Journal of Allergology
Author(s): Magdalena Czarnecka-Operacz, Anna Sadowska-Przytocka
Atopic dermatitis (AD) is one of the most common inflammatory skin diseases diagnosed all over the world. The course of this complicated disease is chronic and relapsing and there have been many variants both endogenic and phenotypic already described and despite of our better understanding of AD we have no well "structured" therapeutical approach to many of our patients. Mainly because we do not understand it in an adequate way and complexity of treatment must be highly individualized. Recent studies suggest prevention of AD can be achieved through early intervention to protect the disturbed skin barrier. While the skin lesions are developed AD requires appropriate control of local and systemic immune activation for optimal management which obviously may cause the whole variety of adverse events. Therefore it seems that early intervention might improve long-term outcomes of AD and reduce the risk of development of systemic sensitization that leads to associated allergic/atopic diseases within the gastrointestinal and respiratory tract. For some time probiotics have been suggested as an intervention to prevent allergic diseases such as AD. Therefore besides many publications, a systematic review of randomized trials assessing the effect of any probiotics administered to pregnant women breast-feeding mothers, and/or infants have been analyzed in this review paper in order to state what is the "real truth" about this type of preventive approach.

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Characteristics of size-resolved atmospheric inorganic and carbonaceous aerosols in urban Shanghai

Publication date: October 2017
Source:Atmospheric Environment, Volume 167
Author(s): X.X. Ding, L.D. Kong, C.T. Du, A. Zhanzakova, H.B. Fu, X.F. Tang, L. Wang, X. Yang, J.M. Chen, T.T. Cheng
Size-segregated aerosol particles were collected with a 10-stage Micro-Orifice Uniform Deposit Impactor (MOUDI) at an urban site in Shanghai, China for four non-consecutive months representing four seasons from 2015 to 2016. Chemical composition, including water-soluble ions as well as organic carbon (OC), elemental carbon (EC) and secondary organic carbon (SOC) of size-resolved (0.056–18 μm) atmospheric aerosols in four seasons and in different polluted cases were studied. The size distributions of sulfate, nitrate and ammonium (SNA) and carbonaceous aerosol (OC, EC and SOC) were discussed and the potential sources of PM1.8-associated secondary species (SO4²⁻, NO3⁻, SNA and SOC) in different seasons were identified by potential source contribution function (PSCF) model. Results showed that atmospheric ultrafine and fine particle pollution in Shanghai were very serious during the study period. Most of the water-soluble ions tended to be enriched in fine particles, especially being abundant in the droplet mode in polluted cases. Compared with sulfate, size distributions of nitrate and ammonium presented more significant seasonal variations and showed distinctive characteristics in polluted days. Abundant nitrate was concentrated in fine particles in cold seasons (spring and winter), whereas it was enriched in coarse mode during summer and autumn. The droplet mode sulfate with high concentration did not result in the aggravation of air pollution, while the nucleation mode sulfate may have made a great contribution to the air pollution in urban Shanghai. It was also found that the formation of air pollution in urban Shanghai had a significant link with nitrate and ammonium, especially with nitrate and ammonium in condensation mode and droplet mode, and the contribution of sulfate to the pollution formation in Shanghai would somehow be surpassed by the increasing nitrate and ammonium. OC and EC concentrations from spring to winter were found to be 11.10, 7.10, 12.30, 20.16, and 3.73, 2.84, 4.63, 7.10 μg m⁻³, respectively, distinctly presenting the summer minima and winter maxima in this study. The maximum OC/EC was in the droplet mode and the minimum was in the nucleation mode for both clean and polluted days. The great contribution of SOC to OC in droplet mode and the occurrence of PM pollution necessarily had an important bearing on the SOC formation in droplet mode particles. Particle acidity may play a key role in secondary organic aerosol formation and the particles with the size of 0.056–0.1 μm was the most sensitive particles to acid catalysis in SOA formation. The similar PSCF results of PM1.8-associated SOC to those of SO4²⁻, NO3⁻ and SNA indicated possible connections between the formation of SOC and secondary inorganic species in PM.

Graphical abstract

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Vocal Tract Morphology in Inhaling Singing: Characteristics During Vowel Production—A Case Study in a Professional Singer

A professional singer produced various vowels on a comfortable loudness and pitch in an inspiratory and expiratory phonation manner. The present study investigates the morphological differences and tries to find a link with the acoustical characteristics.

