Understanding the molecular basis of embryonic implantation is of great clinical and biological relevance. Little is currently known about the adhesion receptors that determine endometrial ...receptivity for embryonic implantation in humans.
Using two human endometrial cell lines characterized by low and high receptivity, we identified the membrane receptor CD98 as a novel molecule selectively and significantly associated with the receptive phenotype. In human endometrial samples, CD98 was the only molecule studied whose expression was restricted to the implantation window in human endometrial tissue. CD98 expression was restricted to the apical surface and included in tetraspanin-enriched microdomains of primary endometrial epithelial cells, as demonstrated by the biochemical association between CD98 and tetraspanin CD9. CD98 expression was induced in vitro by treatment of primary endometrial epithelial cells with human chorionic gonadotropin, 17-β-estradiol, LIF or EGF. Endometrial overexpression of CD98 or tetraspanin CD9 greatly enhanced mouse blastocyst adhesion, while their siRNA-mediated depletion reduced the blastocyst adhesion rate.
These results indicate that CD98, a component of tetraspanin-enriched microdomains, appears to be an important determinant of human endometrial receptivity during the implantation window.
The mechanisms underlying autoimmune thyroid disease (AITD) remain elusive. Identification of such mechanisms would reveal novel and/or better therapeutic targets. Here, we use integrated analysis of ...miRNAs and mRNAs expression profiling to identify potential therapeutic targets involved in the mechanisms underlying AITD.
miRNA and mRNA from twenty fresh-frozen thyroid tissues (15 from AITD patients and 5 from healthy controls) were subjected to next-generation sequencing. An anti-correlated method revealed potential pathways and disease targets, including proteins involved in the formation of primary cilia. Thus, we examined the distribution and length of primary cilia in thyroid tissues from AITD and controls using immunofluorescence and scanning electron microscopy, and parsed cilia formation in thyroid cell lines in response to inflammatory stimuli in the presence of miRNA mimics.
We found that the expression of miR-21-5p, miR-146b-3p, miR-5571-3p and miR-6503-3p was anti-correlated with Enolase 4 (ENO4), in-turned planar cell polarity protein (INTU), kinesin family member 27 (KIF27), parkin co-regulated (PACRG) and serine/threonine kinase 36 (STK36) genes. Functional classification of these miRNA/mRNAs revealed that their differential expression was associated with cilia organization. We demonstrated that the number and length of primary cilia in thyroid tissues was significantly lower in AITD than in control (frequency of follicular ciliated cells in controls = 67.54% vs a mean of 22.74% and 21.61% in HT and GD respectively p = 0.0001, by one-way ANOVA test). In addition, pro-inflammatory cytokines (IFNγ and TNFα) and specific miRNA mimics for the newly identified target genes affected cilia appearance in thyroid cell lines.
Integrated miRNA/gene expression analysis has identified abnormal ciliogenesis as a novel susceptibility pathway that is involved in the pathogenesis of AITD. These results reflect that ciliogenesis plays a relevant role in AITD, and opens research pathways to design therapeutic targets in AITD.
Instituto de Salud Carlos III, Comunidad de Madrid, Grupo Español de Tumores Neuroendocrinos y Endocrinos, Ministerio de Economía y Empresa and FEDER.
Women have been shown to be a vulnerable group in relation to mental health problems over time. Despite this, gender-focused studies are uncommon. The aim of this research is to study mental health ...in a sample of people with mental health problems and to analyze the differences and predictors focusing on gender.
A cross-sectional study is conducted in a heterogeneous clinical sample in terms of mental health problems (N = 160). Interviews with hetero-reported standardized questionnaires to collect the data are conducted. Descriptive analyses, mean difference and a regression analysis on mental health are carried out taking into account different sociodemographic, clinical and psychosocial variables.
Women in the study present worse levels of mental health and subjective severity of the disorder. The main predictors of mental health are being female, followed by severity, shorter time with the diagnosis and internalized stigma.
Being female is the most robust predictor of worse mental health and symptomatology. Recommendations according to the results found proposing a gender perspective are suggested.
Women; Gender; Mental health; Stigma.
Insecure attachment has been described as mediating the relationship between childhood trauma and dysfunctional personality traits in different mental disorders. Despite the role insecure attachment ...and childhood trauma have independently demonstrated to play as determinants of borderline personality disorder, less is known about the mediating mechanisms explaining these associations. For the first time, we assessed adult attachment, childhood trauma and dimensional personality pathology in a sample of outpatients with borderline personality disorder and tested whether the association between childhood trauma and personality dysfunction was at least partially attributable to insecure attachment. The results showed that attachment anxiety fully mediated the relationship between specific types of trauma (emotional abuse and physical neglect) and emotional dysregulation. Further, emotional abuse was both directly associated with dissocial behaviour and indirectly via attachment anxiety (partial mediation). Emotional abuse has been described as an essential environmental factor for the development of borderline personality disorder and emotional dysregulation, on its part, as the core feature of the condition. Our results indicate that attachment anxiety explains the link between these central aspects of borderline personality disorder. Our findings are consistent with previous research and current etiological understanding of the condition and provide support for recommending a careful assessment of childhood traumatic experiences and adult attachment style to gain a more comprehensive insight into the symptoms and its heterogeneity. As a secondary aim, we assessed the effect parental mental illness may have in these mediation models, but no significant influence on childhood trauma, attachment or personality was found.
