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PDF file - 122KB, qRT-PCR primers validation.

PDF file - 119KB, Identified HRAS mutations.

PDF file - 138KB, MEK inhibition and cetuximab sensitivity.

PDF file - 164KB, Supplementary info for shRNA silencing of HRAS gene, supplementary table 1 (mutation detection oligos) and supplementary table 2 (qRT-PCR oligos).

Purpose: Cetuximab, an antibody directed against the EGF receptor, is an effective clinical therapy for patients with head and neck squamous cell cancer (HNSCC). Despite great clinical promise, intrinsic or acquired cetuximab resistance hinders successful treatment outcomes but little is known about the underlying mechanism.Experimental Design: To study the role of oncogenic HRAS in cetuximab resistance in HNSCC, the frequency of oncogenic HRAS mutations was determined in a cohort of 180 genomic DNAs from head and neck cancer specimens. We also used a combination of cetuximab-resistant cell lines and a transgenic mouse model of RAS-driven oral cancer to identify an oncogenic RAS-specific gene expression signature that promotes cetuximab resistance.Results: Here, we show that activation of RAS signaling leads to persistent extracellular signal–regulated kinase 1/2 signaling and consequently to cetuximab resistance. HRAS depletion in cells containing oncogenic HRAS or PIK3CA restored cetuximab sensitivity. In our study, the gene expression signature of c-MYC, BCL-2, BCL-XL, and cyclin D1 upon activation of MAPK signaling was not altered by cetuximab treatment, suggesting that this signature may have a pivotal role in cetuximab resistance of RAS-activated HNSCC. Finally, a subset of patients with head and neck cancer with oncogenic HRAS mutations was found to exhibit de novo resistance to cetuximab-based therapy.Conclusions: Collectively, these findings identify a distinct cetuximab resistance mechanism. Oncogenic HRAS in HNSCC promotes activation of ERK signaling, which in turn mediates cetuximab resistance through a specific gene expression signature. Clin Cancer Res; 20(11); 2933–46. ©2014 AACR.

PDF file - 125KB, qRT-PCR analysis.

PDF file - 108KB, Oncogenic HRAS effect on phospho-AKT levels.

PDF file - 134KB, Regression analysis examining the relationship between time to progression and HRAS mutation.

PDF file - 149KB, Cetuximab growth response of head and neck cancer cell lines.

Sjögren syndrome (SS) is a multisystem autoimmune disease, primarily targeting salivary and lacrimal glands; skin, nasal and vaginal dryness, along with musculoskeletal pain and fatigue are the most commonly reported symptoms. Hearing loss is hypothesized to be frequent as well. The purpose of this systematic review was to estimate the prevalence of Hearing loss and its different subtypes in patients with Sjögren syndrome. PRISMA guidelines were followed to ensure highest quality for our systematic review. A random effects model meta-analysis and meta-regression was conducted using I

Fibromyalgia is a chronic medical condition of unclear etiopathology that diminished patients' quality of life; chronic pain is the main symptom, yet patients with fibromyalgia struggle also with depression, anxiety, and insomnia. For many years, pharmaceutical management of pain was the mainstay of treatment. In the latest decade, conventional low-impact aerobic exercise and complementary and alternative medical (CAM) exercise have become important when structuring a personalized therapeutic plan, since side effects are practically inexistent. Heterogenous studies with different methodological approaches have failed to display a clear clinical effect. We conducted a systematic review with meta-analysis of clinical trials putting emphasis on standardized measurable outcomes (Fibromyalgia Impact Questionnaire, FIQ) in our effort to draw a safe conclusion on CAM exercise's effect. After analyzing 14 studies, including 886 patients, meta analysis showed CAM exercise had a beneficial effect on patients' FIQ score reports: standardized mean difference (SMD) 1.330 (95% CI 0.733-1.928). Among them, dance and Tai chi, had a more profound effect: SMD 1.969 (95% CI 0.575-3.364) and SMD 1.852 (95% CI 0.119-3.584), respectively. However, the risk of bias was overall medium to high and statistical heterogeneity was very high. Our meta-regression analysis failed to identify any variable that could account for high heterogeneity. Even though more experimental studies should be done on this subject, CAM exercise seems beneficial for patients with Fibromyalgia.

