Abstract Chronic ruptures of the Achilles tendon are more difficult to treat than acute tendon rupture. It has been shown that surgical treatment of chronic Achilles tendon rupture provides better ...functional results than nonoperative treatment. We present a case of neglected Achilles tendon rupture with a 12-cm defect that was repaired using an Achilles tendon allograft with interferential screws to fix the graft in the calcaneus. The patient recovered his ankle function to normal activities after rehabilitation.
Hepatocellular carcinoma (HCC) pathogenesis is associated with alterations in splicing machinery components (spliceosome and splicing factors) and aberrant expression of oncogenic splice variants. We ...aimed to analyze the expression and potential role of the spliceosome component PRPF8 (pre-mRNA processing factor 8) in HCC. PRPF8 expression (mRNA/protein) was analyzed in a retrospective cohort of HCC patients (n = 172 HCC and nontumor tissues) and validated in two in silico cohorts (TCGA and CPTAC). PRPF8 expression was silenced in liver cancer cell lines and in xenograft tumors to understand the functional and mechanistic consequences. In silico RNAseq and CLIPseq data were also analyzed. Our results indicate that PRPF8 is overexpressed in HCC and associated with increased tumor aggressiveness (patient survival, etc.), expression of HCC-related splice variants, and modulation of critical genes implicated in cancer-related pathways. PRPF8 silencing ameliorated aggressiveness in vitro and decreased tumor growth in vivo. Analysis of in silico CLIPseq data in HepG2 cells demonstrated that PRPF8 binds preferentially to exons of protein-coding genes, and RNAseq analysis showed that PRPF8 silencing alters splicing events in multiple genes. Integrated and in vitro analyses revealed that PRPF8 silencing modulates fibronectin (FN1) splicing, promoting the exclusion of exon 40.2, which is paramount for binding to integrins. Consistent with this finding, PRPF8 silencing reduced FAK/AKT phosphorylation and blunted stress fiber formation. Indeed, HepG2 and Hep3B cells exhibited a lower invasive capacity in membranes treated with conditioned medium from PRPF8-silenced cells compared to medium from scramble-treated cells. This study demonstrates that PRPF8 is overexpressed and associated with aggressiveness in HCC and plays important roles in hepatocarcinogenesis by altering FN1 splicing, FAK/AKT activation and stress fiber formation.
Background S-nitrosothiols are potent endogenous bronchodilators depleted in asthmatic airway lining fluid. S-nitrosoglutathione reductase (GSNOR; also known as alcohol dehydrogenase 5 or ...formaldehyde dehydrogenase) catalyzes the metabolism of S-nitrosoglutathione (GSNO) and controls intracellular levels of S-nitrosothiols. GSNOR knockout mice have increased lung S-nitrosothiol levels and are therefore protected from airway hyperresponsiveness after methacholine or allergen challenge. Objective We sought to investigate whether genetic variation in GSNOR is associated with childhood asthma and atopy. Methods We genotyped 5 tagging and 2 additional single nucleotide polymorphisms (SNPs) in GSNOR in 532 nuclear families consisting of asthmatic children aged 4 to 17 years and both parents in Mexico City. Atopy was determined by means of skin prick testing. Results Carrying 1 or 2 copies of the minor allele of SNP rs1154404 was associated with decreased risk of asthma (relative risk RR, 0.77; 95% CI, 0.61-0.97; P = .028 for 1 copy and RR, 0.66; 95% CI, 0.44-0.99; P = .046 for 2 copies). Homozygosity for the minor allele of SNP rs28730619 was associated with increased risk of asthma (RR, 1.60; 95% CI, 1.13-2.26; P = .0077). Haplotype analyses supported the single SNP findings. GSNOR SNPs were not associated with the degree of atopy. Conclusion This is the first study of genetic polymorphisms in GSNOR and asthma. These data suggest that genetic variation in GSNOR might play a role in asthma susceptibility. Clinical implications The association of GSNOR polymorphisms with asthma suggests a potential therapeutic target.
To evaluate percutaneous tibial nerve stimulation (PTNS) effectiveness, durability, and impact on the pathophysiology of overactive bladder syndrome (OAB) in patients who have been previously treated ...with antimuscarinics without success.