Limited data are available on the effectiveness and tolerability of direct-acting antivirals (DAAs) therapies in the real world for HCV-infected patients with comorbidities. This study aimed to ...describe the effectiveness of OBV/PTV/r ± DSV (3D/2D regimen) with or without ribavirin (RBV) in HCV or HCV/HIV co-infected patients with GT1/GT4 and CKD (IIIb-V stages), including those under hemodialysis and peritoneal dialysis in routine clinical practice in Spain in 2015.
Non-interventional, retrospective, multicenter data collection study in 31 Spanish sites. Socio-demographic, clinical variables, study treatment characteristics, effectiveness and tolerability data were collected from medical records.
Data from 135 patients with a mean age (SD) of 58.3 (11.4) years were analyzed: 92.6% GT1 (81.6% GT1b and 17.6% GT1a) and 7.4% GT4, 14 (10.4%) HIV/HCV co-infected, 19.0% with fibrosis F3 and 28.1% F4 by FibroScan®, 52.6% were previously treated with pegIFN and RBV. 11.1%, 14.8% and 74.1% of patients had CKD stage IIIb, IV and V respectively. 68.9% of patients were on hemodialysis; 8.9% on peritoneal dialysis and 38.5% had history of renal transplant. A total of 125 (96.2%) of 135 patients were treated with 3D, 10 (7.4%) with 2D and 30.4% received RBV. The overall intention-to-treat (ITT) sustained virologic response at week 12 (SVR12) was 92.6% (125/135) and the overall modified-ITT (mITT) SVR12 was 99.2% (125/126). The SVR12 rates (ITT) per sub-groups were: HCV mono-infected (91.7%), HCV/HIV co-infected (100%), GT1 (92.0%), GT4 (100%), CKD stage IIIb (86.7%), stage IV (95%) and stage V (93%). Among the 10 non-SVR there was only 1 virologic failure (0.7%); 4 patients had missing data due lost to follow up (3.0%) and 5 patients discontinued 3D/2D regimen (3.7%): 4 due to severe adverse events (including 3 deaths) and 1 patient´s decision.
These results have shown that 3D/2D regimens are effective and tolerable in patients with advanced CKD including those in dialysis with GT 1 or 4 chronic HCV mono-infection and HIV/HCV coinfection in a real-life cohort. The overall SVR12 rates were 92.6% (ITT) and 99.2% (mITT) without clinically relevant changes in eGFR until 12 weeks post-treatment. These results are consistent with those reported in clinical trials.
This study aimed to: 1) analyze the inflammatory profile of Rheumatoid Arthritis (RA) patients, identifying clinical phenotypes associated with cardiovascular (CV) risk; 2) evaluate biologic and ...targeted-synthetic disease-modifying antirheumatic drugs (b-DMARDs and ts-DMARDs’: TNFi, IL6Ri, JAKinibs) effects; and 3) characterize molecular mechanisms in immune-cell activation and endothelial dysfunction.
A total of 387 RA patients and 45 healthy donors were recruited, forming three cohorts: i) 208 RA patients with established disease but without previous CV events; ii) RA-CVD: 96 RA patients with CV events, and iii) 83 RA patients treated with b-DMARDs/ts-DMARDs for 6 months. Serum inflammatory profiles (cytokines/chemokines/growth factors) and NETosis/oxidative stress-linked biomolecules were evaluated. Mechanistic in vitro studies were performed on monocytes, neutrophils and endothelial cells (EC).
In the first RA-cohort, unsupervised clustering unveiled three distinct groups: cluster 3 (C3) displayed the highest inflammatory profile, significant CV-risk score, and greater atheroma plaques prevalence. In contrast, cluster 1 (C1) exhibited the lowest inflammatory profile and CV risk score, while cluster 2 (C2) displayed an intermediate phenotype. Notably, 2nd cohort RA-CVD patients mirrored C3's inflammation.
Treatment with b-DMARDs or ts-DMARDs effectively reduced disease-activity scores (DAS28) and restored normal biomolecules levels, controlling CV risk. In vitro, serum from C3-RA or RA-CVD patients increased neutrophils activity and CV-related protein levels in cultured monocytes and EC, which were partially prevented by pre-incubation with TNFi, IL6Ri, and JAKinibs.
