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Transposable elements (TEs) are abundant in the human genome, and they provide the sources for genetic and functional diversity. The regulation of TEs expression and their functional consequences in physiological conditions and cancer development remain to be fully elucidated. Previous studies suggested TEs are repressed by DNA methylation and chromatin modifications. The effect of 3D chromatin topology on TE regulation remains elusive. Here, by integrating transcriptome and 3D genome architecture studies, we showed that haploinsufficient loss of NIPBL selectively activates alternative promoters at the long terminal repeats (LTRs) of the TE subclasses. This activation occurs through the reorganization of topologically associating domain (TAD) hierarchical structures and recruitment of proximal enhancers. These observations indicate that TAD hierarchy restricts transcriptional activation of LTRs that already possess open chromatin features. In cancer, perturbation of the hierarchical chromatin topology can lead to co-option of LTRs as functional alternative promoters in a context-dependent manner and drive aberrant transcriptional activation of novel oncogenes and other divergent transcripts. These data uncovered a new layer of regulatory mechanism of TE expression beyond DNA and chromatin modification in human genome. They also posit the TAD hierarchy dysregulation as a novel mechanism for alternative promoter-mediated oncogene activation and transcriptional diversity in cancer, which may be exploited therapeutically.
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Communities neighboring monoculture plantations are vulnerable to different forms of pollution associated with agro-industrial operations. Herein, we examine the case of El Tiple, a rural Afro descendant community embedded within one of the largest sugarcane plantations in the Americas. We implemented a participatory approach to assess water pollution, exposure via water ingestion, and non-carcinogenic health risks associated with the use of local water sources available to the community. We conducted household surveys to unveil demographic characteristics and family dynamics linked to water consumption. Additionally, we measured water quality parameters and assessed the concentration glyphosate, its major metabolite (aminomethylphosphonic acid) and metals and metalloids. Drinking water El Tiple households is sourced from three primary sources: the local aqueduct system, water delivery trucks, and private deep wells. Tests on water samples from both the local aqueduct and delivery trucks showed no traces of pesticides, metals, or metalloids surpassing regulatory limits set by Colombian or EPA standards. However, we found concentration of contaminants of primary concern, including mercury (up to 0.0052 ppm) and lead (up to 0.0375 ppm) that exceed the permissible regulatory thresholds in water from groundwater wells. Residents of the peripheric subdivisions of El Tiple are four times more reliant on well water extraction than residents of the central area of the town due to lack of access to public drinking water and sanitation infrastructure. Finally, adult women and school-age children have a higher health risk associated with exposure to local pollutants than adult men due to their constant presence in the town. We conclude that expanding the coverage of clean water and sanitation infrastructure to include all households of the community would be the most recommended measure to minimize exposure and risk via ingestion of water pollutants.
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Saccharum , Contaminantes Químicos del Agua , Colombia , Contaminantes Químicos del Agua/análisis , Humanos , Medición de Riesgo , Agricultura , Agua Potable/química , Monitoreo del Ambiente , Contaminación del Agua/estadística & datos numéricos , Contaminación del Agua/análisis , Glicina/análogos & derivados , Glicina/análisis , Exposición a Riesgos Ambientales/estadística & datos numéricos , Exposición a Riesgos Ambientales/análisis , Abastecimiento de Agua , GlifosatoRESUMEN
BACKGROUND: Epstein-Barr Virus (EBV) viral loads in hematopoietic stem cell transplant (HSCT) recipients are typically monitored using quantitative molecular assays. The Cobas EBV test (Roche Molecular, Pleasanton, CA) has recently been FDA-cleared for the monitoring of EBV viral loads in plasma samples of transplant patients. In this study, we compared the viral loads obtained by a laboratory-developed test (EBV LDT) using Altona Analyte specific reagents (ASR) to those obtained on the Cobas EBV test. METHODS: The analytical performance of the assay was established using the EBV verification panel from Exact Diagnostics and the EBV ATCC strain B95-8. The clinical evaluation was performed using 343 plasma samples initially tested on the EBV LDT. RESULTS: The analytical sensitivity (<18.8 IU/mL), precision (SD < 0.17 log) and linear range (35.0 IU/mL to 1E + 08 IU/mL) of the Cobas EBV assay established by the manufacturers were confirmed. The strength of the qualitative agreement was substantial between the cobas EBV and the EBV LDT (85.6 %; κ = 0.71) and almost perfect when discordant results were resolved (96.4 %; κ = 0.93). The quantitative agreement was moderate (82.9 %; κ = 0.53) with the viral load obtained on the Cobas EBV test being lower across the linear range of the two tests (mean log difference of 1.0). While the absolute values of the viral loads were markedly different, the overall trends observed in patients with multiple consecutive results were similar between the two tests. CONCLUSIONS: The Cobas EBV test provides an accurate and valid, in vitro diagnostic (IVD) option for monitoring of EBV viral loads in transplant patients and should provide an opportunity for increased standardization and commutability of tests results across laboratories.