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A Survey on Breast Cancer Awareness Among Medical, Paramedical, and General Population in North India Using Self-Designed Questionnaire: a Prospective Study

Abstract

Breast cancer (BC) has become the most common cancer in urban women. Unfortunately, most women are not aware of BC symptoms/signs, prevention, and management. In resource-limited countries like India where we do not have structured screening/awareness programs, a majority of women present with locally advanced BC. The aim of our study is to identify the present status of awareness about BC prevention, early detection, symptoms, and management in urban and rural Indian women (medical, paramedical, and nonmedical) and to assess whether education and socioeconomic strata have any role in better awareness about BC or not. We did a prospective cross-sectional observation study among the medical, paramedical, and nonmedical women in the northern part of India. We designed a questionnaire keeping in mind the three domains about BC—knowledge (questions 1–25 include risk factors, genetics, lifestyle changes, hormones, associated cancers, and modes of presentation like lump, nipple/skin changes), breast self-examination (questions 25–37), and attitude to prevention and early detection (questions 38–44). We also asked how many do breast self-examination (BSE) and what they think are the three main factors responsible for late presentation and the three main ways to increase BC awareness. The Likert scale was used for objective assessment. We analyzed the whole data using SPSS software version 15. A total of 220 women out of 270 completed the questionnaire. Out of 220 women, 26.4% were medical, 20.9% paramedical, and 52.7% nonmedical. Most women were educated (82.7%) and married (65%). 59.5% women resided in urban areas and the rest (40.5%) were from rural areas. We found that there was relatively more knowledge in the medical group; however, the skills of BSE and attitude to prevention and early detection in all the three subgroups and among rural and urban women were suboptimal and not different significantly. The three main factors responsible for delayed presentation were shyness and not knowing BSE, ignorance about BC symptoms, and social stigma of cancer along with financial constraints. The three main ways to improve BC awareness suggested were to have more advertisements on television and social media, roadside campaigns and in colleges along with group discussions and debates, and at grassroots level to involve Anganwadi workers and nurses to create more awareness in villages. There was less breast cancer knowledge and awareness among the nonmedical women compared to those among the medical and paramedical, the skills of BSE and attitude to prevention and early detection were suboptimal in all the three groups. Rural or urban dwellings did not make much difference in BC knowledge, skills of BSE, and attitude to prevention. More awareness regarding breast cancer symptoms with early detection and BSE need to be addressed with more information dissemination via social media, campaigns, and involvement of paramedics and social workers.

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ERAS—Anticipated outcomes and realistic goals

Enhanced recovery programs emphasize implementation of perioperative measures to reduce stress and restore baseline function. Complications and length of stay are greatly improved as a result, but the field is moving toward more patient centric and longer term outcomes that better reflect functional recovery. Programs demonstrating value in these domains will undoubtedly see corollary gains in traditional metrics. Thus, greater focus on patient well-being and treatment success is key to successful implementation of enhanced recovery.

The optimal approach when initiating an enhanced recovery program is to focus on patient-centric well-being and outcomes. Programs that demonstrate value in these domains will see corollary gains in more physician/hospital centric metrics. Basically, the residue of a well-intentioned enhanced recovery program is shorter LOS, decreased complication rates and lower costs of care.

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Enhanced recovery after surgery—Summary recommendations

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ERAS—Value based surgery

This paper reviews implementation of ERAS and its financial implications. Literature on clinical outcomes and financial implications were reviewed. Reports from many different surgery types shows that implementation of ERAS reduces complications and shortens hospital stay. These improvements have major impacts on reducing the cost of care even when costs for implementation, and investment in time for personnel and training is accounted for. The conclusion is that ERAS is an excellent example of value based surgery.

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Enhanced recovery after surgery: Pain management

Effective pain management is fundamental to enhanced recovery after surgery. Selection of strategies should be tailored to patient and operation. As well as improving the quality of recovery, effective analgesia reduces the host stress response, facilitates mobilization and allows resumption of oral intake. Multi-modal regimens combining paracetamol, non-steroidal anti-inflammatory agents where indicated, a potent opioid and a local anaesthetic technique achieve effective analgesia while limiting the dose and thereby side effects of any one agent.

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GNAQ and GNA11 mutations and downstream YAP activation in choroidal nevi

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Intracrine VEGF signalling mediates colorectal cancer cell migration and invasion

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GEIS-21: a multicentric phase II study of intensive chemotherapy including gemcitabine and docetaxel for the treatment of Ewing sarcoma of children and adults: a report from the Spanish sarcoma group (GEIS)

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Randomised Phase 2 study of maintenance linsitinib (OSI-906) in combination with erlotinib compared with placebo plus erlotinib after platinum-based chemotherapy in patients with advanced non-small cell lung cancer

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Lauren subtypes of advanced gastric cancer influence survival and response to chemotherapy: real-world data from the AGAMENON National Cancer Registry

