Gustafssonnicolajsen6710

Alzheimer's disease (AD), the leading cause of age-related dementia, is characterized by abnormal β-amyloid accumulation. During learning, memory formation and consolidation, increased levels of histone H3 and H4 acetylation are observed. The present study reported significantly decreased level of H4K16ac in the plasma of patients with AD compared with healthy subjects via western blotting and reverse transcription-quantitative (RT-q)PCR. Lysine acetyltransferase 8 (KAT8) expression, the major lysine acetyltransferase responsible for the acetylation of H4K16, was significantly decreased in patients with AD compared with healthy subjects as determined via western blotting and RT-qPCR. #link# The results indicated that aberrant expression patterns of H4K16ac and KAT8 might be associated with AD progression. Moreover, western blot analysis demonstrated that KAT8-overexpression cells displayed increased levels of H4K16ac, accompanied by higher levels of neuroprotective soluble amyloid precursor protein (sAPP)α and β-seclogical process of AD; therefore, miRNA may serve as a potential drug target for AD.Neonates with coarctation of the aorta (CoA) combined with a bicuspid aortic valve (BAV) show significant structural differences compared to neonatal CoA patients with a normal tricuspid aortic valve (TAV). These effects are likely to change over time in response to growth. This study investigated proteomic differences between coarcted aortic tissue of BAV and TAV patients in children older than one month. link2 Aortic tissue just proximal to the coarctation site was collected from 10 children (BAV; n=6, 1.9±1.7 years, TAV; n=4, 1.7±1.5 years, (mean ± SEM, P=0.92.) Tissue were snap frozen, proteins extracted, and the extracts used for proteomic and phosphoproteomic analysis using Tandem Mass Tag (TMT) analysis. A total of 1811 protein and 76 phosphoprotein accession numbers were detected, of which 40 proteins and 6 phosphoproteins were significantly differentially expressed between BAV and TAV patients. Several canonical pathways involved in inflammation demonstrated enriched protein expression, including acute phase response signalling, EIF2 signalling and macrophage production of IL12 and reactive oxygen species. Acute phase response signalling also demonstrated enriched phosphoprotein expression, as did Th17 activation. Other pathways with significantly enriched protein expression include degradation of superoxide radicals and several pathways involved in apoptosis. This work suggests that BAV CoA patients older than one month have an altered proteome consistent with changes in inflammation, apoptosis and oxidative stress compared to TAV CoA patients of the same age. There is no evidence of structural differences, suggesting the pathology associated with BAV evolves with age in paediatric CoA patients.

To provide real-world data and summarize current clinical evidence on the efficacy and safety of sirolimus in active systemic lupus erythematosus (SLE) patients.

This was a prospective real-world clinical study. Included SLE patients should have Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) ⩾ 2. They were treated with sirolimus and followed up regularly. The SLEDAI-2K, Physician Global Assessment (PGA), serological activity indices, and remission of organ manifestations were evaluated. We also performed a meta-analysis to integrate current evidence of sirolimus in SLE.

A total of 49 patients were included in the final analysis. After treatment, the SLEDAI-2K (6.2 ± 3.1

4.0 ± 3.4,

 = 0.001) decreased significantly, and the prednisone dosage was tapered successfully (9.9 ± 8.8 mg/day

5.9 ± 4.0 mg/day,

 = 0.002). Serological activity indices also improved [complement 3 (C3) 0.690 ± 0.209 g/l

0.884 ± 0.219 g/l,

 < 0.001; complement 4 0.105 ± 0.059 g/l

0.141 ± 0.069 g/l,

 < 0.001; anti-dsDNA antibody, 200 ± 178 IU/ml

156 ± 163 IU/ml,

 = 0.022]. The remission proportions of arthritis, skin rash, and thrombocytopenia were 100%, 88.8%, and 46.2%, respectively. A total of 41.2% of lupus nephritis (LN) patients achieved renal remission, but the average 24-h urine protein level was not significantly changed. Meta-analysis enrolled five studies with 149 patients included, and revealed similar results regarding the changes of SLEDAI-2K [-3.5 (-5.0, -2.1)], C3 [0.224 (0.136, 0.311) g/l] and daily dosage of prednisone [-12.7 (-19.9, -5.6) mg/day].

Sirolimus might be effective and tolerated in SLE. The role of sirolimus in LN requires further study.

Sirolimus might be effective and tolerated in SLE. The role of sirolimus in LN requires further study.Osteoarthritis (OA) is an evolving chronic joint disease with a huge global impact. Given AR-42 of the etiopathogenesis and subsequent high heterogeneity in the clinical course of OA, it is crucial to discriminate between etiopathogenic endotypes and clinical phenotypes, especially in the early stages of the disease. In this sense, we propose that an OA phenotype should be properly assessed with a set of outcome measures including those specifically related to the main underlying pathophysiological mechanisms. Thus, each OA phenotype can be related to different and clinically meaningful outcomes. OA phenotyping would lead to an adequate patient stratification in well-designed clinical trials and the discovery of precise therapeutic approaches. A significant effort will be required in this field in light of inconclusive results of clinical trials of tissue-targeting agents for the treatment of OA.