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Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Sensibilidad y Especificidad , Centros de Atención Terciaria , Carga Viral , Humanos , Carga Viral/métodos , Infecciones por Virus de Epstein-Barr/diagnóstico , Infecciones por Virus de Epstein-Barr/virología , Herpesvirus Humano 4/aislamiento & purificación , Herpesvirus Humano 4/genética , Persona de Mediana Edad , Femenino , Adulto , Masculino , Anciano , Adulto Joven , Adolescente , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Diagnóstico Molecular/normas , Trasplante de Células Madre Hematopoyéticas , Niño , Preescolar , ADN Viral/sangre , Juego de Reactivos para Diagnóstico/normasRESUMEN
PURPOSE: Develop and deploy a robust discovery platform that encompasses heterogeneity, clinical annotation, and molecular characterization and overcomes the limited availability of prostate cancer models. This initiative builds on the rich MD Anderson (MDA) prostate cancer (PCa) patient-derived xenograft (PDX) resource to complement existing publicly available databases by addressing gaps in clinically annotated models reflecting the heterogeneity of potentially lethal and lethal prostate cancer. EXPERIMENTAL DESIGN: We performed whole-genome, targeted, and RNA sequencing in representative samples of the same tumor from 44 PDXs derived from 38 patients linked to donor tumor metadata and corresponding organoids. The cohort includes models derived from different morphologic groups, disease states, and involved organ sites (including circulating tumor cells), as well as paired samples representing heterogeneity or stages before and after therapy. RESULTS: The cohort recapitulates clinically reported alterations in prostate cancer genes, providing a data resource for clinical and molecular interrogation of suitable experimental models. Paired samples displayed conserved molecular alteration profiles, suggesting the relevance of other regulatory mechanisms (e.g., epigenomic) influenced by the microenvironment and/or treatment. Transcriptomically, models were grouped on the basis of morphologic classification. DNA damage response-associated mechanisms emerged as differentially regulated between adenocarcinoma and neuroendocrine prostate cancer in a cross-interrogation of PDX/patient datasets. CONCLUSIONS: We addressed the gap in clinically relevant prostate cancer models through comprehensive molecular characterization of MDA PCa PDXs, providing a discovery platform that integrates with patient data and benchmarked to therapeutically relevant consensus clinical groupings. This unique resource supports robust hypothesis generation and testing from basic, translational, and clinical perspectives.
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Neoplasias de la Próstata , Humanos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Masculino , Animales , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto , Biomarcadores de Tumor/genética , Xenoinjertos , Regulación Neoplásica de la Expresión Génica , Perfilación de la Expresión GénicaRESUMEN
PURPOSE: There are insufficient large-scale studies comparing the performance of screening mammography in women of different races. This study aims to compare the screening performance metrics across racial and age groups in the National Mammography Database (NMD). METHODS: All screening mammograms performed between January 1, 2008, and December 31, 2021, in women aged 30-100 years from 746 mammography facilities in 46 U.S. states in the NMD were included. Patients were stratified by 10-year age intervals and 5 racial groups (African American, American Indian, Asian, White, unknown). Incidence of risk factors (breast density, personal history, family history of breast cancer, age), and time since prior exams were compared. Five screening mammography metrics were calculated: recall rate (RR), cancer detection rate (CDR), positive predictive values for recalls (PPV1), biopsy recommended (PPV2) and biopsy performed (PPV3). RESULTS: 29,479,655 screening mammograms performed in 13,181,241 women between January 1, 2008, and December 31, 2021, from the NMD were analyzed. The overall mean performance metrics were RR 10.00% (95% CI 9.99-10.02), CDR 4.18/1000 (4.16-4.21), PPV1 4.18% (4.16-4.20), PPV2 25.84% (25.72-25.97), PPV3 25.78% (25.66-25.91). With advancing age, RR significantly decreases, while CDR, PPV1, PPV2, and PPV3 significantly increase. Incidence of personal/family history of breast cancer, breast density, age, prior mammogram availability, and time since prior mammogram were mostly similar across all races. Compared to White women, African American women had significantly higher RR, but lower CDR, PPV1, PPV2 and PPV3. CONCLUSIONS: Benefits of screening mammography increase with age, including for women age > 70 and across all races. Screening mammography is effective; with lower RR and higher CDR, PPV2, and PPV3 with advancing age. African American women have poorer outcomes from screening mammography (higher RR and lower CDR), compared to White and all women in the NMD. Racial disparity can be partly explained by higher rate of African American women lost to follow up.
