Revascularization outcomes following acute ischemic stroke in patients taking direct oral anticoagulants: a single hospital cohort study

Journal of Thrombosis and Thrombolysis - Successful revascularization therapy is of paramount importance in patients suffering acute ischemic stroke (AIS). However, there is currently only limited...     

Clinical and Radiological Characteristics Associated with Respiratory Failure in Unilateral Lateral Medullary Infarction

BackgroundThe prognosis for unilateral lateral medullary infarction (ULMI) is generally good but may be aggravated by respiratory failure with fatal outcome. Respiratory failure has been reported in patients with severe bulbar dysfunction and large rostral medullary lesions, but its associated factors have not been systematically studied. We aimed to assess clinical and radiological characteristics associated with respiratory failure in patients with pure acute ULMI.Materials and MethodsSeventy-one patients (median age 55 years, 59 males) with MRI-confirmed acute pure ULMI were studied retrospectively. Clinical characteristics were assessed and bulbar symptoms were scored using a scale developed for this study. MRI lesions were classified into 4 groups based on their vertical extent (localized/extensive) and the involvement of the open and/or closed medulla. Clinical characteristics, bulbar scores and MRI lesion characteristics were compared between patients with and without respiratory failure.ResultsRespiratory failure occurred in 8(11%) patients. All patients with respiratory failure were male (p = 0.336), had extensive lesions involving the open medulla (p = 0.061), progression of bulbar symptoms (p=0.002) and aspiration pneumonia (p < 0.001). Peak bulbar score (OR, 7.9 [95% CI, 2.3–160.0]; p < 0.001) and older age (OR, 1.2 [95%CI, 1.0-1.6]; p=0.006) were independently associated with respiratory failure.ConclusionsExtensive damage involving the open/rostral medulla, clinically presenting with severe bulbar dysfunction, in conjunction with factors such as aspiration pneumonia and older age appears to be crucial for the development of respiratory failure in pure ULMI. Further prospective studies are needed to identify other potential risk factors, pathophysiology, and effective preventive measures for respiratory failure in these patients.     

Cetuximab plus FOLFOX6 or FOLFIRI in metastatic colorectal cancer: CECOG trial

AIM: To investigate efficacy and safety of cetuximab combined with two chemotherapy regimens in patients with unresectable metastatic colorectal cancer (mCRC). METHODS: Randomized patients received cetuximab with 5-fluorouracil (5-FU), folinic acid (FA) and oxaliplatin (FOLFOX) 6 (arm A, n = 74) or 5-FU, FA and irinotecan (FOLFIRI) (arm B, n = 77). KRAS mutation status was determined retrospectively in a subset of tumors (n = 117). RESULTS: No significant difference was found between treatment arms A and B ...     

Molecular mechanisms of insulin resistance and associated diseases

Insulin resistance is a state in which higher than normal concentrations of insulin are required for normal response. The most common underlying cause is central obesity, although primary insulin resistance in normal-weight individuals is also possible. Excess abdominal adipose tissue has been shown to release increased amounts of free fatty acids which directly affect insulin signalling, diminish glucose uptake in muscle, drive exaggerated triglyceride synthesis and induce gluconeogenesis in the liver. Other factors presumed to play the role in insulin resistance are tumour necrosis factor alpha, adiponectin, leptin, IL-6 and some other adipokines. Hyperinsulinaemia which accompanies insulin resistance may be implicated in the development of many pathological states, such as hypertension and hyperandrogenaemia. Insulin resistance underlies metabolic syndrome and is further associated with polycystic ovary syndrome and lipodystrophies. When beta-cells fail to secrete the excess insulin needed, diabetes mellitus type 2 emerges, which is, besides coronary heart disease, the main complication of insulin resistance and associated diseases.     