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Cancer-associated fibroblasts promote bone invasion in oral squamous cell carcinoma

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Choosing wisely: a model-based analysis evaluating the trade-offs in cancer benefit and diagnostic referrals among alternative HPV testing strategies in Norway

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Vitamin D receptor and calcium-sensing receptor polymorphisms and colorectal cancer survival in the Newfoundland population

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Pre-clinical imaging of transgenic mouse models of neuroblastoma using a dedicated 3-element solenoid coil on a clinical 3T platform

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Expression of L1CAM in curettage or high L1CAM level in preoperative blood samples predicts lymph node metastases and poor outcome in endometrial cancer patients

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miR-125b predicts childhood acute lymphoblastic leukaemia poor response to BFM chemotherapy treatment

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Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis

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Regulation of hypoxia-induced autophagy in glioblastoma involves ATG9A

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Predicting response to radical (chemo)radiotherapy with circulating HPV DNA in locally advanced head and neck squamous carcinoma

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Novel immunohistochemistry-based signatures to predict metastatic site of triple-negative breast cancers

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Evidence of advanced stage colorectal cancer with longer diagnostic intervals: a pooled analysis of seven primary care cohorts comprising 11 720 patients in five countries

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Active multiple myeloma suppresses and typically eliminates coexisting MGUS

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The inflammatory potential of diet and ovarian cancer risk: results from two prospective cohort studies

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Differentiating brain radionecrosis from tumour recurrence: a role for contrast-enhanced ultrasound?

Abstract

Differentiating radionecrosis from tumour recurrence is a major issue in neuro-oncology. Conventional imaging is far from being validated as an alternative to histological assessment. We report the case of a patient operated on for suspected recurrence of brain metastasis 9 months after cyberknife radiosurgery. While magnetic resonance imaging showed strong enhancement of the lesion, intraoperative contrast-enhanced ultrasonography (CEUS) surprisingly did not—different from what is expected for brain metastases. Histopathological examination documented radionecrosis. For the first time, we describe radionecrosis with CEUS; further investigation is needed; however, the lack of enhancement could represent an important hallmark in differential diagnosis with neoplastic tissue.

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EMCrit 207 – A Case to Acid Test your Resus Logistics

Acid Test your Resus

EMCrit by Scott Weingart.

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Subretinal fibrin absorption after 577-nm subthreshold micropulse laser therapy in a CSC case: a brief report

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The Lipid Kinase PIKfyve Coordinates the Neutrophil Immune Response through the Activation of the Rac GTPase [INNATE IMMUNITY AND INFLAMMATION]

Neutrophils rapidly arrive at an infection site because of their unparalleled chemotactic ability, after which they unleash numerous attacks on pathogens through degranulation and reactive oxygen species (ROS) production, as well as by phagocytosis, which sequesters pathogens within phagosomes. Phagosomes then fuse with lysosomes and granules to kill the enclosed pathogens. A complex signaling network composed of kinases, GTPases, and lipids, such as phosphoinositides, helps to coordinate all of these processes. There are seven species of phosphoinositides that are interconverted by lipid kinases and phosphatases. PIKfyve is a lipid kinase that generates phosphatidylinositol-3,5-bisphosphate and, directly or indirectly, phosphatidylinositol-5-phosphate [PtdIns(5)P]. PIKfyve inactivation causes massive lysosome swelling, disrupts membrane recycling, and, in macrophages, blocks phagosome maturation. In this study, we explored for the first time, to our knowledge, the role of PIKfyve in human and mouse neutrophils. We show that PIKfyve inhibition in neutrophils does not affect granule morphology or degranulation, but it causes LAMP1⁺ lysosomes to engorge. Additionally, PIKfyve inactivation blocks phagosome–lysosome fusion in a manner that can be rescued, in part, with Ca²⁺ ionophores or agonists of TRPML1, a lysosomal Ca²⁺ channel. Strikingly, PIKfyve is necessary for chemotaxis, ROS production, and stimulation of the Rac GTPases, which control chemotaxis and ROS. This is consistent with observations in nonleukocytes that showed that PIKfyve and PtdIns(5)P control Rac and cell migration. Overall, we demonstrate that PIKfyve has a robust role in neutrophils and propose a model in which PIKfyve modulates phagosome maturation through phosphatidylinositol-3,5-bisphosphate–dependent activation of TRPML1, whereas chemotaxis and ROS are regulated by PtdIns(5)P-dependent activation of Rac.