Ataxia-telangiectasia and Rad3 related protein kinase (ATR) is an essential regulator of the DNA damage response in various cancers; however, its expression and roles in osteosarcoma are unclear. We therefore chose to evaluate the significance and mechanism of ATR in metastatic osteosarcoma, as well as its potential to be a therapeutic target.

The osteosarcoma tissue microarrays constructed from 70 patient specimens underwent immunohistochemistry to quantify ATR and activated phospho-ATR (pATR) expression and their correlation with clinical outcomes. ATR sublocalization within the metastatic osteosarcoma cells was confirmed by immunofluorescence assay. Cell proliferation, apoptosis, and migration were evaluated following treatment with ATR siRNA or the selective inhibitor Berzosertib. Antitumor effects were determined with

three-dimensional (3D) culture models, and the impacts on the DNA damage repair pathways were measured with Western blotting.

Elevated ATR and activated pATR expression correlated with shorter patient survival and less necrosis following neoadjuvant chemotherapy. Intranuclear sublocalization of ATR and pATR suggested a mechanism related to DNA replication. ATR knockdown with siRNA or inhibition with Berzosertib suppressed cell proliferation in a time- and dose-dependent manner and induced apoptosis. In addition, ATR inhibition decreased Chk1 phosphorylation while increasing γH

AX expression and PARP cleavage, consistent with the interference of DNA damage repair. The ATR inhibitor Berzosertib also produced the characteristic cytoplasmic vacuolization preceding cell death, and suppressed

3D spheroid formation and cell motility.

The faithful dependence of cells on ATR signaling for survival and progression makes it an emerging therapeutic target in metastatic osteosarcoma.

The faithful dependence of cells on ATR signaling for survival and progression makes it an emerging therapeutic target in metastatic osteosarcoma.

Palliative chemotherapy has been the mainstay treatment for patients with recurrent or metastatic nasopharyngeal carcinoma (R/M-NPC). However, little is known about the efficacy and toxicity of nimotuzumab (NTZ) - a monoclonal antibody drug targeting epidermal growth factor receptor - plus chemotherapy (CT)

CT alone for these patients.

The database at Cancer Hospital of Chinese Academy of Medical Sciences was queried for patients diagnosed with NPC who received CT with or without NTZ between 2004 and 2018. Treatment compliance, survival outcomes, and adverse effects were compared among these groups.

Records of 70 patients with R/M-NPC were reviewed 21 (30%) received NTZ plus CT (NTZ+CT) and 49 (70%) received CT. CT regimens included gemcitabine plus platinum, taxane plus platinum (TP), and fluorouracil plus platinum. Comparing the CT group with NTZ+CT group, the median follow up was 62 months (range = 3-133)

59 months (range = 9-117); median progression free survival was 7.5 [95% confidence interval (CI) 6.552-8.381] months

8.5 (95% CI 6.091-10.976) months,

 = 0.424; median overall survival (OS) was 25.6 (95% CI 18.888-32.379) months

48.6 (95% CI 35.619-61.581) months,

 = 0.017, respectively. Multivariable analysis established treatment group (CT

NTZ+CT) as an independent prognostic factor for OS (hazard ratio, 0.5; 95% CI 0.255-0.979;

 = 0.043). No significant difference with regard to toxicities was observed between the two groups. Among them, a subgroup analysis was performed in 53 (75.7%) patients who received TP with or without NTZ, which showed similar results.

Our findings suggested that NTZ+CT provides a novel treatment option and prolongs survival significantly for R/M-NPC.

Our findings suggested that NTZ+CT provides a novel treatment option and prolongs survival significantly for R/M-NPC.

EGFR/c-Met activation/amplification and co-expression, mTOR upregulation/activation, and Akt/Wnt signaling upregulation have been individually associated with more aggressive disease and characterized as potential prognostic markers for lung cancer patients.

Tumors obtained from 109 participants with stage I-IV non-small cell lung cancer (NSCLC) were studied for EGFR/c-Met co-localization as well as for total and active forms of EGFR, c-Met, mTOR, S6K, beta-catenin, and Axin2. Slides were graded by two independent blinded pathologists using a validated scoring system. Protein expression profile correlations were assessed using Pearson correlation and Spearman's rho. Prognosis was assessed using Kaplan-Meier analysis.

Protein expression profile analysis revealed significant correlations between EGFR/p-EGFR (

 = 0.0412) and p-mTOR/S6K (

 = 0.0044). link3 Co-localization of p-EGFR/p-c-Met was associated with increased p-mTOR (

 = 0.0006), S6K (

 = 0.0018), and p-S6K (

 < 0.0001) expression. In contrast, e findings suggest that increased EGFR/c-Met signaling is correlated with upregulated mTOR/S6K signaling, which may in turn be associated with shorter median survival in late-stage NSCLC.The management of human epidermal growth factor receptor (HER2)-positive breast cancer has improved over the past decade. However, despite improvements in systemic control, a substantial proportion of patients with advanced HER2-positive breast cancer suffer from central nervous system metastases and even intracranial progression after aggressive local treatment. There is paucity of data and no consensus on the systemic therapies for patients with intracranial progression. This review discusses both local and systemic treatments for HER2-positive breast cancer with brain metastases with a special focus on the response of central nervous system metastases. A recommended practical treatment algorithm to guide physicians in selecting the most appropriate anti-HER2 therapy for their patients is suggested.