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The high mobility group protein HMG20A cooperates with the histone reader PHF14 to modulate TGFβ and Hippo pathways.
No full textHigh mobility group (HMG) proteins are chromatin regulators with essential functions in development, cell differentiation and cell proliferation. The protein HMG20A is predicted by the AlphaFold2 software to contain three distinct structural elements, which we have functionally characterized: i) an amino-terminal, intrinsically disordered domain with transactivation activity; ii) an HMG box with higher binding affinity for double-stranded, four-way-junction DNA than for linear DNA; and iii) a long coiled-coil domain. Our proteomic study followed by a deletion analysis and structural modeling demonstrates that HMG20A forms a complex with the histone reader PHF14, via the establishment of a two-stranded alpha-helical coiled-coil structure. siRNA-mediated knockdown of either PHF14 or HMG20A in MDA-MB-231 cells causes similar defects in cell migration, invasion and homotypic cell-cell adhesion ability, but neither affects proliferation. Transcriptomic analyses demonstrate that PHF14 and HMG20A share a large subset of targets. We show that the PHF14-HMG20A complex modulates the Hippo pathway through a direct interaction with the TEAD1 transcription factor. PHF14 or HMG20A deficiency increases epithelial markers, including E-cadherin and the epithelial master regulator TP63 and impaired normal TGFβ-trigged epithelial-to-mesenchymal transition. Taken together, these data indicate that PHF14 and HMG20A cooperate in regulating several pathways involved in epithelial-mesenchymal plasticity
Hippocampal sclerosis caused by repetitive parieto-insular seizures through a possible kindling mechanism.
No full text37-year-old woman with a right parietal oligodendroglioma developed focal epilepsy with 10 years of infrequent parietal seizures. Four days after surgery due to tumor recurrence, she had focal non-convulsive status epilepticus with impaired consciousness and slightly different parieto-insular semiology (one-hour subintrant manifestations of numbness in both hands and the perioral region, dystonic posture of the left hand and left oculocephalic version, along with mild impairment of consciousness), controlled with different anti-seizure drugs. Three weeks later, postoperative MRI showed right hippocampal hyper-perfusion and swelling (figure 1), as well as the total tumor resection.S
Circulating Isovalerylcarnitine and Lung Cancer Risk: Evidence from Mendelian Randomization and Prediagnostic Blood Measurements.
No full textTobacco exposure causes 8 of 10 lung cancers, and identifying additional risk factors is challenging due to confounding introduced by smoking in traditional observational studies. We used Mendelian randomization (MR) to screen 207 metabolites for their role in lung cancer predisposition using independent genome-wide association studies (GWAS) of blood metabolite levels (n = 7,824) and lung cancer risk (n = 29,266 cases/56,450 controls). A nested case-control study (656 cases and 1,296 matched controls) was subsequently performed using prediagnostic blood samples to validate MR association with lung cancer incidence data from population-based cohorts (EPIC and NSHDS). An MR-based scan of 207 circulating metabolites for lung cancer risk identified that blood isovalerylcarnitine (IVC) was associated with a decreased odds of lung cancer after accounting for multiple testing (log10-OR = 0.43; 95% CI, 0.29-0.63). Molar measurement of IVC in prediagnostic blood found similar results (log10-OR = 0.39; 95% CI, 0.21-0.72). Results were consistent across lung cancer subtypes. Independent lines of evidence support an inverse association of elevated circulating IVC with lung cancer risk through a novel methodologic approach that integrates genetic and traditional epidemiology to efficiently identify novel cancer biomarkers. Our results find compelling evidence in favor of a protective role for a circulating metabolite, IVC, in lung cancer etiology. From the treatment of a Mendelian disease, isovaleric acidemia, we know that circulating IVC is modifiable through a restricted protein diet or glycine and L-carnatine supplementation. IVC may represent a modifiable and inversely associated biomarker for lung cancer.Mattias Johansson and Karl Smith-Byrne were supported by grants from the US National Cancer Institute under award number U19CA203654 and Cancer Research UK (C18281/A29019). This work was also supported by the Canadian Institutes of Health Research, the Canadian Foundation for Innovation, the Fonds de Recherche Santé Québec (FRSQ), and the FRQS Clinical Research Scholarship. Metabolite GWAS studies were conducted within TwinsUK, which is funded by the Wellcome Trust, Medical Research Council, European Union, the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility, and Biomedical Research Centre based at Guy's and St Thomas's NHS Foundation Trust in partnership with King's College London. The INTEGRAL-ILCCO OncoArray data collection was supported by National Institute of Health under award number U19CA203654.
