MEK Inhibitors for Neurofibromatosis Type 1 Manifestations: Clinical Evidence and Consensus

alexandrossfakianakis shared this article with you from Inoreader MEK Inhibitors for Neurofibromatosis Type 1 Manifestations: Clinical Evidence and Consensus via Neuro-Oncology Advance Access Abstract The wide variety of clinical manifestations of the genetic syndrome neurofibromatosis type 1 (NF1) are driven by overactivation of the RAS pathway. Mitogen-activated protein kinase kinase inhibitors (MEKi) block downstream targets of RAS. The recent regulatory approvals of the MEKi selumetinib for inoperable symptomatic plexiform neurofibromas in children with NF1 has made it the first medical therapy approved for this indication in the United States, the European Union and elsewhere. Several recently published and ongoing clinical trials have demonstrated that MEKi may have potential benefit for a variety of other NF1 manifestations, and there is broad interest in the field regarding the appropriate clinical use of these agents. In this review, we present the current evidence regarding the use of existing MEKi for a variety of NF1-related manifestations, including tumor (neurofibromas, malignant peripheral nerve sheath tumors, low grade glioma, and juvenile myelomonocytic leukemia) and non-tumor (bone, pain, and neurocognitive) manifestations. We discuss the potential utility of MEKi in related genetic conditions characterized by overactivation of the RAS pathway (RASopathies). In addition, we review practical treatment considerations for the use of MEKi as well as provide consensus recommendations regarding their clinical use from a panel of experts. View on Web

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Sound Induced Vibrations Deform the Organ of Corti Complex in the Low-Frequency Apical Region of the Gerbil Cochlea for Normal Hearing

alexandrossfakianakis shared this article with you from Inoreader Sound Induced Vibrations Deform the Organ of Corti Complex in the Low-Frequency Apical Region of the Gerbil Cochlea for Normal Hearing via JARO - Journal of the Association for Research in Otolaryngology via MedWorm.com AbstractHuman speech primarily contains low frequencies. It is well established that such frequencies maximally excite the cochlea near its apex. But, the micromechanics that precede and are involved in this transduction are not well understood. We measured vibrations from the low-frequency, second turn in intact gerbil cochleae using optical coherence tomography (OCT). The data were used to create spatial maps that detail the sound-evoked motions across the sensory organ of Corti complex (OCC). These maps were remarkably similar across animals and showed little variation with frequency or level. We identify four, anatomically distinct, response regions within the OCC: the basilar membrane (BM), the outer hair cells (OHC), the lateral compartment (lc), and the tectorial membrane (TM). Resu... View on Web

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Present and future avenues of cell‐based therapy for brain injury: The enteric nervous system as a potential cell source

alexandrossfakianakis shared this article with you from Inoreader Present and future avenues of cell‐based therapy for brain injury: The enteric nervous system as a potential cell source via Brain Pathology Abstract Cell therapy is a promising strategy in the field of regenerative medicine; however, several concerns limit the effective clinical use, namely a valid cell source. The gastrointestinal tract, which contains a highly organized network of nerves called the enteric nervous system (ENS), is a valuable reservoir of nerve cells. Together with neurons and neuronal precursor cells, it contains glial cells with a well described neurotrophic potential and a newly identified neurogenic one. Recently, enteric glia is looked at as a candidate for cell therapy in intestinal neuropathies. Here, we present the therapeutic potential of the ENS as cell source for brain repair, too. The example of stroke is introduced as a brain injury where cell therapy appears promising. This disease is the first cause of handicap in adults. The therapies developed in recent years allow a partial response to the consequences of the disease. The only prospect of recovery in the chronic phase is currently based on r ehabilitation. The urgency to offer other treatments is therefore tangible. In the first part of the review, some elements of stroke pathophysiology are presented. An update on the available therapeutic strategies is provided, focusing on cell- and biomaterial-based approaches. Following, the ENS is presented with its anatomical and functional characteristics, focusing on glial cells. The properties of these cells are depicted, with particular attention to their neurotrophic and, recently identified, neurogenic properties. Finally, preliminary data on a possible therapeutic approach combining ENS-derived cells and a biomaterial are presented. View on Web

