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Cell cycle checkpoints, activated by stressful events, halt the cell cycle progression, and prevent the transmission of damaged DNA. These checkpoints prompt cell repair but also trigger cell death if damage persists. Decision-making between these responses is multifactorial and context-dependent, with the tumor suppressor p53 playing a central role. In many tumor cells, p53 alterations lead to G1/S checkpoint loss and the weakening of the G2 checkpoint, rendering cell viability dependent on the strength of the latter through mechanisms not fully characterized. Cells with a strong pro-survival drive can evade cell death despite substantial DNA lesions. Deciphering the integration of survival pathways with p53-dependent and -independent mechanisms governing the G2/M transition is crucial for understanding G2 arrest functionality and predicting tumor cell response to chemotherapy. The serine/threonine kinase GRK2 emerges as a signaling node in cell cycle modulation. In cycling cells, but not in G2 checkpoint-arrested cells, GRK2 protein levels decline during G2/M transition through a process triggered by CDK2-dependent phosphorylation of GRK2 at the S670 residue and Mdm2 ubiquitination. We report now that this downmodulation in G2 prevents the unscheduled activation of the PI3K/AKT pathway, allowing cells to progress into mitosis. Conversely, higher GRK2 levels lead to tyrosine phosphorylation by the kinase c-Abl, promoting the direct association of GRK2 with the p85 regulatory subunit of PI3K and AKT activation in a GRK2 catalytic-independent manner. Hyperactivation of AKT is conditioned by p53's scaffolding function, triggering FOXO3a phosphorylation, impaired Cyclin B1 accumulation, and CDK1 activation, causing a G2/M transition delay. Upon G2 checkpoint activation, GRK2 potentiates early arrest independently of p53 through AKT activation. However, its ability to overcome the G2 checkpoint in viable conditions depends on p53. Our results suggest that integrating the GRK2/PI3K/AKT axis with non-canonical functions of p53 might confer a survival advantage to tumor cells.
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BACKGROUND: Therapeutic exercise (TE) recommendations for non-specific low back pain (LBP) are meant to support therapy choices for people who suffer from this condition. The aim of this study was to reach an agreement on the definition and use of TE in the care of people with LBP. METHODS: A Delphi study was carried out with a formal consensus procedure and sufficient scientific evidence, using an established methodology. Four rounds of anonymous questionnaires were administered to create useful suggestions and instructions in terms of the therapeutic activity for patients with LBP, and a group consensus conference. RESULTS: A consensus was reached on most of the questions after 35 physiotherapists completed the questionnaires. Participants agreed that proper TE requires correct posture, body awareness, breathing, movement control, and instruction. Patients with LBP were advised to participate in supervised sessions twice a week for 30 to 60 min for a period of 3 to 6 months. Participants added that tailored evaluation and exercise prescription, monitoring, and functional integration of exercise, as well as using specific equipment, would benefit patients with LBP. CONCLUSIONS: TE recommendations for patients with LBP should be dosed and customized based on their personal psychological needs, level of fitness, and kinesiophobia.
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BACKGROUND/AIM: The optimal imaging test for delineation of the gross tumor volume (GTV) in hepatocellular carcinoma has not been defined. The hypothesis is that magnetic resonance imaging (MRI) allows for better visualization of the extent of tumor and will optimize the accuracy of tumor delineation for liver stereotactic radiotherapy compared with computed tomography (CT) only. We evaluated the interobserver agreement in GTV of hepatocellular carcinoma in a multicenter panel and compared MRI and CT in GTV delineation. MATERIALS AND METHODS: After the institutional review boards approved the study, we analyzed anonymous CT and MRI obtained from five patients with hepatocellular carcinoma. Eight radiation oncologists at our center used CT and MRI to delineate five GTVs of liver tumors. In both CT and MRI, the GTV volumes were compared. RESULTS: The median GTV volume on MRI was 2.4 cm3 (range=0.59-15.6 cm3) compared to 3.5 cm3 (range=0.52-24.9 cm3) on CT (p=0.36). The GTV volume as defined on MRI was larger or at least as large as the GTV volume on CT in two cases. Variance and standard deviation between observers in CT and MRI were minor (6 vs. 7.87 cm3, and 2.5 vs. 2.8 cm3 respectively). CONCLUSION: In cases with well-defined tumors, CT is easier and reproducible. In cases with no defined tumor in CT, other tools are needed and MRI can be complementary. The interobserver variability in target delineation of hepatocellular carcinoma in this study is noteworthy.