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Cytokine-Mediated Regulation of Human Lymphocyte Development and Function: Insights from Primary Immunodeficiencies [BRIEF REVIEWS]

Cytokine-mediated intracellular signaling pathways are fundamental for the development, activation, and differentiation of lymphocytes. These distinct processes underlie protection against infectious diseases after natural infection with pathogens or immunization, thereby providing the host with long-lived immunological memory. In contrast, aberrant cytokine signaling can also result in conditions of immune dysregulation, such as early-onset autoimmunity. Thus, balanced signals provided by distinct cytokines, and delivered to specific cell subsets, are critical for immune homeostasis. The essential roles of cytokines in human immunity have been elegantly and repeatedly revealed by the discovery of individuals with mutations in cytokine ligands, receptors, and downstream transcription factors that cause primary immunodeficiency or autoimmune conditions. In this article, we review how the discovery and characterization of such individuals has identified nonredundant, and often highly specialized, functions of specific cytokines and immune cell subsets in human lymphocyte biology, host defense against infections, and immune regulation.

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In This Issue [IN THIS ISSUE]

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Cutting Edge: 2B4-Mediated Coinhibition of CD4+ T Cells Underlies Mortality in Experimental Sepsis [CUTTING EDGE]

Sepsis is a leading cause of death in the United States, but the mechanisms underlying sepsis-induced immune dysregulation remain poorly understood. 2B4 (CD244, SLAM4) is a cosignaling molecule expressed predominantly on NK cells and memory CD8⁺ T cells that has been shown to regulate T cell function in models of viral infection and autoimmunity. In this article, we show that 2B4 signaling mediates sepsis lymphocyte dysfunction and mortality. 2B4 expression is increased on CD4⁺ T cells in septic animals and human patients at early time points. Importantly, genetic loss or pharmacologic inhibition of 2B4 significantly increased survival in a murine cecal ligation and puncture model. Further, CD4-specific conditional knockouts showed that 2B4 functions on CD4⁺ T cell populations in a cell-intrinsic manner and modulates adaptive and innate immune responses during sepsis. Our results illuminate a novel role for 2B4 coinhibitory signaling on CD4⁺ T cells in mediating immune dysregulation.

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IL-33 Signaling Regulates Innate IL-17A and IL-22 Production via Suppression of Prostaglandin E2 during Lung Fungal Infection [INNATE IMMUNITY AND INFLAMMATION]

Members of the IL-1 family play protective and regulatory roles in immune defense against the opportunistic mold Aspergillus fumigatus. In this study, we investigated the IL-1 family member IL-33 in lung defense against A. fumigatus. IL-33 was detected in the naive lung, which further increased after exposure to A. fumigatus in a dectin-1–independent manner. Mice deficient in the receptor for IL-33 (Il1rl1^–/–) unexpectedly demonstrated enhanced lung clearance of A. fumigatus. IL-33 functioned as a negative regulator of multiple inflammatory cytokines, as IL-1α, IL-1β, IL-6, IL-17A, and IL-22 were significantly elevated in fungal-exposed Il1rl1^–/– mice. Subsequently, IL-33 administration to normal mice attenuated fungal-induced IL-17A and IL-22, but not IL-1α, IL-1β, or IL-6, production. IL-33–mediated regulation of IL-17A and IL-22 did not involve the modulation of IL-23 but rather PGE₂; PGE₂ was significantly increased in fungal-exposed Il1rl1^–/– mice, and normal mice produced less PGE₂ after fungal exposure when administered IL-33, suggesting that IL-33–mediated regulation of IL-17A and IL-22 occurred at the level of PGE₂. This was confirmed by in vivo cyclooxygenase 2 inhibition, which attenuated fungal-induced IL-17A and IL-22, as well as IL-1α, IL-1β, and IL-6, production in Il1rl1^–/– mice, resulting in impaired fungal clearance. We also show that a PGE₂ receptor agonist increased, whereas a PGE₂ synthase inhibitor decreased, the levels of IL-17A and IL-22 but not IL-1α, IL-1β, or IL-6. This study establishes novel mechanisms of innate IL-17A/IL-22 production via PGE₂ and regulation of the PGE₂/IL-17A/IL-22 axis via IL-33 signaling during lung fungal exposure.

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Cutting Edge: IL-2-Induced Expression of the Amino Acid Transporters SLC1A5 and CD98 Is a Prerequisite for NKG2D-Mediated Activation of Human NK Cells [CUTTING EDGE]

Priming of human NK cells with IL-2 is necessary to render them functionally competent upon NKG2D engagement. We examined the underlying mechanisms that control NKG2D responsiveness in NK cells and found that IL-2 upregulates expression of the amino acid transporters SLC1A5 and CD98. Using specific inhibitors to block SLC1A5 and CD98 function, we found that production of IFN- and degranulation by CD56^bright and CD56^dim NK cells following NKG2D stimulation were dependent on both transporters. IL-2 priming increased the activity of mTORC1, and inhibition of mTORC1 abrogated the ability of the IL-2–primed NK cells to produce IFN- in response to NKG2D-mediated stimulation. This study identifies a series of IL-2–induced cellular changes that regulates the NKG2D responsiveness in human NK cells.