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Neoplasias de la Mama , Mamografía , Humanos , Femenino , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/epidemiología , Detección Precoz del Cáncer , Valor Predictivo de las Pruebas , Biopsia , Tamizaje MasivoRESUMEN
Haematopoietic stem cell transplantation (HSCT) is a curative approach for blood cancers, yet its efficacy is undermined by a range of acute and chronic complications. In light of mounting evidence to suggest that these complications are linked to a dysbiotic gut microbiome, we aimed to evaluate the feasibility of faecal microbiota transplantation (FMT) delivered during the acute phase after HSCT. Of note, this trial opted for FMT prepared using the individual's own stool (autologous FMT) to mitigate the risks of disease transmission from a donor stool. Adults (>18 years) with multiple myeloma were recruited from a single centre. The stool was collected prior to starting first line therapy. Patients who progressed to HSCT were offered FMT via 3 × retention enemas before day +5 (HSCT = day 0). The feasibility was determined by the recruitment rate, number and volume of enemas administered, and the retention time. Longitudinally collected stool samples were also collected to explore the influence of auto-FMT using 16S rRNA gene sequencing. n = 4 (2F:2M) participants received auto-FMT in 12 months. Participants received an average of 2.25 (1-3) enemas 43.67 (25-50) mL total, retained for an average of 60.78 (10-145) min. No adverse events (AEs) attributed to the FMT were identified. Although the minimum requirements were met for the volume and retention of auto-FMT, the recruitment was significantly impacted by the logistical challenges of the pretherapy stool collection. This ultimately undermined the feasibility of this trial and suggests that third party (donor) FMT should be prioritised.
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The cell-to-cell signaling role of d-amino acids (d-AAs) in the mammalian endocrine system, particularly in the islets of Langerhans, has drawn growing interest for their potential involvement in modulating glucose metabolism. Previous studies found colocalization of serine racemase [produces d-serine (d-Ser)] and d-alanine (d-Ala) within insulin-secreting beta cells and d-aspartate (d-Asp) within glucagon-secreting alpha cells. Expressed in the islets, functional N-methyl-d-aspartate receptors are involved in the modulation of glucose-stimulated insulin secretion and have binding sites for several d-AAs. However, knowledge of the regulation of d-AA levels in the islets during glucose stimulation as well as the response of islets to different levels of extracellular d-AAs is limited. In this study, we determined the intracellular and extracellular levels of d-Ser, d-Ala, and d-Asp in cultures of isolated rodent islets exposed to different levels of extracellular glucose. We found that the intracellular levels of the enantiomers demonstrated large variability and, in general, were not affected by extracellular glucose levels. However, significantly lower levels of extracellular d-Ser and d-Ala were observed in the islet media supplemented with 20 mM concentration of glucose compared to the control condition utilizing 3 mM glucose. Glucose-induced oscillations of intracellular free calcium concentration ([Ca2+]i), a proxy for insulin secretion, were modulated by the exogenous application of d-Ser and d-Ala but not by their l-stereoisomers. Our results provide new insights into the roles of d-AAs in the biochemistry and function of pancreatic islets.