Tumour necrosis factor superfamily member 11 gene promoter polymorphisms modulate promoter activity and influence bone mineral density in postmenopausal women with osteoporosis

Tumour necrosis factor superfamily member 11 (TNFSF11) gene, that codes for receptor activator of nuclear factor-kappaB ligand, is one of the candidate genes for the genetic susceptibility to osteoporosis. As variations in the TNFSF11 gene promoter could alter its expression, the aim of the study was to evaluate the functional influence of three polymorphisms in the promoter and to investigate their association with bone mineral density (BMD) and biochemical markers in postmenopausal women. A total of 404 postmenopausal women were genotyped for the presence of TNFSF11 gene promoter polymorphisms -290C>T, -643C>T and -693G>C. Two common haplotypes, CCG and TTC, which occur in 44.3 and 49.3% of subjects respectively, were subjected to functional analysis. Amplified fragments were cloned into pGL3-basic reporter plasmid, which was co-transfected with pRL-TK plasmid into HEK293 cells. Dual luciferase reporter assay was performed. BMD and biochemical markers were measured. Reporter gene analysis showed significantly higher luciferase activity in CCG than in TTC haplotype (P=0.018). Both showed association with lumbar spine BMD (BMD-ls; P=0.005 and 0.007 for TTC and CCG respectively), whereas in femoral neck there was no association with BMD. In postmenopausal osteoporosis, association with BMD-ls was established in -290C>T, -643C>T and -693G>C (P values: 0.001, 0.041 and 0.013 respectively). Association with femoral neck BMD was shown in -693G>C (P=0.049). No association was found with biochemical markers in any of the groups. Our results suggest that in postmenopausal osteoporosis, TNFSF11 gene promoter polymorphisms -290C>T, -643C>T and -693G>C play a functional role in the genetic regulation of BMD.     

TNFRSF11B gene polymorphisms 1181G > C and 245T > G as well as haplotype CT influence bone mineral density in postmenopausal women

Objectives

Osteoprotegerin (OPG) inhibits osteoclast function by acting as a decoy receptor for receptor activator of nuclear factor-κB ligand (RANKL), thus being an important candidate gene for osteoporosis. Three recent genome-wide association studies also identified the TNFRSF11B gene, coding for OPG, as playing a key role in bone mineral density (BMD) regulation. As variations in the TNFRSF11B gene could alter the susceptibility to osteoporosis, the aim of study was to investigate association of two TNFRSF11B gene polymorphisms with BMD and serum OPG concentration in postmenopausal women.

Study design

478 postmenopausal women were genotyped for the presence of TNFRSF11B gene polymorphisms 245T > G (rs3134069) and 1181G > C (rs2073618). BMDs and serum OPG concentrations were measured.

Results

Two common haplotypes GT and CT occurred in 41.2% and 52.4% of subjects. In osteoporotic postmenopausal women, lumbar spine BMD was associated with polymorphisms 245T > G and 1181G > C, as well as with CT haplotype (p values 0.013, 0.006 and 0.006, respectively). Additionally, femoral neck BMD showed the association with 245T > G (p = 0.047). No other statistically significant associations with BMD were found for the studied SNPs and haplotypes. No association with serum OPG concentration was shown in any of the studied groups.

Conclusions

Our results suggest that, in postmenopausal osteoporosis, polymorphisms 245T > G and 1181G > C, as well as haplotype CT in TNFRSF11B gene influence BMD.     

Analysis of Association of LRP5, LRP6, SOST, DKK1, and CTNNB1 Genes with Bone Mineral Density in a Slovenian Population

The Wnt pathway has a bifunctional role in bone mass regulation, influencing osteoblasts and osteoclasts. The Wnt pathway genes are therefore candidate genes for susceptibility to osteoporosis. In our study, we focused on the effects of polymorphisms in selected Wnt pathway genes: low-density lipoprotein receptor-related proteins 5 and 6 (LRP5 and LRP6), Dickkopf1 (DKK1), sclerostin (SOST), and β-catenin (CTNNB1). We genotyped 652 subjects for the following polymorphisms: A1330V in LRP5; I1062V in LRP6; E232K in DKK1; D32Y, G34V, and N287S in CTNNB1; and -1397_-1396insGGA in SOST. Bone mineral density (BMD) was also measured. The allele frequencies were as follows: for A1330V C:T = 87%:13%, for I1062V C:T = 20%:80%, and for -1397_-1396insGGA-:GGA = 64%:36%. The studied nucleotide changes in the DKK1 and CTNNB1 genes were shown not to be polymorphic. In a Slovenian population, no association was shown between lumbar spine and femoral neck BMD in A1330V (P = 0.151 and 0.243) and in I1062V (P = 0.209 and 0.405). We observed a difference between SOST genotypes, corresponding to an allele dose effect, which was borderline significant for lumbar spine and femoral neck BMD (P = 0.047 and 0.085); but this did not survive the adjustment for multiple testing. These results indicate that a larger sample size would be necessary to detect these subtle effects. Our results suggest that A1330V in LRP5, I1062V in LRP6, and -1397_-1396insGGA in SOST are not associated with BMD in the Slovenian population.     