Background: Familial hypercholesterolaemia (FH) is a genetically determined lipid disorder, affecting 1 per 200-500 individuals in the general population. It is significantly and independently associated with an increased risk of Cardiovascular Disease (CVD), although it remains still an underrecognized and undertreated disease. Lipoprotein (a) [Lp(a)] is a low-density-lipoprotein (LDL)-like molecule, containing an additional protein, apolipoprotein (a). Objective: This review aims to present and discuss available data on the role of Lp(a) in patients with FH, in terms of its potential augmentation of CVD risk. Methods: A comprehensive search of the literature was performed to identify studies evaluating the CV effects of Lp(a) in patients with FH. Results: Lp(a) has been recognised as an independent risk factor for CVD, mainly coronary artery disease (CAD). Most, but not all, studies show increased Lp(a) concentrations in adults and children with FH. There is also evidence of an independent association between Lp(a) and CVD (mainly CAD) risk in these patients. Conclusion: Some therapeutic modalities, such as niacin, oestrogens, tibolone and proprotein convertase subtilisin/ kexin type 9 (PCSK9) inhibitors may effectively reduce Lp(a) concentrations by 25-30%, although their clinical benefit of this effect remains to be established.

Objective/Design Menopausal transition has been associated with a derangement of glucose metabolism. However, it is not known if early menopause (EM, defined as age at menopause Methods A comprehensive search was conducted in PubMed, CENTRAL and Scopus, up to January 31, 2018. Data are expressed as odds ratio (OR) with 95% confidence intervals (CI). The I 2 index was employed for heterogeneity. Results Thirteen studies were included in the qualitative and quantitative analysis (191 762 postmenopausal women, 21 664 cases with T2DM). Both women with EM and POI were at higher risk of T2DM compared with those of age at menopause of 45–55 years (OR: 1.15, 95% CI: 1.04–1.26, P = 0.003; I 2: 61%, P P = 0.033; I 2: 75.2%, P 45 years (OR: 1.12, 95% CI: 1.01–1.20, P I 2: 78%, P P = 0.035; I 2: 78%, P Conclusions Both EM and POI are associated with increased risk of T2DM.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that can affect virtually any organ, including middle and/or inner ear. The objective of the current systematic review and meta-analysis was to investigate the association of SLE with the different subtypes of hearing loss. This systematic review and meta-analysis was conducted in agreement with the PRISMA guidelines. The review protocol was registered in the PROSPERO international prospective register of systematic reviews ( https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=216353 ). A random effects model meta-analysis was carried out while heterogeneity was appraised by I2. Subgroup analysis and sensitivity analysis were also performed. Nine studies comprising 7,654 SLE patients and 37,244 controls were included in this systematic review. Four of them were rated to a moderate rate of bias, while five of them were rated to a low rate of bias. SLE patients had significantly increased odds of sensorineural hearing loss (SNHL) compared with controls (OR 2.31; 95%CI 1.48–3.60; I2 = 0). SLE patients did not have significantly increased odds of Conductive Hearing Loss (CHL) (OR 1.30; 95% CI 0.23–7.45; I2 = 0). Only one study reported on the outcome of Mixed Hearing Loss (MHL) (3 events in SLE group vs. 0 events in control group). Subgroup analysis, based on study design and detection method of hearing loss also showed significantly increased odds of SNHL in SLE patients. The significantly increased odds of SNHL in SLE persisted even after sensitivity analysis. In conclusion, SLE is significantly associated with SNHL; SLE is not associated with CHL, while, due to lack of data, we could not reach a conclusion regarding the odds of MHL in SLE patients. Pure tone audiometry as a screening test and follow-up test in SLE patients could be of essence. Management and prognosis of hearing loss in SLE patients should be discussed.