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Real‐life impact of tenofovir disoproxil fumarate and entecavir therapy on lipid profile, glucose and uric acid in chronic hepatitis B patients

alexandrossfakianakis shared this article with you from Inoreader Real‐life impact of tenofovir disoproxil fumarate and entecavir therapy on lipid profile, glucose and uric acid in chronic hepatitis B patients via Journal of Medical Virology Abstract Background & Aims The impact of long-term nucleos(t)ide analogs treatment on host metabolism is a concern. Hence, we conducted this study to compare the effect of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) on metabolic parameters among CHB patients. Methods In this real-life retrospective study, 2,030 CHB outpatients treated with ETV or TDF at Nanfang Hospital, China, were included. For treatment-naïve patients, pretreatment and semiannual metabolic parameters were collected. For treatment-experienced patients, metabolic parameters were collected at the first visit. Propensity score matching (PSM) was used to balance the effects of potential confounding factors. Results Among 122 treatment-naïve patients and 1908 treatment-experienced patients, ETV-treated patients were older with a higher percentage of metabolic syndrome. After PSM, the characteristics were comparable between the two groups. For treatment-naïve patients, fou r lipid parameters, including total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein and triglyceride levels showed a decreasing trend during the 42-month TDF treatment, while they remained relatively stable or increased during ETV treatment. At month 30, the levels of TC and LDL among TDF-treated patients were significantly lower than those among ETV-treated patients (TC: 4.7 vs. 3.9 mmol/L, p=0.004; LDL: 3.0 vs. 2.4 mmol/L, p=0.009). For treatment-experienced patients, we also observed lower levels of lipid parameters in patients with different durations of TDF treatment. The levels of glucose and uric acid were similar among ETV- and TDF-treated patients. Conclusion TDF has a lipid-lowering effect in CHB patients, which provides a basis for the selection of antiviral drugs for aging CHB patients. This article is protected by copyright. All rights reserved. View on Web

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Longitudinal follow‐up of HPV16 sequence after cervical infection: low intra‐host variation and no correlation with clinical evolution

alexandrossfakianakis shared this article with you from Inoreader Longitudinal follow‐up of HPV16 sequence after cervical infection: low intra‐host variation and no correlation with clinical evolution via Journal of Medical Virology ABSTRACT Human papillomavirus (HPV) 16 exhibits different variants that may differ in their carcinogenic risk. In order to identify some high-risk variants, we sequenced and compared HPV16 whole genomes obtained from a longitudinal cohort of 34 HPV16-infected women who had either spontaneously cleared their infection (clearance group or "C"), or developed cervical high-grade lesions following a viral persistence (group persistence or "P"). Phylogenetic analysis of paired samples obtained at the beginning (C0 or P0) and at the end (C2 or P2) of the follow-up (median intervals between C0-C2 and between P0-P2 were 16 and 36.5 months, respectively) revealed a low genetic variability within the host compared to the genetic inter-host diversity. By comparing our HPV16 sequences to a reference sequence, we observed 301 different substitutions, more often transitions (60.9%) than transversions (39.1%), that occurred throughout the viral genome, but with a low frequen cy in E6 and E7 oncogenes (10 and 9 substitutions), suggesting a high conservation of these genes. Deletions and insertions were mostly observed in intergenic regions of the virus. The only significant substitution found between the subgroups C2 and P2 was observed in the L2 gene (L330F), with an unclear biological relevance. Our results suggest a low longitudinal intra-host evolution of HPV16 sequences and no correlation between genetic variations and clinical evolution. This article is protected by copyright. All rights reserved. View on Web

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Voice and communication after open partial horizontal laryngectomies: A cross‐sectional outcome study

alexandrossfakianakis shared this article with you from Inoreader Voice and communication after open partial horizontal laryngectomies: A cross‐sectional outcome study via Head & Neck Abstract Objective The present study evaluates voice and communication after open partial horizontal laryngectomies (OPHLs), according to surgery and patient-related variables. Methods Fifty-eight patients were included: 18 type I OPHL, 20 type II OPHL and 20 type III OPHL. Acoustic, aerodynamic, endoscopic, perceptual and self-assessment analyses were carried out. Surgery-related variables and patient-related variables were considered for the analysis. Results Type I OPHL revealed the best phonatory outcomes. Type II and type III OPHL showed similar and poor results, with a highly deteriorated voice quality. A significant difference in MTP was found for patients who had both arytenoids/cricoarytenoid units preserved. Age and time from surgery showed significant correlations with voice quality after OPHLs. Conclusions Voice and communication outcomes after OPHLs are heterogeneous and might be influenced by several factors. Knowing variables with a substantial impact on phonatory outcomes may help clinicians in the preoperative decision-making process and the postoperative rehabilitative program. View on Web