We thank our collaborators from the International Lung Cancer Consortium (ILCCO) Adonina Tardon, Angela Risch, Angeline Andrew, Chu Chen, David Christiani, Demetrios Albanes, Erich Wichmann, Gadi Rennert, Geoffrey Liu, Hans Brunnström, Heike Bickeböller, Hongbing Shen, Jian-Min Yuan, John K. Field, John R. McLaughlin, Kjell Grankvist, Lambertus A. Kiemeney, Loic Le Marchand, M. Dawn Teare, Maria Teresa Landi, Matthew B. Schabath, Melinda C. Aldrich, Mikael Johansson, Neil Caporaso, Olle Melander, Philip Lazarus, Richard Houlston, Sanjay S. Shete, Shan Zienolddiny, Stephen Lam, Stig E. Bojesen, Susanne Arnold, Thorunn Rafnar, Victoria Stevens, Ying Wang, and Yun-Chul Hong.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.S
Spanish COPD Guideline (GesEPOC) Update: Comorbidities, Self-Management and Palliative Care.
No full textLos modelos de atención sanitaria actuales descritos en GesEPOC indican la mejor manera de hacer un diagnóstico correcto, la categorización de los pacientes, la adecuada selección de la estrategia terapéutica y el manejo y la prevención de las agudizaciones. Además, en la EPOC concurren diversos aspectos que resultan cruciales en una aproximación integrada de la atención sanitaria a estos pacientes. La evaluación de las comorbilidades en el paciente con EPOC representa un reto asistencial. Dentro de una valoración integral debe estudiarse la presencia de comorbilidades que tengan relación con la presentación clínica, con alguna técnica diagnóstica o con algunos tratamientos relacionados con la EPOC. Asimismo, son necesarias intervenciones en hábitos de vida saludables, la adhesión a tratamientos complejos, desarrollar capacidades para poder reconocer los signos y síntomas de la exacerbación, saber qué hacer para prevenirlos y tratarlos enmarcados en un plan de automanejo. Finalmente, los cuidados paliativos constituyen uno de los pilares en el tratamiento integral del paciente con EPOC, con los que se buscan prevenir o tratar los síntomas de una enfermedad, los efectos secundarios del tratamiento, y los problemas físicos, psicológicos y sociales de los pacientes y sus cuidadores. Por tanto, el objetivo principal de estos cuidados paliativos no es prolongar la esperanza de vida, sino mejorar su calidad. En este capítulo de GesEPOC 2021 se presenta una actualización sobre las comorbilidades más importantes, las estrategias de automanejo y los cuidados paliativos en la EPOC, y se incluye una recomendación sobre el uso de opiáceos para el tratamiento de la disnea refractaria en la EPOC.The current health care models described in GesEPOC indicate the best way to make a correct diagnosis, the categorization of patients, the appropriate selection of the therapeutic strategy and the management and prevention of exacerbations. In addition, COPD involves several aspects that are crucial in an integrated approach to the health care of these patients. The evaluation of comorbidities in COPD patients represents a healthcare challenge. As part of a comprehensive assessment, the presence of comorbidities related to the clinical presentation, to some diagnostic technique or to some COPD-related treatments should be studied. Likewise, interventions on healthy lifestyle habits, adherence to complex treatments, developing skills to recognize the signs and symptoms of exacerbation, knowing what to do to prevent them and treat them within the framework of a self-management plan are also necessary. Finally, palliative care is one of the pillars in the comprehensive treatment of the COPD patient, seeking to prevent or treat the symptoms of a disease, the side effects of treatment, and the physical, psychological and social problems of patients and their caregivers. Therefore, the main objective of this palliative care is not to prolong life expectancy, but to improve its quality. This chapter of GesEPOC 2021 presents an update on the most important comorbidities, self-management strategies, and palliative care in COPD, and includes a recommendation on the use of opioids for the treatment of refractory dyspnea in COPD.S
Hemopatch® is effective and safe to use: real-world data from a prospective European registry study.
