Πέμπτη 11 Μαρτίου 2021

Neem leaf glycoprotein salvages T cell functions from Myeloid-derived suppressor cells-suppression by altering IL-10/STAT3 axis in melanoma tumor microenvironment

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imageMyeloid-derived suppressor cells (MDSCs) suppress antitumor immune functions. We have observed that an immunomodulator, neem leaf glycoprotein (NLGP), inhibits tumor-resident MDSCs and enhances antitumor CD8+ T cell immunity. NLGP inhibits the number as well as functions of tumor-resident MDSCs (Gr1±CD11b±) and enhances antitumor CD8± T cell immunity by downregulating arginase 1 and inducible nitric oxide synthase production in MDSCs. Accordingly, decreased T cell anergy and helper to regulatory T cell conversion have been observed in the presence of NLGP, which ultimately augments T cell functions. M echanistically, NLGP-mediated rectification of T cell suppressive functions of MDSCs was primarily associated with downregulation of the interleukin (IL)-10/signal transducer and activator of transcription 3 (STAT3) signaling axis within the tumor microenvironment, as confirmed by knockdown of STAT3 (by STAT3-siRNA) and using IL-10−/− mice. Thus, NLGP-mediated suppression of MDSC functions in tumor hosts is appeared to be another associated effective mechanism for the eradication of murine melanoma by NLGP.
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The efficacy of immunotherapy for in-transit metastases of melanoma: an analysis of randomized controlled trials

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imageNearly 10% of patients with high-risk early-stage melanoma will develop satellite or in-transit metastases (ITM), classified as stage III disease similar to lymph node metastases. The pivotal registration trials of the CTLA-4 antibody ipilimumab, and the PD-1 antibodies nivolumab and pembrolizumab, also included patients with unresectable stage III disease. However, there has been no analysis of patients with ITM, and anecdotal retrospective small series have indicated a potential lesser effect. This study aimed to identify patients with unresectable ITM within the randomized trials, and to determine respon se, progression-free survival and overall survival. The pivotal phase III randomized intervention trials that included melanoma patients with ITM, with or without nodal metastasis, and were treated with ipilimumab, nivolumab or pembrolizumab was identified. The datasets from each trial were then searched to identify the specific details of the investigated patient population for a pooled analysis. The primary endpoint was complete response rate. Seven trials that included stage III patients, and with accessible datasets, were identified. There was a total of 4711 patients, however, no patients with ITM could be identified, as this data was not captured by the case report forms. Evidence from prospective clinical trials on the use of immunotherapy in patients with ITM is lacking. We recommend pooling data from multiple institutions to examine efficacy of available drug therapies in this patient population, but more importantly, prospective clinical trials of locoregional treatments w ith or without systemic drug therapies are required.
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BAP1 deletion abrogates growth and metastasis of murine cutaneous melanoma

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imageAlthough germline mutations in BRCA-associated protein-1 (BAP1) predispose to cutaneous melanoma (CM), BAP1 is rarely mutated in primary CM outside the familial context. The role of BAP1 in the pathogenesis of CM remains obscure. Here, we discovered an unexpected role of BAP1 in suppressing CM growth and metastasis. BAP1 deletion by CRISPR-Cas9 system severely compromises colony-forming capability of murine CM cell line B16-F10 and human CM cell lines, SK-MEL-28 and A375. Furthermore, BAP1 loss abrogates tumor growth and lung metastasis in murine syngeneic tumor models. Deletion of BAP1 in B16-F10 cells leads to preferential downregulation of genes accompanied with increased H2A ubiquitination at lysine 119. Transcriptomic characterization of BAP1 deletion reveals multiple deregulated cellular functions including extracellular matrix-receptor interaction and MAPK signaling pathway which may contribute to BAP1's effect on metastasis and proliferation. Our findings indicate that BAP1 could be a potential therapeutic target for CM.
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A case of sudden brain metastases progression after temporary targeted therapy discontinuation: when to regret a drug holiday