Early menopause (EM, age at menopause 45 years) and premature ovarian insufficiency (POI, age at menopause 40 years) are associated with an increased risk of osteoporosis. However, their association with increased fracture risk has not been established, with studies yielding conflicting results. The primary aim of this systematic review and meta-analysis was to synthesize studies evaluating the association between age at menopause and fracture risk. The secondary aim was to evaluate this effect concerning the site of fractures.A comprehensive search was conducted in PubMed, CENTRAL and Scopus, up to 31 January 2018. Data were expressed as odds ratio (OR) with 95% confidence intervals (CI). The IEighteen studies were included in the qualitative and quantitative analysis (462,393 postmenopausal women, 12,130 fractures). Compared with women with age at menopause 45 years, women with EM demonstrated higher fracture risk (OR 1.36, 95% CI 1.11-1.66, p 0.002, I² 81.5%). Women with POI did not display any difference in fracture risk compared either with women with age at menopause 40 (OR 1.23, 95% CI 0.72-2.09, p = 0.436, I² 62.5%) or45 years (OR 0.54, 95% CI 0.22-1.29, p = 0.17, IThis is the first meta-analysis showing that EM is associated with increased fracture risk compared with normal age at menopause, without any distinct effect on the site of the fracture.

Introduction Immune response following viral infections has been suggested as a probable mechanism leading to subacute thyroiditis (SAT). A few cases of SAT following SARS-CoV-2 infection have been described since the outbreak of the pandemic in 2019. Cases of SAT after vaccination against influenza have also been reported. We describe two female patients with thyroiditis after vaccination against SARS-CoV-2. Presentation of cases The first patient presented with fever and pain in the thyroid area typical of SAT two weeks after vaccination with the BNT162B2 mRNA (Pfizer-BioNTech) COVID-19 vaccine. The second patient presented with biochemical and imaging features consistent with silent thyroiditis three weeks after vaccination with the ChAdOx1-S (AstraZeneca) vaccine. Both patients were asymptomatic prior to vaccination and PCR of nasopharyngeal swab for SARS-CoV-2 and other respiratory viruses associated with SAT was negative. Serology testing for measles, mumps, rubella, CMV and EBV viruses was suggestive of immunity. Antibody titre against spike S protein of SARS-CoV-2 was measured for both patients and was indicative of adequate post vaccination antibody response. Two months after initial assessment, both patients were euthyroid and asymptomatic. Conclusions Subacute as well as silent thyroiditis may rarely occur after vaccination against COVID-19. Further research is needed to investigate the prevalence and pathogenesis of thyroid dysfunction following vaccination against COVID-19., Highlights • Thyroid function abnormalities are common in COVID-19 patients. • Thyroiditis is a rare complication of influenza, HPV and HBV vaccination. • We report two cases of thyroiditis after vaccination against COVID-19.

Objective/Design: Menopausal transition has been associated with a derangement of glucose metabolism. However, it is not known if early menopause (EM, defined as age at menopause 45 years (OR: 1.12, 95% CI: 1.01–1.20, P < 0.02; I 2 : 78%, P < 0.001 and OR: 1.53, 95% CI: 1.03–2.27, P = 0.035; I 2 : 78%, P < 0.001), respectively). Conclusions: Both EM and POI are associated with increased risk of T2DM. © 2019 European Society of Endocrinology Printed in Great Britain Published by Bioscientifica Ltd.

Purpose: Early menopause (EM, age at menopause < 45 years) and premature ovarian insufficiency (POI, age at menopause < 40 years) are associated with an increased risk of osteoporosis. However, their association with increased fracture risk has not been established, with studies yielding conflicting results. The primary aim of this systematic review and meta-analysis was to synthesize studies evaluating the association between age at menopause and fracture risk. The secondary aim was to evaluate this effect concerning the site of fractures. Methods: A comprehensive search was conducted in PubMed, CENTRAL and Scopus, up to 31 January 2018. Data were expressed as odds ratio (OR) with 95% confidence intervals (CI). The I 2 index was employed for quantifying heterogeneity. Results: Eighteen studies were included in the qualitative and quantitative analysis (462,393 postmenopausal women, 12,130 fractures). Compared with women with age at menopause > 45 years, women with EM demonstrated higher fracture risk (OR 1.36, 95% CI 1.11–1.66, p < 0.002, I² 81.5%). Women with POI did not display any difference in fracture risk compared either with women with age at menopause > 40 (OR 1.23, 95% CI 0.72–2.09, p = 0.436, I² 62.5%) or >45 years (OR 0.54, 95% CI 0.22–1.29, p = 0.17, I 2 0%). No difference was evident when a separate analysis was performed for vertebral, non-vertebral and hip fractures. Conclusions: This is the first meta-analysis showing that EM is associated with increased fracture risk compared with normal age at menopause, without any distinct effect on the site of the fracture. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.