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PURPOSE: Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft-tissue sarcomas that lack effective treatments, underscoring the urgent need to uncover novel mediators of MPNST pathogenesis that may serve as potential therapeutic targets. Tumor angiogenesis is considered a critical event in MPNST transformation and progression. Here, we have investigated whether endoglin (ENG), a TGFß coreceptor with a crucial role in angiogenesis, could be a novel therapeutic target in MPNSTs. EXPERIMENTAL DESIGN: ENG expression was evaluated in human peripheral nerve sheath tumor tissues and plasma samples. Effects of tumor cell-specific ENG expression on gene expression, signaling pathway activation and in vivo MPNST growth and metastasis, were investigated. The efficacy of ENG targeting in monotherapy or in combination with MEK inhibition was analyzed in xenograft models. RESULTS: ENG expression was found to be upregulated in both human MPNST tumor tissues and plasma-circulating small extracellular vesicles. We demonstrated that ENG modulates Smad1/5 and MAPK/ERK pathway activation and pro-angiogenic and pro-metastatic gene expression in MPNST cells and plays an active role in tumor growth and metastasis in vivo. Targeting with ENG-neutralizing antibodies (TRC105/M1043) decreased MPNST growth and metastasis in xenograft models by reducing tumor cell proliferation and angiogenesis. Moreover, combination of anti-ENG therapy with MEK inhibition effectively reduced tumor cell growth and angiogenesis. CONCLUSIONS: Our data unveil a tumor-promoting function of ENG in MPNSTs and support the use of this protein as a novel biomarker and a promising therapeutic target for this disease.
Subject(s)
Nerve Sheath Neoplasms , Neurofibrosarcoma , Humans , Biomarkers , Cell Line, Tumor , Endoglin/genetics , Mitogen-Activated Protein Kinase Kinases/metabolism , Nerve Sheath Neoplasms/drug therapy , Nerve Sheath Neoplasms/genetics , Nerve Sheath Neoplasms/metabolism , Signal TransductionABSTRACT
BACKGROUND: People who use cannabis daily or near-daily vary considerably in their daily dosage and use frequency, impacting both experienced effects and adverse consequences. This study identified heavy cannabis user groups according to consumption patterns and factors associated with class membership. METHODS: We conducted a cross-sectional study of 380 Spanish residents (61.8% male; average age = 30.3 years) who had used cannabis ≥ 3 days/week throughout the past year. Participants were recruited through chain referral and cannabis social clubs. We applied latent class analysis (LCA) to cluster participants according to use intensity. LCA indicators included frequency of weekly cannabis use, joints smoked each day, cannabis dosage, and if cannabis was consumed throughout the day or only at specific times. Associations between class membership and socio-demographics, use patterns, motives, supply sources, adverse outcomes, and use of other substances were measured using ANOVA and chi-squared tests. Multinomial regression identified the factors associated with latent class membership. RESULTS: Three latent classes (moderately heavy: 21.8%, heavy: 68.2%, very heavy: 10%) had average weekly cannabis intakes of 2.4, 5.5, and 18.3 g, respectively. Very heavy users were older ([Formula: see text]=17.77, p < 0.01), less educated [Formula: see text]=36.80, p < 0.001), and had used cannabis for longer (F = 4.62, p = 0.01). CAST scores (F = 26.51, p < 0.001) increased across the classes. The prevalence of past-month alcohol use was lower among the heaviest users ([Formula: see text]=5.95, p = 0.05). Cannabis was usually obtained from a club by very heavy users ([Formula: see text]=20.95, p < 0.001). CONCLUSIONS: People who use cannabis heavily present three groups according to frequency and quantity of cannabis consumption. Use intensity is associated with increased cannabis-related problems. Differences among heavy users must be considered in harm reduction interventions in cannabis clubs and indicated prevention.