No full textSurgical procedures are often impeded by bleeding and/or leakage of body fluids. These complications cannot always be resolved by conventional surgical techniques. Hemopatch® is a hemostatic patch that also functions as a sealant. Here we document the effectiveness and safety of Hemopatch® for routine procedures of multiple surgical disciplines. To this end, we performed a prospective, multicenter, single-arm, observational registry study. Patients were eligible if they had received Hemopatch® during an open or minimally invasive procedure in one of these specialties: hepatobiliary, cardiovascular, urological, neurological/spinal, general, or lung surgery. Patients were excluded if they had a known hypersensitivity to bovine proteins or brilliant blue, intraoperative pulsatile or severe bleeding and/or infection at the target application site (TAS). The primary endpoint for intraoperative effectiveness was hemostasis assessed as the percentage of patients achieving hemostasis within 2 min and the percentage of patients achieving hemostasis without re-bleeding at the time of surgical closure. The registry enrolled 621 patients at 23 study sites in six European countries. Six hundred twenty patients had completed follow-up information. Hemostasis within 2 min was achieved at 463 (74.5%) of all 621 TASs. Hemostasis without re-bleeding was observed at 620 (99.8%) TASs. Adverse events were reported in 64 patients (10.3%). This Hemopatch® registry shows that Hemopatch® efficiently establishes hemostasis and sealing in a variety of surgical specialties, including minimally invasive procedures. Furthermore, we provide evidence for the safety of Hemopatch® across all the specialties included in the registry. This study is registered at clinicaltrials.gov: NCT03392662
Structural brain alterations associated with suicidal thoughts and behaviors in young people: results from 21 international studies from the ENIGMA Suicidal Thoughts and Behaviours consortium.
No full textIdentifying brain alterations associated with suicidal thoughts and behaviors (STBs) in young people is critical to understanding their development and improving early intervention and prevention. The ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium analyzed neuroimaging data harmonized across sites to examine brain morphology associated with STBs in youth. We performed analyses in three separate stages, in samples ranging from most to least homogeneous in terms of suicide assessment instrument and mental disorder. First, in a sample of 577 young people with mood disorders, in which STBs were assessed with the Columbia Suicide Severity Rating Scale (C-SSRS). Second, in a sample of young people with mood disorders, in which STB were assessed using different instruments, MRI metrics were compared among healthy controls without STBs (HC; N = 519), clinical controls with a mood disorder but without STBs (CC; N = 246) and young people with current suicidal ideation (N = 223). In separate analyses, MRI metrics were compared among HCs (N = 253), CCs (N = 217), and suicide attempters (N = 64). Third, in a larger transdiagnostic sample with various assessment instruments (HC = 606; CC = 419; Ideation = 289; HC = 253; CC = 432; Attempt=91). In the homogeneous C-SSRS sample, surface area of the frontal pole was lower in young people with mood disorders and a history of actual suicide attempts (N = 163) than those without a lifetime suicide attempt (N = 323; FDR-p = 0.035, Cohen's d = 0.34). No associations with suicidal ideation were found. When examining more heterogeneous samples, we did not observe significant associations. Lower frontal pole surface area may represent a vulnerability for a (non-interrupted and non-aborted) suicide attempt; however, more research is needed to understand the nature of its relationship to suicide risk.S
Editorial: Microbiome and Machine Learning.
No full textThe human microbiome has attracted more and more attention in the last decade. It has been recognized as a major player in the homeostasis of the host, and in this manner, in the pathophysiology of different diseases. One of the focus points of microbiome research has been advancing the development of personalized medicine approaches, which are potentially necessary to treat multifactorial diseases presenting with heterogenous phenotypes. While significant efforts have been made in terms of sampling, sequencing and analysis multiple well-described disease cohorts and controls, subsequent translation of this information into clinical use has unfortunately been slower than expected.S
Broad Transcriptomic Impact of Sorafenib and Its Relation to the Antitumoral Properties in Liver Cancer Cells.