A prospective study that included 200 women diagnosed with OAB between 2007 and 2015 at Virgen de la Victoria University Hospital (Málaga, Spain) was conducted. OAB patients were treated with PTNS therapy after antimuscarinic treatment failed. To evaluate OAB symptoms, clinical and urodynamic studies were performed before and after PTNS treatment. Treatment's success was defined as a reduction of clinical parameters by >50% and an improvement of at least 2 urodynamic parameters by >50%. The Kolmogorov-Smirnov test and Student's t test or Wilcoxon test were used based on the data. A linear correlation analysis and a multivariate linear regression analysis were performed to determine factors associated with the success of PTNS therapy.
Of the patients, 94% experienced a positive response to PTNS considering clinical and urodynamic parameters. PTNS benefits were extended by 24 months. We identified daytime urinary frequency (r = −0.165; P = .024; 95% confidence interval, −0.248 to −0.018) and first sensation of bladder filling (r = 0.208; P = .030; 95% confidence interval, 0.001-0.028) as significant independent predictor factors for PTNS success.
The current data confirmed a high effectiveness of PTNS improving OAB symptoms through 24 months. Furthermore, daytime urinary frequency and first sensation of bladder filling act as a significant independent predictor factors for PTNS success.
Transforming growth factor beta-1 (TGFB1) may influence asthma by modulating allergic airway inflammation and airway remodeling. The role of single nucleotide polymorphisms (SNPs) of TGFB1 in asthma ...remains inconclusive. We examined TGFB1 SNPs in relation to asthma risk and degree of atopy among 546 case-parent triads, consisting of asthmatics aged 4-17 years and their parents in Mexico City. Atopy to 24 aeroallergens was determined by skin prick tests. We genotyped five TGFB1 SNPs, including two known functional SNPs C-509T (rs1800469), T869C (rs1982073) and three others (rs7258445, rs1800472, rs8179181), using TaqMan and Masscode assays. We analyzed the data using log-linear and polytomous logistic methods. Three associated SNPs, including the two known functional SNPs, were statistically significantly related to asthma risk. Individuals carrying the T allele of C-509T had an increased risk of asthma relative risk (RR)=1.42, 95% confidence interval (CI)=1.08-1.87 for one copy; RR (95%CI)=1.95 (1.36-2.78) for two copies. For T869C, the RRs (95%CI) were 1.47 (1.09-1.98) for one and 2.00 (1.38-2.90) for two copies of the C allele. Similar results were found for rs7258445. The haplotype containing all three risk alleles conferred an increased risk of asthma (RR=1.48, 95% CI=1.11-1.95 for one copy; RR=1.77, 95% CI=1.22-2.57 for two copies). These three SNPs were also related to the degree of atopy. This largest study to date of genetic variation in TGFB1 and asthma and atopy adds to increasing evidence for a role in these disorders.
A recent microarray study implicated arginase I (
ARG1) and arginase II (
ARG2) in mouse allergic asthma models and human asthma.
To examine the association between genetic variation in
ARG1 and
ARG2 ...and childhood asthma and atopy risk.
We enrolled 433 case-parent triads, consisting of patients with asthma 4 to 17 years old and their biologic parents, from the allergy clinic of a public hospital in Mexico City between 1998 and 2003. Atopy to 24 aeroallergens was determined by skin prick tests. We genotyped 4 single nucleotide polymorphisms (SNPs) of
ARG1 and 4 SNPs of
ARG2 with minor allele frequencies higher than 10% by using the TaqMan assay (Roche Molecular Systems, Pleasanton, Calif).
ARG1 SNPs and haplotypes were not associated with asthma, but all 4
ARG1 SNPs were associated with the number of positive skin tests (
P = .007-.018). Carrying 2 copies of minor alleles for either of 2 highly associated
ARG2 SNPs was associated with a statistically significant increased relative risk (RR) of asthma (1.5, 95% CI = 1.1-2.1 for arg2s1; RR = 1.6, 95% CI = 1.1-2.3 for arg2s2). The association was slightly stronger among children with a smoking parent (arg2s1 RR = 2.1, 95% CI = 1.2 - 3.9 with a smoking parent; RR = 1.2, 95% CI = 0.8-1.9 without; interaction
P = .025). Haplotype analyses reduced the sample size but supported the single SNP results. One
ARG2 SNP was related to the number of positive skin tests (
P = .027).
Variation in arginase genes may contribute to asthma and atopy in children.