Subject(s)
Cannabis , Humans , Male , Adult , Female , Latent Class Analysis , Cross-Sectional Studies , Alcohol Drinking/epidemiologyABSTRACT
Endoglin (CD105) is an auxiliary receptor of transforming growth factor (TGF)-ß family members that is expressed in human melanomas. It is heterogeneously expressed by primary and metastatic melanoma cells, and endoglin targeting as a therapeutic strategy for melanoma tumors is currently been explored. However, its involvement in tumor development and malignancy is not fully understood. Here, we find that endoglin expression correlates with malignancy of primary melanomas and cultured melanoma cell lines. Next, we have analyzed the effect of ectopic endoglin expression on two miRNAs (hsa-mir-214 and hsa-mir-370), both involved in melanoma tumor progression and endoglin regulation. We show that compared with control cells, overexpression of endoglin in the WM-164 melanoma cell line induces; (i) a significant increase of hsa-mir-214 levels in small extracellular vesicles (EVs) as well as an increased trend in cells; and (ii) significantly lower levels of hsa-mir-370 in the EVs fractions, whereas no significant differences were found in cells. As hsa-mir-214 and hsa-mir-370 are not just involved in melanoma tumor progression, but they can also target endoglin-expressing endothelial cells in the tumor vasculature, these results suggest a complex and differential regulatory mechanism involving the intracellular and extracellular signaling of hsa-mir-214 and hsa-mir-370 in melanoma development and progression.
Subject(s)
Extracellular Vesicles , Melanoma , MicroRNAs , Humans , Endoglin/metabolism , Endothelial Cells/metabolism , Melanoma/pathology , MicroRNAs/genetics , Extracellular Vesicles/metabolism , Transforming Growth Factor beta/metabolismABSTRACT
INTRODUCTION: Cancer patients are more susceptible to infections, and infection can be more severe than in patients without cancer diagnosis. We conducted this retrospective study in patients admitted for SARS-CoV-2 infection in order to find differences in inflammatory markers and mortality in cancer patients compared to others. METHODS: We reviewed the electronic records of patients admitted for SARS-CoV-2 infection confirmed by PCR from March to September 2020. Data on socio-demographics, comorbidities, inflammatory makers, and cancer-related features were analyzed. RESULTS: 2,772 patients were admitted for SARS-CoV-2, to the Hospital Universitario Ramón y Cajal in Madrid during this period. Of these, 2,527 (91%) had no history of neoplastic disease, 164 (5.9%) patients had a prior history of cancer but were not undergoing oncological treatment at the time of infection, and 81 (2.9%) were in active treatment. Mortality in patients without a history of cancer was 19.5%, 28.6% for patients with a prior history of cancer, and 34% in patients with active cancer treatment. Patients in active oncology treatment with the highest mortality rate were those diagnosed with lung cancer (OR 5.6 95% CI: 2.2-14.1). In the multivariate study, active oncological treatment (OR 2.259 95% CI: 1.35-3.77) and chemotherapy treatment (OR 3.624 95% CI: 1.17-11.17), were statistically significant factors for the risk of death for the whole group and for the group with active oncological treatment, respectively. CONCLUSION: Cancer patients on active systemic treatment have an increased risk of mortality after SARS-CoV-2 infection, especially with lung cancer or chemotherapy treatment.