Overall, analyzing circulating molecular profiles in RA patients holds potential for personalized clinical management, addressing CV risk and assisting healthcare professionals in tailoring treatment, ultimately improving outcomes.
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•Unsupervised clustering of RA profiles revealed 3 groups with diverse inflammatory, oxidative, and netotic profiles.•RA patients without CV events but highest CV-risk showed inflammatory profiles akin to those with prior CV events.•TNFi, IL6Ri, and JAKi treatment for six months restores normal inflammatory biomolecule levels, cutting-RA-related CV-risk.•High CV risk RA serum activates neutrophils, modulates monocytes, and disrupts endothelial cells, reversed by b/ts-DMARDS.•Analyzing RA patients' molecular profiles enhances personalized management, addressing their cardiovascular risk.
Objectives:
To evaluate the effectiveness of high-intensity laser therapy on shoulder pain and function in subacromial impingement syndrome.
Design:
Clinical controlled trial with alternate ...allocation.
Setting:
Hospital Department of Rehabilitation.
Subjects:
A total of 46 participants with subacromial impingement syndrome.
Intervention:
Participants were sequence allocated to an intervention group (high-intensity laser therapy + exercise therapy) and control group (sham-laser + exercise therapy) and received 15 sessions (five days a week during three weeks).
Main measures:
Patiens were evaluated at baseline, after 15 sessions, and at one month and at three months after completing the intervention. The main outcome variables were pain and functionality as measured by visual analogue scale; pressure pain threshold; Shoulder Pain and Disability Index; Constant-Murley Score; and QuickDASH. Secondary outcomes were number of sessions at discharge and drug use.
Results:
A total of 21 patients in high-intensity laser therapy group (56.7 ± 8.9 years) and 22 patients in sham-laser group (61.3 ± 8.9 years) concluded the study. Visual analogue scale (cm) at baseline, one-month, and three-months were 6.2 ± 0.5, 3 ± 2.6, and 2.6 ± 2.4 for the control group and 5.4 ± 1.5, 3.6 ± 1.3, and 1.8 ± 1.7 for experimental group, respectively. Shoulder Pain and Disability Index (points) at baseline, one-month, and three-monts were 51.8 ± 16.1, 16.3 ± 16.1, and 13.6 ± 17.1 in the control group and 41.8 ± 20.6, 20.5 ± 19.7, 11 ± 14.5 in experimental group, respectively. No differences were found between groups (P > 0.05).
Conclusion:
The effect of high-intensity laser therapy plus exercise is not higher than exercise alone to reduce pain and improve functionality in patients with subacromial syndrome.
The PEARL study showed that palbociclib plus endocrine therapy (palbociclib/ET) was not superior to capecitabine in improving progression-free survival in postmenopausal patients with metastatic ...breast cancer resistant to aromatase inhibitors, but was better tolerated. This analysis compared patient-reported outcomes.
The PEARL quality of life (QoL) population comprised 537 patients, 268 randomised to palbociclib/ET (exemestane or fulvestrant) and 269 to capecitabine. Patients completed the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23 and EQ-5D-3L questionnaires. Changes from the baseline and time to deterioration (TTD) were analysed using linear mixed-effect and stratified Cox regression models, respectively.
Questionnaire completion rate was high and similar between treatment arms. Significant differences were observed in the mean change in global health status (GHS)/QoL scores from the baseline to cycle 3 (2.9 for palbociclib/ET vs. −2.1 for capecitabine (95% confidence interval CI, 1.4–8.6; P = 0.007). The median TTD in GHS/QoL was 8.3 months for palbociclib/ET versus 5.3 months for capecitabine (adjusted hazard ratio, 0.70; 95% CI, 0.55–0.89; P = 0.003). Similar improvements for palbociclib/ET were also seen for other scales as physical, role, cognitive, social functioning, fatigue, nausea/vomiting and appetite loss. No differences were observed between the treatment arms in change from the baseline in any item of the EQ-5D-L3 questionnaire as per the overall index score and visual analogue scale.
Patients receiving palbociclib/ET experienced a significant delay in deterioration of GHS/QoL and several functional and symptom scales compared with capecitabine, providing additional evidence that palbociclib/ET is better tolerated.
NCT02028507 (ClinTrials.gov).
2013-003170-27.
•The PEARL study population was postmenopausal patients with metastatic breast cancer resistant to aromatase inhibitors.•Palbociclib plus endocrine therapy (ET) delayed global health status/quality of life (QoL) deterioration compared with capecitabine.•Palbociclib plus ET better allowed patients to maintain health-related QoL (HRQoL) than capecitabine.•Palbociclib plus ET impacted more positively on the HRQoL that capecitabine.
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