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imageTargeted therapy improves outcomes in BRAF V600-mutant metastatic melanoma with active brain metastases. We present the case of a patient with rapid brain disease progression upon temporary targeted therapy discontinuation and unusual rapid disease response upon treatment resumption. This report presents a 78-year-old woman with metastatic BRAF V600E positive melanoma (bladder and brain localizations). The patient started first-line dabrafenib and trametinib with good tolerability and evidence of complete response (CR). After 8 months of maintained CR, the patient took a drug holiday for 14 days. Brain MRI performed after treatment pause showed extensive disease progression, whereas extracranial staging was negative. The patient was asymptomatic: she restarted targeted therapy and underwent evaluation for whole-brain radiotherapy. Brain computed tomography scan and subsequent MRI performed to plan radiotherapy showed brain CR after only 10 days of targeted therapy resumption. The patient continued treatment, and radiotherapy indication was withheld. Repeated brain MRI confirmed maintained CR. Treatment with dabrafenib and trametinib is ongoing with excellent tolerability. Rapid intracranial progression is a well-known finding after discontinuation of combined targeted therapy in the case of extracranial progressive disease. This is the first report of documented disease progression upon temporary treatment discontinuation for reasons other than toxicity, with an unusual response after retreatment. Caution should be used in tailoring treatment during targeted therapy, allowing p auses for reasons other than toxicity. Strict adherence to treatment is paramount to guarantee disease control.
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Mapping sentinel lymph nodes in cutaneous melanoma: a vast array of perioperative imaging modalities

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imageSentinel lymph node biopsy (SLNB) is a decisive step in the staging process of melanoma, critically impacting patients' oncological outcome and driving the decision-making process. SLNB limits the extent of the dissection in cases where no metastases are found. Conversely, when metastases are detected, SLNB has the potential to improve regional control of the disease when complete lymphadenectomy or early administration of adjuvant treatment are indicated. Thus, accurately identifying sentinel lymph nodes represents an important prognostic factor. Several strategies have been studied, including novel procedur es that are not commonly used in the clinical setting. This review highlights the different tracers, preoperative and intraoperative imaging modalities studied to perform SLNB in cutaneous melanoma. The development of innovative modalities has been fueled by a need to optimize current approaches, offering new alternatives that can overcome some of the limitations of the standard method.
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Immunohistochemistry analysis reveals lysyl oxidase-like 3 as a novel prognostic marker for primary melanoma

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imageLysyl oxidase-like 3 (LOXL3) is an extracellular enzyme involved in the synthesis of collagen and elastin, and it has been reported to promote melanoma cell proliferation and invasion in vitro. However, the expression level of LOXL3 at different stages of melanocytic lesions and the role of LOXL3 in melanoma pathogenesis remain unknown. Immunohistochemical staining of LOXL3 in a tissue microarray of 373 biopsies at different melanocytic stages was conducted. The correlation between LOXL3 expression and patient survival was examined using Kaplan–Meier survival analysis. Univariate and multivariate Cox regres sion analyses were conducted to study the hazard ratios. The tissue microarray study revealed that stronger expression of LOXL3 protein was found at more advanced melanocytic stages (P 
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A Comparitive Study of Endoscopic Skull Base Reconstruction in CSF rhinorrea using Nasoseptal Flap with  Septal Cartilage v/s Fascia Lata With Fat

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Abstract

The objective of the study is to evaluate the surgical outcome between free nasoseptal mucoperichondrial flap using septal cartilage vs fascia lata using fat in terms of morbidity, hospital stay and postoperative complications. It is a retrospective comparitive study of 127 patients, diagnosed with CSF leak and who underwent repair of anterior skull base defect using free nasoseptal mucoperichondrial graft with septal cartilage in 73 cases compared with fascia lata with fat in 54 cases over the time frame of 5 years. The success rate with free nasoseptal flap with septal cartilage was 97.3% and that with fascia lata with fat was 96.3%. There was a significant association between mean hospital stay and the technique of CSF repair (unpaired t test, p −0.02). In our study the complications following the repair with free nasoseptal flap with septal cartilage was significantly less (p < 0.05, chi square test ). The above study concludes that in patients treated with free nasoseptal flap using septal cartilage has less hospital stay, less post-operative morbidity in the form of pain, movement and dependence for cleaning and dressing in comparison to fascia lata using fat.

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Providing open-label placebos remotely—A randomized controlled trial in allergic rhinitis

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Via Rhinitis

journal.pone.0248367.g006&size=inline

by Tobias Kube, Verena E. Hofmann, Julia A. Glombiewski, Irving Kirsch

Background

Placebos can reduce physical symptoms even when provided with full honesty and disclosure. Yet, the precise mechanisms underlying the effects of "open-label placebos" (OLPs) have remained subject of debate. Furthermore, it is unclear whether OLPs are similarly effective when provided remotely, as is sometimes required e.g. in the current COVID-19 pandemic.