Subject(s)
COVID-19 , Lung Neoplasms , Humans , COVID-19/epidemiology , Medical Oncology , Retrospective Studies , SARS-CoV-2ABSTRACT
Background and Aim: The optimal imaging test for gross tumor volume (GTV) delineation in non-spine bone metastases has not been defined. The use of stereotactic body radiotherapy (SBRT) requires accurate target delineation. Magnetic resonance imaging (MRI) and/or 18fludesoxyglucose positron emission tomography (18FDG-PET) allow for better visualization of the extent of bone metastases and optimizes the accuracy of tumor delineation for stereotactic radiotherapy compared to computed tomography (CT) alone. We evaluated the interobserver agreement in GTV of non-spine bone metastases in a single center and compared MRI and/or 18FDG-PET and CT in GTV delineation. Methods: Anonymous CT and MRI and/or 18FDG-PET obtained from 10 non-spine bone metastases were analyzed by six radiation oncologists at our center. Images acquired by CT and MRI and/or 18FDG-PET were used to delineate 10 GTVs of non-spine bone metastases in the pelvis, extremities, and skull. The cases showed different characteristics: blastic and lytic metastases, and different primary cancers (lung, breast, prostate, rectum, urothelial, and biliary). In both CT and MRI and/or 18FDG-PET, the GTV volumes were compared. The index of agreement was evaluated according to Landis and Koch protocol. Results: The GTV volume as defined on MRI was in all cases larger or at least as large as the GTV volume on CT (P=0.25). The median GTV volume on MRI was 3.15 cc (0.027-70.64 cc) compared to 2.8 cc on CT (0.075-77.95 cc). Interobserver variance and standard deviation were lower in CT than MRI (576.3 vs. 722.2 and 24.0 vs. 26.9, respectively). The level of agreement was fair (kappa=0.36) between CT and MRI. The median GTV volume on 18FDG-PET in five patients was 5.8 cc (0.46-64.17 cc), compared to 4.1 cc on CT (0.99-54.2 cc) (P=0.236). Interobserver variance and standard deviation in CT, MRI, and 18FDG-PET were 576.3 versus 722.2 versus 730.5 and 24 versus 26.9 versus 27.0, respectively. The level of agreement was slight (kappa=0.08) between CT and 18FDG-PET. Conclusions: Interobserver variance in non-spine bone metastases was equal when MRI and PET were compared to CT. CT was associated with the lowest variance and standard deviation. Compared to CT GTVs, the GTVs rendered from MRI images had fair agreement, while the GTVs rendered from 18FDG-PET had only slight agreement. Relevance for Patients: The delimitation of the treatment volume in non-spine bone metastases with SBRT is important for the results determining its efficacy. It is therefore essential to know the variability and to manage it to achieve the highest quality of treatment.
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There is a widely accepted belief in new technologies that the digital divide in using a service will disappear as the service reaches an advanced level of maturity. The work presented here shows that this idea is debatable. Data from Spain, a country where daily internet users are 75.9 percent of the population, prove that the gender gap still exists. The paper explores if this gap can be entirely explained by the socioeconomic differences between men and women. We build a micro panel model and incorporate a set of socioeconomic variables (age, education, income, employment status, digital skills, and resident population) that allow us to isolate the effects of gender on the decision to become a daily Internet user. The results conclude that the Internet gap is a phenomenon with a specific gender component. Other things being equal a woman negatively affects the probability of using the Internet. Applying a similar model to 15 Internet services, we obtain that gender is always significant to explain the likelihood of being a user of each service. However, in some services (7 out of 15), the effect is favorable to women, and for other services (8), the gender effect favors men. The work concludes by analyzing the impact of the first wave of the Covid-19 pandemic on the use of Internet services, paying particular attention to its possible implications for the gender gap.
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Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft-tissue sarcomas that represent an important clinical challenge, particularly given their strong tendency to relapse and metastasize and their relatively poor response to conventional therapies. To date, targeted, noncytotoxic treatments have demonstrated limited clinical success with MPNSTs, highlighting the need to explore other key pathways to find novel, improved therapeutic approaches. Here, we review evidence supporting the crucial role of the RAS/MEK/ERK pathway and angiogenesis in MPNST pathogenesis, and we focus on the potential of therapies targeting these pathways to treat this disease. We also present works suggesting that the combination of MEK inhibitors and antiangiogenic agents could represent a promising therapeutic strategy to manage MPNSTs. In support of this notion, we discuss the preclinical rational and clinical benefits of this combination therapy in other solid tumor types. Finally, we describe other emerging therapeutic approaches that could improve patient outcomes in MPNSTs, such as immune-based therapies.