Adverse Events During Immunotherapy in Slovenian Patients with Metastatic Melanoma Reveal a Positive Correlation with Better Treatment Outcomes

BackgroundImmunotherapy with CTLA-4 inhibitors and PD1 checkpoint inhibitors has initiated a breakthrough in the treatment and prognosis of patients with metastatic melanoma. The survival of these patients has increased from the expected survival time of less than 12 months to at least forty months. However, immunotherapy with either anti-CTLA-4 antibodies or PD1 inhibitors alone or in combination has a broad palette of significant immune-related adverse events. The aim of the study was to assess the correlation of immune-related adverse events with treatment outcomes defined as significant differences in the overall response rate (ORR) and progression-free survival (PFS) of patients, who developed immune-related adverse events during immunotherapy.Patients and methodsA retrospective analysis of patients with metastatic melanoma treated with immunotherapy in 2020 at the Oncology Institute of Ljubljana was performed. Only patients with radiological evaluation of the immunotherapy response were included. The patients were divided into two cohorts: a cohort of patients with immune-related adverse events (irAE group) and a cohort of patients with no immune-related adverse events (NirAE group). Significantly better overall response and progression-free survival in the irAE cohort defined the primary aim of our study. To investigate the differences in progression-free survival between the irAE cohort and NirAE cohort, we used survival analysis. In particular, a Cox proportional hazards model with covariates of time to progression and adverse events was used for survival analysis. The Kruskal-Wallis H-test was applied, and a p-value of p <= 0.05 was considered the cut-off point for a statistically significant difference between the groups.ResultsAmong the 120 patients treated with immunotherapy, radiological response evaluation was performed for 99 patients: 38 patients in the irAE cohort and 61 patients in the NirAE cohort. The ORRs for the irAE and NirAE cohorts were 57% and 37%, respectively. The PFS was significantly better for the irAE cohort (301.6 days) than for the NirAE cohort (247.29 days). The results of the survival regression analysis showed a significant increase in the survival probability from less than 60% for the NirAE cohort to almost 80% for the irAE cohort.ConclusionsPatients with metastatic melanoma treated with immunotherapy who developed immune-related adverse events showed better treatment outcomes with longer times to disease progression and better overall response rates than patients treated with immunotherapy who did not develop immune-related adverse events, with a significant increase in the survival probability from less than 60% for the NirAE cohort to almost 80% for the irAE cohort.Key words: immune related adverse events, immunotherapy, melanoma, metastases, response, survival     

Hypoxia mimetic deferoxamine influences the expression of histone acetylation- and DNA methylation-associated genes in osteoblasts

Purpose of the study: Sufficient oxygen supply to bone tissue is essential for normal bone development and efficient bone repair. Hypoxia and hypoxia-inducible factor 1α (HIF1α) signaling pathway have been shown to exhibit profound effects on proliferation, differentiation as well as gene and protein expression in osteoblasts, osteoclasts and mesenchymal stem cells; however, as epigenetic mechanisms also perform an important regulatory role in these cells, our aim was to elucidate whether hypoxia mimetic deferoxamine could influence epigenetic mechanisms in bone cells by modulating the gene expression levels of chromatin-modifying enzymes.

Materials and methods: Osteoblast cell line HOS was exposed to deferoxamine, a widely used hypoxia mimetic, and expression profile of 40 genes associated with histone acetylation, deacetylation and DNA methylation was determined using quantitative real time polymerase chain reaction (qPCR) array followed by individual qPCR analyses. In addition, genes associated with hypoxia response, RANK/RANKL/OPG system, WNT/β-catenin signaling pathway and oxidative stress were also analyzed.

Results: We observed induced expression of histone deacetylase 9 (HDAC9) and suppressed expression of K(lysine) acetyltransferase 5 (KAT5) and DNA methyltransferase 3A (DNMT3A) demonstrating for the first time that expression of genes encoding chromatin-modifying enzymes could be influenced by hypoxia mimetic in HOS cells.

Conclusions: Based on our results we can conclude that hypoxia mimetic deferoxamine influences expression of histone acetylation- and DNA methylation-associated genes in osteoblasts and that further studies of hypoxia-induced epigenetic changes in bone cells should be undertaken.