Methods

In a randomized-controlled trial, we examined the effects of OLP plus treatment as usual (TAU) compared to TAU alone on symptom reduction in people with allergic rhinitis (N = 54) over the course of two weeks. Due to the COVID-19 pandemic, OLP was provided remotely (i.e. sent via postal service). To investigate the potential influence of the clinical encounter on the effects of OLP, we manipulated the perception of the virtual clinical encounter, both with respect to verbal and nonverbal factors (augmented vs. limited encounter).

Results

The results of the manipulation check confirmed that the augmented clinical encounter was evaluated more positively than the limited encounter, in terms of perceived warmth of the provider. Participants from all treatment groups showed significant symptom reduction from baseline to two weeks later, but OLP had no incremental effect over TAU. Participants benefitted more from OLP when they did not take any other medication against allergic symptoms than when taking medication on demand. When controlling for baseline symptoms, a significant treatment by encounter interaction was found, pointing to greater symptom improvement in the OLP group when the encounter was augmented, whereas the control group improved more when the encounter was limited.

Discussion

The study demonstrates that providing OLP and enhancing the encounter remotely is possible, but their effectiveness might be lower in comparison to previous studies relying on physical patient-provider interaction. The study raises questions for future research about the p otential and challenges of remote placebo studies and virtual clinical encounters. The study has been registered as a clinical trial at ISRCTN (record number: 39018).

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Tympanometrie zur Mittelohrdiagnostik

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Sprache · Stimme · Gehör 2021; 45: 5-5
DOI: 10.1055/a-1256-2331



Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
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Katzenschrei-Syndrom

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Message:

Beim Cri-du-chat Syndrom handelt es sich um eine Chromosomenstörung, bei der ein Teil des kurzen Armes des Chromosoms 5 fehlt. Ein Wiederholungsrisiko besteht nur, wenn sich bei einem Elternteil auch eine Störung am Chromosom 5 findet (Translokation).

Cri-du-chat Syndrom, Katzenschrei Syndrom - Medizin | UKBB

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Sprache · Stimme · Gehör 2021; 45: 51-52
DOI: 10.1055/a-1256-2275



Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Full text

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Decreased retinal nerve fiber and choroidal thickness in chronic rhinosinusitis

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Eur Arch Otorhinolaryngol. 2021 Mar 11. doi: 10.1007/s00405-020-06552-0. Online ahead of print.

ABSTRACT

PURPOSE: The assessment of the retina and choroid of patients with chronic rhinosinusitis (CRS), via spectral domain-optical coherence tomography (SD-OCT), was aimed in this study. We proposed that chronic upper airway restriction caused by chronic sinusitis could deteriorate the retinal and choroid morphology.

METHODS: This prospective controlled study included a total of 90 eyes of 90 patients, 30 of whom were CRS with nasal polyposis (CRSwNP), 30 of whom were CRS without nasal polyposis (CRSsNP) and 30 of whom were healthy controls (HC). Only the right eye of the patients were evaluated. All patients underwent full otorhinolaryngologic and ophthalmologic examinations, including SD-OCT.

RESULTS: Average retinal nerve fiber layer (RNFL) and RNFL in superior and inferior quadrants were measured significantly lower in CRS patients compared to HC. Ganglion cell-inner plexiform layer (GCIPL) thickness in all sectors was thinner in patients with CRS than in HC with significantly lower values in all sectors except inferior. Mean average GCIPL thickness and GCIPL thickness in the inferior sector were significantly lower in CRSwNP than CRSsNP patients.

CONCLUSION: CRS may lead to thinning in the choroidal thickness, RNFL thickness, especially in the superior and inferior quadrants and GCIPL thickness, presumably related with hypoxia, endothelial dysfunction, inflammation and vascular dysregulation. Ocular manifestations of the CRS should be taken in the consideration during the management of this disease.

PMID:33704528 | DOI:10.1007/s00405-020-06552-0

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Tumor volume as a prognostic factor of locally advanced laryngeal cancer

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Eur Arch Otorhinolaryngol. 2021 Mar 11. doi: 10.1007/s00405-021-06734-4. Online ahead of print.

NO ABSTRACT

PMID:33704527 | DOI:10.1007/s00405-021-06734-4

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