Subject(s)
Nerve Sheath Neoplasms , Neurofibrosarcoma , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/therapeutic use , Humans , Mitogen-Activated Protein Kinase Kinases , Neoplasm Recurrence, Local/drug therapy , Nerve Sheath Neoplasms/drug therapy , Neurofibrosarcoma/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic useABSTRACT
A spotlight has been shone on endoglin in recent years due to that fact of its potential to serve as both a reliable disease biomarker and a therapeutic target. Indeed, endoglin has now been assigned many roles in both physiological and pathological processes. From a molecular point of view, endoglin mainly acts as a co-receptor in the canonical TGFß pathway, but also it may be shed and released from the membrane, giving rise to the soluble form, which also plays important roles in cell signaling. In cancer, in particular, endoglin may contribute to either an oncogenic or a non-oncogenic phenotype depending on the cell context. The fact that endoglin is expressed by neoplastic and non-neoplastic cells within the tumor microenvironment suggests new possibilities for targeted therapies. Here, we aimed to review and discuss the many roles played by endoglin in different tumor types, as well as the strong evidence provided by pre-clinical and clinical studies that supports the therapeutic targeting of endoglin as a novel clinical strategy.
Subject(s)
Biomarkers, Tumor , Endoglin/metabolism , Molecular Targeted Therapy , Neoplasms/drug therapy , Neoplasms/metabolism , Animals , Cell Communication , Endoglin/antagonists & inhibitors , Endoglin/genetics , Gene Expression Regulation, Neoplastic/drug effects , Humans , Liquid Biopsy , Neoplasms/diagnosis , Neoplasms/etiology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/metabolism , Signal Transduction/drug effects , Tumor Microenvironment/drug effects , Tumor Microenvironment/geneticsABSTRACT
INTRODUCTION AND OBJECTIVES: Cases of viral hepatitis reported in Mexico are typically identified as hepatitis A, B and C. However, unspecified cases are reported annually. Hepatitis E virus (HEV) is an emergent agent that causes a self-limiting infection that can evolve to chronic in immunosuppressed individuals. In Mexico, HEV genotype 2 is considered endemic, though it's the prevalence is not well known. Therefore, the present study was designed to determine the prevalence of HEV among patients at the "Hospital Infantil de Mexico Federico Gomez". MATERIALS AND METHODS: The study included 99 patients, anti-HEV antibody (IgG and IgM) were detected by indirect ELISA and viral genome was identified using RT-PCR technique. Two PCR products of positive cases were sequenced. RESULTS: ELISA results were positive in 3% and 6%, for IgG and IgM respectively, 54.5% prevalence was found by PCR. Low lymphocyte count (p<0.05) and malnutrition (p<0.005) were significant factors for high PCR prevalence and could increase the possibility of infection. Two samples were sequenced and confirmed the presence of HEV genotype 3. CONCLUSIONS: This report reveals the incidence of HEV in pediatric patients in Mexico. Moreover, the identification of HEV genotype 3 in human samples suggests a potential zoonotic risk that requires further research.
Subject(s)
Hepatitis E virus/genetics , Hepatitis E/epidemiology , Alanine Transaminase/blood , Aspartate Aminotransferases/blood , Bilirubin/blood , Child , Cross-Sectional Studies , DNA, Viral/blood , Female , Genome, Viral/genetics , Genotype , Hepatitis A , Hepatitis A Antibodies/blood , Hepatitis Antibodies , Hepatitis B Antibodies/blood , Hepatitis C Antibodies/blood , Hepatitis E/blood , Hepatitis E/immunology , Hepatitis E/virology , Humans , Immunoglobulin G/immunology , Immunoglobulin M/immunology , Longitudinal Studies , Male , Mexico/epidemiology , RNA, Viral/blood , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Seroepidemiologic Studies , Viral Proteins/geneticsABSTRACT
Prenatal exposure to sex hormones exerts organizational effects on the brain which have observable behavioural correlates in adult life. There are reasons to expect that social behaviours-fundamental for the evolutionary success of humans-might be related to biological factors such as prenatal sex hormone exposure. Nevertheless, the existing literature is inconclusive as to whether and how prenatal exposure to testosterone and oestrogen, proxied by the second-to-fourth digit ratio (2D : 4D), may predict non-selfish behaviour. Here, we investigate this question using economic experiments with real monetary stakes and analyse five different dimensions of social behaviour in a comparatively large sample of Caucasian participants (n = 560). For both males and females, our results show no robust association between right- or left-hand 2D : 4D and generosity, bargaining or trust-related behaviours. Moreover, no differences in behaviour were found according to sex. We conclude that there is no direct correlation between 2D : 4D and these social behaviours.