The first-in-class inhibitor of exportin-1 (XPO1) selinexor is currently under clinical investigation in combination with the BTK inhibitor ibrutinib for patients with chronic lymphocytic leukaemia ...(CLL) or non-Hodgkin lymphoma. Selinexor induces apoptosis of tumour cells through nuclear retention of tumour suppressor proteins and has also recently been described to modulate natural killer (NK) cell and T cell cytotoxicity against lymphoma cells. Here, we demonstrate that XPO1 inhibition enhances NK cell effector function against primary CLL cells via downregulation of HLA-E and upregulation of TRAIL death receptors DR4 and DR5. Furthermore, selinexor potentiates NK cell activation against CLL cells in combination with several approved treatments; acalabrutinib, rituximab and obinutuzumab. We further demonstrate that lymph node associated signals (IL-4 + CD40L) inhibit NK cell activation against CLL cells via upregulation of HLA-E, and that inhibition of XPO1 can overcome this protective effect. These findings allow for the design of more efficacious combination strategies to harness NK cell effector functions against CLL.
We assessed the efficacy and safety of biologic therapy in severe and refractory Peripheral Ulcerative Keratitis (PUK).
Open-label multicenter study of biologic-treated patients with severe PUK ...refractory to conventional immunosuppressive drugs.
We studied 34 patients (44 affected eyes) (24 women/10 men; mean age, 55.26±17.4 years). PUK was associated with a well-defined condition in 29 of them (rheumatoid arthritis n = 20, psoriatic arthritis n = 2, inflammatory bowel disease n = 2, Behçet disease n = 1, granulomatosis with polyangiitis n = 1, microscopic polyangiitis n = 1, systemic lupus erythematosus n = 1 and axial spondyloarthritis n = 1). Besides topical and oral systemic glucocorticoids, patients had received: methylprednisolone pulses n = 9, and conventional immunosuppressive drugs, mainly methotrexate n = 18, and leflunomide n = 7. Eleven patients had required ocular surgery prior to biologic therapy.
Following biologic therapy, baseline main outcomes were compared with those found at 1st week, 1st and 6th months and 1st year.
Efficacy and safety of biologic therapy. Efficacy was analyzed by the assessment of corneal inflammation (corneal thinning, central keratolysis and ocular perforation); other causes of ocular surface inflammation (scleritis, episcleritis); intraocular inflammation (uveitis); visual acuity and glucocorticoid sparing effect.
The first biologic agents used were anti-TNFα drugs (n = 25); adalimumab (n = 16), infliximab (n = 8), etanercept (n = 1), and non-TNFα agents (n = 9); rituximab (n = 7), tocilizumab (n = 1) belimumab (n = 1) and abatacept (n = 1). During the follow-up, switching to a second biologic agent was required in 12 of the 25 (48%) patients treated with anti-TNFα drugs. However, no switching was required in those undergoing biologic therapy different from anti-TNFα agents. The main outcome variables showed a rapid and maintained improvement after a mean follow-up of 23.7 ± 20 months. Major adverse effects were tachyphylaxis, relapsing respiratory infections, supraventricular tachycardia, pulmonary tuberculosis and death, one each.
Biologic therapy is effective and relatively safe in patients with severe and refractory PUK. Non-anti-TNFα agents appear to be effective in these patients.
Background: Polymorphisms in the proinflammatory cytokine genes tumor necrosis factor-α (TNF) and lymphotoxin-α (LTA, also called TNF-β) have been associated with asthma and atopy in some studies. ...Parental smoking is a consistent risk factor for childhood asthma. Secondhand smoke and ozone both stimulate TNF production. Objectives: Our goal was to investigate whether genetic variation in TNF and LTA is associated with asthma and atopy and whether the association is modified by parental smoking in a Mexican population with high ozone exposure. Methods: We genotyped six tagging single nucleotide polymorphisms (SNPs) in TNF and LTA, including functional variants, in 596 nuclear families consisting of asthmatics 4-17 years of age and their parents in Mexico City. Atopy was determined by skin prick tests. Results: The A allele of the TNF-308 SNP was associated with increased risk of asthma relative risk (RR) = 1.54; 95% confidence interval (CI), 1.04-2.28, especially among children of nonsmoking parents (RR = 2.06; 95% CI, 1.19-3.55; p for interaction = 0.09). Similarly, the A allele of the TNF-238 SNP was associated with increased asthma risk among children of nonsmoking parents (RR = 2.21; 95% CI, 1.14-4.30; p for interaction = 0.01). LTA SNPs were not associated with asthma. Haplotype analyses reflected the single SNP findings in magnitude and direction. TNF and LTA SNPs were not associated with the degree of atopy. Conclusions: Our results suggest that genetic variation in TNF may contribute to childhood asthma and that associations may be modified by parental smoking.
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