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HIV-1 Infection Is Associated with Depletion and Functional Impairment of Mycobacterium tuberculosis-Specific CD4 T Cells in Individuals with Latent Tuberculosis Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

Coinfection with HIV is the single greatest risk factor for reactivation of latent Mycobacterium tuberculosis infection (LTBI) and progression to active tuberculosis disease. HIV-associated dysregulation of adaptive immunity by depletion of CD4 Th cells most likely contributes to loss of immune control of LTBI in HIV-infected individuals, although the precise mechanisms whereby HIV infection impedes successful T cell–mediated control of M. tuberculosis have not been well defined. To further delineate mechanisms whereby HIV impairs protective immunity to M. tuberculosis, we evaluated the frequency, phenotype, and functional capacity of M. tuberculosis-specific CD4 T cells in HIV-infected and HIV-uninfected adults with LTBI. HIV infection was associated with a lower total frequency of cytokine-producing M. tuberculosis-specific CD4 T cells, and preferential depletion of a discrete subset of M. tuberculosis-specific IFN-⁺IL-2^–TNF-α⁺ CD4 T cells. M. tuberculosis-specific CD4 T cells in HIV-infected individuals expressed significantly higher levels of Ki67, compared with HIV-uninfected individuals, thus indicating recent activation and turnover of these cells in vivo. The ex vivo proliferative capacity of M. tuberculosis-specific CD4 T cells was markedly impaired in HIV-infected individuals, compared with HIV-uninfected individuals. Moreover, HIV infection was associated with increased M. tuberculosis Ag-induced CD4 T cell death ex vivo, indicating a possible mechanism contributing to impaired proliferative capacity of M. tuberculosis-specific CD4 T cells in HIV-infected individuals. These data provide new insights into the parameters of M. tuberculosis-specific CD4 T cell immunity that are impaired in HIV-infected individuals with LTBI, which may contribute to their increased risk of developing active tuberculosis disease.

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Cutting Edge: Murine NK Cells Degranulate and Retain Cytotoxic Function without Store-Operated Calcium Entry [CUTTING EDGE]

Sustained Ca²⁺ signaling, known as store-operated calcium entry (SOCE), occurs downstream of immunoreceptor engagement and is critical for cytotoxic lymphocyte signaling and effector function. CD8⁺ T cells require sustained Ca²⁺ signaling for inflammatory cytokine production and the killing of target cells; however, much less is known about its role in NK cells. In this study, we use mice deficient in stromal interacting molecules 1 and 2, which are required for SOCE, to examine the contribution of sustained Ca²⁺ signaling to murine NK cell function. Surprisingly, we found that, although SOCE is required for NK cell IFN- production in an NFAT-dependent manner, NK cell degranulation/cytotoxicity and tumor rejection in vivo remained intact in the absence of sustained Ca²⁺ signaling. Our data suggest that mouse NK cells use different signaling mechanisms for cytotoxicity compared with other cytotoxic lymphocytes.

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DOCK8 Drives Src-Dependent NK Cell Effector Function [INNATE IMMUNITY AND INFLAMMATION]

Mutations in the dedicator of cytokinesis 8 (DOCK8) gene cause an autosomal recessive form of hyper-IgE syndrome, characterized by chronic immunodeficiency with persistent microbial infection and increased incidence of malignancy. These manifestations suggest a defect in cytotoxic lymphocyte function and immune surveillance. However, how DOCK8 regulates NK cell–driven immune responses remains unclear. In this article, we demonstrate that DOCK8 regulates NK cell cytotoxicity and cytokine production in response to target cell engagement or receptor ligation. Genetic ablation of DOCK8 in human NK cells attenuated cytokine transcription and secretion through inhibition of Src family kinase activation, particularly Lck, downstream of target cell engagement or NKp30 ligation. PMA/Ionomycin treatment of DOCK8-deficient NK cells rescued cytokine production, indicating a defect proximal to receptor ligation. Importantly, NK cells from DOCK8-deficient patients had attenuated production of IFN- and TNF-α upon NKp30 stimulation. Taken together, we reveal a novel molecular mechanism by which DOCK8 regulates NK cell–driven immunity.

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Αρχειοθήκη ιστολογίου

Τρίτη 5 Σεπτεμβρίου 2017

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