Subject(s)
Fingers , Testosterone , Adult , Female , Gonadal Steroid Hormones , Humans , Male , Pregnancy , Sex Characteristics , Social BehaviorABSTRACT
Resumen El objetivo de esta investigación fue comprender las representaciones sociales asociadas al VIH y al Sida en un grupo de adolescentes y jóvenes universitarios colombianos. Para ello, se realizó un estudio cualitativo de diseño fenomenológico interpretativo en el que participaron 18 estudiantes universitarios. Las técnicas de recolección empleadas fueron las redes semánticas naturales (RSN) y los grupos de discusión. Las narrativas evidenciaron que existe desconocimiento sobre aspectos generales del VIH y del Sida. También dieron cuenta de la creencia de que el riesgo de contraer VIH recae únicamente en grupos etiquetados en riesgo. Se identificaron, además, actitudes que denotan estigma hacia personas con la enfermedad. Los pares, los padres, la familia y el internet se reportaron como los principales agentes de socialización sobre la enfermedad. En conclusión, se destaca la necesidad de empoderar a los diferentes agentes de socialización y de fortalecer los procesos educativos desde el reconocimiento de los derechos humanos de todas las personas. Se requiere, por tanto, un trabajo articulado, integral y transversal de los diferentes agentes, no solo para la deconstrucción de las creencias y actitudes negativas hacia la enfermedad, sino para la construcción de una sexualidad responsable y saludable que esté centrada en el autocuidado.
Abstract This research aimed to understand the social representations associated with HIV and AIDS in a group of adolescents and university students from Colombia. For this, a qualitative study of phenomenological interpretative design was carried out with 18 university students. The collection techniques used were natural semantic networks (NSN) and discussion groups. The narratives showed that there is lack of knowledge about general aspects of HIV and AIDS. They also reported a belief that the risk of contracting HIV relapses only into at-risk groups. In addition, attitudes that denote stigma towards people with the disease were identified. Partners, parents, family and internet were reported as the main agents of socialization about the disease. In conclusion, the need to empower the different socialization agents and to strengthen educational processes from the recognition of the human rights of all people is highlighted. Therefore, it is required an articulated, integral and transversal work of the different agents, not only for the deconstruction of the negative beliefs and attitudes towards the disease, but for the construction of a responsible and healthy sexuality that is centered in the self-care.
Subject(s)
Humans , Male , Female , Adolescent , Adult , Students , Universities , Health Education , Acquired Immunodeficiency Syndrome , HIV , Qualitative ResearchABSTRACT
PURPOSE: This study investigated the relationship between the individual's self-assessed health status (SAHS) and health-risk factors (smoking, alcohol consumption and obesity), in 16 European countries. The associations were studied for the individual and for the country measures-and in particular, for the unexplored aspect of interaction between individual and country levels of the three risk factors. METHOD: Data for 47,114 adults, who participated in the Survey of Health Aging and Retirement Europe (SHARE), were analyzed using Multilevel Regression Analysis. The individual data were complemented by OECD data that provided country-specific risk measures: percentage of daily smokers, annual per-capita consumption of alcohol (liters), and percentage of obese individuals. RESULTS: We found that the individual's SAHS is negatively associated with smoking and with weight-risk factors and is positively associated with her/his alcohol consumption. The most pronounced associations relate to the weight variables, albeit they are attenuated in countries with higher percentages of obese individuals. Significant differences across countries were evidenced in the association between SAHS and smoking and between SAHS and alcohol consumption. CONCLUSION: Individual health levels are associated with individual risk factors and also with the behaviors in the country. Significant interactions might indicate that psychological factors are at work.