No full textHepatocellular carcinoma (HCC) is one of the most frequent and essentially incurable cancers in its advanced stages. The tyrosine kinase inhibitor Sorafenib (Sfb) remains the globally accepted treatment for advanced HCC. However, the extent of its therapeutic benefit is limited. Sfb exerts antitumor activity through its cytotoxic, anti-proliferative and pro-apoptotic roles in HCC cells. To better understand the molecular mechanisms underlying these effects, we used RNA sequencing to generate comprehensive transcriptome profiles of HepG2 and SNU423, hepatoblastoma- (HB) and HCC-derived cell lines, respectively, following a Sfb treatment at a pharmacological dose. This resulted in similar alterations of gene expression in both cell lines. Genes functionally related to membrane trafficking, stress-responsible and unfolded protein responses, circadian clock and activation of apoptosis were predominantly upregulated, while genes involved in cell growth and cycle, DNA replication and repair, ribosome biogenesis, translation initiation and proteostasis were downregulated. Our results suggest that Sfb causes primary effects on cellular stress that lead to upregulation of selective responses to compensate for its negative effect and restore homeostasis. No significant differences were found specifically affecting each cell line, indicating the robustness of the Sfb mechanism of action despite the heterogeneity of liver cancer. We discuss our results on terms of providing rationalization for possible strategies to improve Sfb clinical outcomes.S
Adherence of Spanish pediatricians to "do not do" guidelines to avoid low-value care in pediatrics
No full textThe main objective of this study was to analyze the degree of knowledge and compliance of Spanish pediatricians with the "do not do" recommendations of the Spanish Association of Pediatrics. A nationwide cross-sectional, descriptive study was carried out using a 25-item questionnaire among Spanish pediatricians. Univariate, bivariate, and multivariate analyses were performed. A total of 1137 pediatricians participated in the study. Most of them were women (75.1%), older than 55 (28.3%), worked in specialized care (56.9%), with public financing (91.2%), and had been working for more than 20 years (44.9%). The median of inappropriate answers per question was 9.1%. The bivariate and multivariate analyses showed that the factors that influenced higher adequacy to the "do not do" recommendations were younger than 45 years, working in specialized care, and working in the public health system. This research is the first nationwide study in Spain to analyze the adequacy of "do not do" pediatric clinical recommendations. The study showed a high level of compliance by Spanish pediatricians with these recommendations. However, there is a lack of knowledge in less frequent infectious pathologies such as HIV or fungal infections, in not prolonging antibiotic treatment unnecessarily and directing it appropriately according to the antibiogram results. These aspects may be improved by designing measures to enhance pediatricians' knowledge in these specific aspects. Some demographical factors are related to higher adequacy. Performing this research in other countries may allow assessing the current clinical practice of pediatricians. • Low-value care is defined as care that delivers little or no benefit, may cause patients harm, or outcomes marginal benefits at a disproportionately increased cost. • Few nationwide studies have assessed adherence to "do not do" guidelines, especially in pediatric settings. • Albeit there is a high level of compliance by Spanish pediatricians with the «do not do» recommendations, there is a lack of knowledge in different aspects that may be improved. • Some demographical factors are related to higher adequacy. Performing this research in other countries may allow assessing the current clinical practice of pediatricians.Ye
Management of genitourinary syndrome of menopause in breast cancer survivors: An update.
No full textThere is increasing attention about managing the adverse effects of adjuvant therapy (Chemotherapy and anti-estrogen treatment) for breast cancer survivors (BCSs). Vulvovaginal atrophy (VVA), caused by decreased levels of circulating estrogen to urogenital receptors, is commonly experienced by this patients. Women receiving antiestrogen therapy, specifically aromatase inhibitors, often suffer from vaginal dryness, itching, irritation, dyspareunia, and dysuria, collectively known as genitourinary syndrome of menopause (GSM), that it can in turn lead to pain, discomfort, impairment of sexual function and negatively impact on multiple domains of quality of life (QoL). The worsening of QoL in these patients due to GSM symptoms can lead to discontinuation of hormone adjuvant therapies and therefore must be addressed properly. The diagnosis of VVA is confirmed through patient-reported symptoms and gynecological examination of external structures, introitus, and vaginal mucosa. Systemic estrogen treatment is contraindicated in BCSs. In these patients, GSM may be prevented, reduced and managed in most cases but this requires early recognition and appropriate treatment, but it is normally undertreated by oncologists because of fear of cancer recurrence, specifically when considering treatment with vaginal estrogen therapy (VET) because of unknown levels of systemic absorption of estradiol. Lifestyle modifications and nonhormonal treatments (vaginal moisturizers, lubricants, and gels) are the first-line treatment for GSM both in healthy women as BCSs, but when these are not effective for symptom relief, other options can be considered, such as VET, ospemifene, local androgens, intravaginal dehydroepiandrosterone (prasterone), or laser therapy (erbium or CO2 Laser). The present data suggest that these therapies are effective for VVA in BCSs; however, safety remains controversial and a there is a major concern with all of these treatments. We review current evidence for various nonpharmacologic and pharmacologic therapeutic modalities for GSM in BCSs and highlight the substantial gaps in the evidence for safe and effective therapies and the need for future research. We include recommendations for an approach to the management of GSM in women at high risk for breast cancer, women with estrogen-receptor positive breast cancers, women with triple-negative breast cancers, and women with metastatic disease