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Deriving prognostic significance from a molecular subtype model of laryngeal carcinoma

alexandrossfakianakis shared this article with you from Inoreader Deriving prognostic significance from a molecular subtype model of laryngeal carcinoma via Head & Neck Abstract Background This study explored whether laryngeal carcinoma could be divided into different subtypes based on molecular differences using a molecular subtype-prediction model. Methods We extracted data from the Cancer Genome Atlas and Gene Expression Omnibus databases and then performed unsupervised cluster analysis to identify discrete molecular subtypes of laryngeal carcinoma. Significance analysis of microarrays was performed to detect differentially expressed genes for each subtype, and gene set enrichment analysis and the GenCliP3 software were used to label gene functions and identify key pathways. Results We categorized 126 patients into C1 and C2 molecular subtypes associated with pathologic grade. The C2 subtype appeared more aggressive, with a worse prognosis. The most significant enrichment pathway of the C2 subtype was the Hedgehog pathway, and GLI1 was a core gene. Conclusions Laryngeal carcinoma can be divided into two subtypes based on differences in molecular expression, which could identify key molecules associated with prognosis. View on Web

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Influence of supplement administration of omega‐3 on the subcutaneous tissue response of endodontic sealers in Wistar Rats

alexandrossfakianakis shared this article with you from Inoreader Influence of supplement administration of omega‐3 on the subcutaneous tissue response of endodontic sealers in Wistar Rats via International Endodontic Journal Abstract Aim Natural substances such as omega-3 have been used in the medical field due to their numerous properties and, in particular, modulating effect on the systemic and local inflammatory processes. Thus, this study evaluated the influence of omega-3 supplementation on the subcutaneous tissue response of endodontic sealers in Wistar Rats. Methodology Polyethylene tubes were implanted in the subcutaneous tissue of 48 animals (one empty for control and three filled with Sealapex, AH Plus or Endofill). The animals were treated with omega-3 (TO) or water (TW). Treatments started 15 days before implantation until euthanasia. After 5, 15 and 30 days (n=8), animals were euthanized and polyethylene tubes and surrounding tissue were removed and processed for histological analysis. The inflammatory reaction was analysed by Haematoxylin and Eosin stain and immunolabeling for IL-6 and TNF-α. The collagen maturity was analysed by picrosirius red stain and calcium deposition by von Kossa stain and polarized light. Results were statistically analysed (p<0.05). Results Among TW sealers groups, Endofill evoked a more intense inflammatory infiltrate compared with AH Plus and control in the 30-day period (p=0.009). However, in TO sealers groups, there was no difference among the sealers and control in all periods (p>0.05). Comparing each sealer as a function of the supplementation with water or omega-3, there are differences for Endofill (p=0.001) and Sealapex (p=0.005) in the 30-day period, presenting lower inflammatory infiltrate in the animals treated with omega 3. A higher percentage of immature fibres was observed at 15 and 30 days in the TO group, compared with TW group (p<0.05). The deposition of calcium particles was observed only by Sealapex in all periods, despite the supplementation procedure. Conclusions Omega-3 supplementation influence the tissue reactions of endodontic sealers, modulating inflammation, the immunolabeling of IL-6 and TNF-α, the repair process and it does not interfere with calcium deposition. View on Web

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Immediate curative effects of exercise therapy in patients with myalgia of the masticatory muscles

alexandrossfakianakis shared this article with you from Inoreader Immediate curative effects of exercise therapy in patients with myalgia of the masticatory muscles via Journal of Oral Rehabilitation Abstract Background Exercise therapy is occasionally considered as an initial treatment for temporomandibular disorders. However, pain can be exacerbated during exercise therapy. Objective To investigate the immediate curative effects of exercise therapy in patients with masticatory muscle myalgia. Methods Fifty-nine patients with masticatory muscle myalgia were included. Therapists performed exercise therapy (stretched the painful masseter and/or cervical muscles along the direction of muscle contraction) in 10 rounds of traction, each lasting 10 seconds. The patient's pain-free maximum mouth opening distance and degree of pain (VAS value) before and immediately after exercise therapy were compared using the Wilcoxon signed rank test. Mann-Whitney U test was used for the subgroup comparisons. Results Mouth opening increased from 41 (IQR 38–43) to 46 (IQR 43–48) mm, and pain alleviation from 48 (IQR 31–56) to 21 (IQR 10–56) immediately following exercise therapy (p < 0.001 for both). None of the patients experienced pain exacerbation or reduction in mouth opening post exercise. No difference in mouth opening distance changes according to sex, painful side, painful site, and therapist were observed (p > 0.05 for all). Pain reduction was greater in patients with unilateral pain (26, IQR 12–39) than those with bilateral (13, IQR 5–25) (p = 0.019). There were no differences in the change in the degree of pain according to sex, painful site, and therapist (p > 0.05 for all). Conclusion Exercise therapy immediately enlarged the mouth opening distance and reduced myalgia; therefore, it could be helpful in managing masticatory muscle myalgia. View on Web

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