Subject(s)
Alcohol Drinking/epidemiology , Health Status , Obesity/epidemiology , Smoking/epidemiology , Aged , Aged, 80 and over , Europe , Female , Health Surveys , Humans , Male , Middle Aged , Multilevel Analysis , Risk Factors , Smoking/adverse effectsABSTRACT
Previous literature on a variety of countries has documented a "healthy immigrant effect" (HIE). Accordingly, immigrants arriving in the host country are, on average, healthier than comparable natives. However, their health status dissipates with additional years in the country. HIE is explained through the positive self-selection of healthy immigrants as well as the positive selection, screening and discrimination applied by host countries. In this article we study the health trajectories of immigrants within the context of selection and migration policies. Using SHARE data we examine the HIE, comparing Israel and 16 European countries that have fundamentally different migration policies. Israel has virtually unrestricted open gates for Jewish people around the world, who in turn have ideological rather than economic considerations to move. European countries have selective policies with regards to the health, education and wealth of migrants, who also self-select themselves. Our results provide evidence that (1) immigrants who move to Israel have compromised health and are significantly less healthy than comparable natives. Their health disadvantage persists for up to 20 years of living in Israel, after which they become similar to natives; (2) immigrants who move to Europe have significantly better health than comparable natives. Their health advantage remains positive for many years. Even though during some time lapses they are not significantly different from natives, their health status never becomes worse than that of natives. Our results are important for migration policy and relevant for domestic health policy.
Subject(s)
Emigrants and Immigrants , Health Status , Europe , Health Policy , Humans , IsraelABSTRACT
BACKGROUND: Sevelamer is a phosphate binder widely used in chronic kidney disease (CKD) patients. Sevelamer, as well as other resin-based binders, can crystallize leading to the formation of concretions. Sevelamer crystals (SC) have been associated with gastrointestinal (GI) mucosal injury. We describe three new cases of GI lesions associated with SC and review previously reported cases. METHODS: We describe three new cases of GI lesions associated with SC and review previously reported cases. RESULTS: We found 16 previously reported cases of SC-induced GI lesions. The mean patient age was 61 years (interquartile range 51.5-71.75), 62.5% were females and 10 patients were diabetic. In 13 cases, SC was found inside the GI mucosa. Six patients had history of major abdominal surgery. GI bleeding was the most common clinical symptom (n = 7), with three patients presenting with acute abdomen requiring surgical intervention. Although, SC-induced lesions were observed in all GI segments, intestine was involved in 81% of the cases. Endoscopic examination revealed mainly erosions and ulcerations (n = 7) and pseudoinflammatory polyps (n = 5). No association between sevelamer doses and the severity of GI lesions was found. However, diabetics patients seemed to develop GI lesions with smaller doses of sevelamer as compared with non-diabetic patients, in spite of their fewer GI comorbidities. CONCLUSIONS: SC-induced GI lesions should be considered in CKD patients treated with sevelamer who present GI symptoms, especially lower GI bleeding, once other causes have been ruled out. Diabetics seem more prone to develop SC- associated GI lesions. Sevelamer therapy should be avoided if possible in patients with a history of major abdominal surgery or chronic constipation, because of the high risk of serious GI complications.
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Development of drug resistance is a major factor limiting the continued success of cancer chemotherapy. To overcome drug resistance, understanding the underlying mechanism(s) is essential. We found that HOXC10 is overexpressed in primary carcinomas of the breast, and even more significantly in distant metastasis arising after failed chemotherapy. High HOXC10 expression correlates with shorter recurrence-free and overall survival in patients with estrogen receptor-negative breast cancer undergoing chemotherapy. We found that HOXC10 promotes survival in cells treated with doxorubicin, paclitaxel, or carboplatin by suppressing apoptosis and upregulating NF-κB Overexpressed HOXC10 increases S-phase-specific DNA damage repair by homologous recombination (HR) and checkpoint recovery in cells at three important phases. For double-strand break repair, HOXC10 recruits HR proteins at sites of DNA damage. It enhances resection and lastly, it resolves stalled replication forks, leading to initiation of DNA replication following DNA damage. We show that HOXC10 facilitates, but is not directly involved in DNA damage repair mediated by HR. HOXC10 achieves integration of these functions by binding to, and activating cyclin-dependent kinase, CDK7, which regulates transcription by phosphorylating the carboxy-terminal domain of RNA polymerase II. Consistent with these findings, inhibitors of CDK7 reverse HOXC10-mediated drug resistance in cultured cells. Blocking HOXC10 function, therefore, presents a promising new strategy to overcome chemotherapy resistance in breast cancer. Cancer Res; 76(15); 4443-56. ©2016 AACR.
Subject(s)
Breast Neoplasms/genetics , Drug Resistance, Neoplasm/genetics , Homeodomain Proteins/metabolism , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , DNA Repair , Female , HumansABSTRACT
Introducción. El trasplante es la opción terapéutica que ofrece mayor supervivencia y calidad de vida frente al fallo de un órgano. Los aspectos psiquiátricos y psicológicos de los candidatos a trasplante son relevantes, especialmente en la etapa de evaluación previa, pues la influencia de estos factores puede dificultar la evolución posquirúrgica, tanto en la supervivencia del órgano implantado como en la calidad de vida de la persona trasplantada. Son de especial importancia los factores vinculados a la patología por uso de sustancias, los trastornos psicopatológicos y el soporte psicosocial. Actualmente, existen pocas Guías que orienten sobre la correcta evaluación de los pacientes candidatos a estos procedimientos complejos. Método. Diecinueve psiquiatras y psicólogos clínicos de 6 hospitales públicos de Cataluña realizaron un trabajo sistemático de consenso para llegar al diseño de un protocolo unificado de evaluación psicológica y psiquiátrica. Se implementó un plan de trabajo anual, se definieron objetivos y se realizó una revisión bibliográfica, se discutieron los criterios de inclusión y exclusión, se seleccionaron los cuestionarios y se elaboró la entrevista estructurada. Resultados. Con el cumplimiento del plan de trabajo, se diseñó el Protocolo de Evaluación que se presenta en este artículo. Conclusiones. El trabajo sistematizado y la colaboración intercentros de psiquiatras y psicólogos clínicos ha facilitado homogeneizar y consensuar un protocolo unificado de evaluación (AU)
Introduction. Transplantation is the treatment option that offers improved survival and quality of life as compared to organ failure. Psychiatric and psychological aspects of transplant candidates are important, especially in the pre-assessment stage, as the influence of these factors can hinder post-surgical outcome in both the implanted organ survival and the quality of life of the transplanted person. Of particular importance, are the factors related to pathology due to substance use, psychopathology, and psychosocial support. There are currently few guidelines on the correct evaluation of patients eligible for these complex procedures. Method. Nineteen psychiatrists and clinical psychologists from six public hospitals in Catalonia conducted a systematic consensus to determine the design of a Unified Protocol psychological and psychiatric evaluation. An annual work plan was implemented, during which; the objectives were defined, a literature review was conducted, the inclusion and exclusion criteria were discussed, questionnaires were selected, and a structured interview was developed. Results. With the implementation of the work plan, the Assessment Protocol presented in this article was designed. Conclusions. systematic work and improving cooperation between psychiatrists and clinical psychologists, has led to homogeneity and consensus on a unified evaluation protocol (AU)
Subject(s)
Female , Humans , Male , Clinical Protocols/classification , Clinical Protocols/standards , Psychological Tests/statistics & numerical data , Psychological Tests/standards , Organ Transplantation/methods , Organ Transplantation/psychology , Psychiatric Somatic Therapies/methodsABSTRACT
A molecular-mechanics computational study is performed in order to analyze the arrangement of (1R,2S)-(-)-ephedrine molecules within the 12-MR channels of the AFI aluminophosphate microporous framework and the influence on the spatial distribution of dopants embedded in the tetrahedral network. Results showed that ephedrine molecules arrange exclusively as dimers by π-π stacking of the aromatic rings within the AFI channels. Interestingly, the asymmetric nature of ephedrine and the presence of H-bond-forming groups (NH2 and OH) involve a preferential orientation where consecutive dimers within the channels are rotated by an angle of +30°; this is driven by the establishment of inter-dimer H-bonds. This preferential orientation leads to the development of a supramolecular enantiomerically-pure helicoidal (chiral) arrangement of ephedrine dimers. In addition, the computational results demonstrate that the particular molecular structure of ephedrine imparts a strong trend to attract negative charges to the vicinity of the NH2(+) positively-charged groups. Hence divalent dopants such as Mg, whose replacement by trivalent Al in the aluminophosphate network involves the generation of a negative charge, will tend to locate close to the NH2(+) molecular groups, suggesting that an imprinting of the organic arrangement to the spatial distribution of dopants would be feasible. Combined with the trend of ephedrine to arrange in a helicoidal fashion, an enantiomerically-pure helicoidal distribution of dopants would be expected, thus inducing a new type of chirality in microporous materials.