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BACKGROUND: The benefits of mammographic screening have been shown to include a decrease in mortality due to breast cancer. Taiwan's Breast Cancer Screening Program is a national screening program that has offered biennial mammographic breast cancer screening for women aged 50-69 years since 2004 and for those aged 45-69 years since 2009, with the implementation of mobile units in 2010. The purpose of this study was to compare the performance results of the program with changes in the previous (2004-2009) and latter (2010-2020) periods. METHODS: A cohort of 3,665,078 women who underwent biennial breast cancer mammography screenings from 2004 to 2020 was conducted, and data were obtained from the Health Promotion Administration, Ministry of Health and Welfare of Taiwan. We compared the participation of screened women and survival rates from breast cancer in the earlier and latter periods across national breast cancer screening programs. RESULTS: Among 3,665,078 women who underwent 8,169,869 examinations in the study population, the screened population increased from 3.9% in 2004 to 40% in 2019. The mean cancer detection rate was 4.76 and 4.08 cancers per 1000 screening mammograms in the earlier (2004-2009) and latter (2010-2020) periods, respectively. The 10-year survival rate increased from 89.68% in the early period to 97.33% in the latter period. The mean recall rate was 9.90% (95% CI: 9.83-9.97%) in the early period and decreased to 8.15% (95%CI, 8.13-8.17%) in the latter period. CONCLUSIONS: The evolution of breast cancer screening in Taiwan has yielded favorable outcomes by increasing the screening population, increasing the 10-year survival rate, and reducing the recall rate through the participation of young women, the implementation of a mobile unit service and quality assurance program, thereby providing historical evidence to policy makers to plan future needs.
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Neoplasias de la Mama , Femenino , Humanos , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/epidemiología , Taiwán/epidemiología , Detección Precoz del Cáncer/métodos , Mamografía/métodos , Tasa de Supervivencia , Tamizaje Masivo/métodosRESUMEN
BACKGROUND: Fragile X syndrome (FXS) is the leading monogenic cause of intellectual disability and autism in males and females. Females with FXS typically display a milder cognitive phenotype than males, despite experiencing significant developmental, behavioral, and social-emotional issues. AIMS: To measure and distinguish the cognitive-behavioral profile of girls with FXS relative to verbal IQ-matched peers. METHODS AND PROCEDURES: Ninety-seven participants (NFXS=55, Ncomparison=42) six to 16 years of age completed assessments evaluating cognition, academic achievement, and adaptive behavior. The comparison group consisted of age-, sex-, and verbal IQ-matched peers. OUTCOMES AND RESULTS: Consistent with previous studies, the FXS group demonstrated mean cognitive skills, academic achievement, and adaptive behavior in the borderline to low average range. On average, the FXS group showed poorer nonverbal reasoning, visual pattern recognition, verbal abstraction, math abilities, attention, inhibitory control, and working memory than the comparison group. There were no significant group differences in adaptive behavior. Different patterns of associations between cognition and selected outcomes emerged in each group. CONCLUSIONS AND IMPLICATIONS: Results highlight the importance of identifying specific cognitive-behavioral profiles in girls with FXS to inform more targeted interventions for optimizing outcomes and quality of life in this population.
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Éxito Académico , Síndrome del Cromosoma X Frágil , Masculino , Femenino , Humanos , Niño , Síndrome del Cromosoma X Frágil/psicología , Calidad de Vida , Cognición , Adaptación PsicológicaRESUMEN
Microbiome-derived metabolites are important for the microbiome-gut-brain axis and the discovery of new disease treatments. D-Alanine (D-Ala) is found in many animals as a potential co-agonist of the N-methyl-D-aspartate receptors (NMDAR), receptors widely used in the nervous and endocrine systems. The gut microbiome, diet and putative endogenous synthesis are the potential sources of D-Ala in animals, although there is no direct evidence to show the distribution and racemization of gut-absorbed L-/D-Ala with regards to host-microbe interactions in mammals. In this work, we utilized germ-free mice to control the interference from microbiota and isotopically labeled L-/D-Ala to track their biodistribution and racemization in vivo. Results showed time-dependent biodistribution of gut-absorbed D-Ala, particularly accumulation of gut-absorbed D-Ala in pancreatic tissues, brain, and pituitary. No endogenous synthesis of D-Ala via racemization was observed in germ-free mice. The sources of D-Ala in mice were revealed as microbiota and diet, but not endogenous racemization. This work indicates the importance of further investigating the in vivo biological functions of gut-microbiome derived D-Ala, particularly on NMDAR-related activities, for D-Ala as a potential signaling molecules in the microbiome-gut-brain axis.
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Microbioma Gastrointestinal , Microbiota , Animales , Ratones , Distribución Tisular , Eje Cerebro-Intestino , Alanina , Receptores de N-Metil-D-Aspartato , MamíferosRESUMEN
Children with fragile X syndrome (FXS) often avoid eye contact, a behavior that is potentially related to hyperarousal. Prior studies, however, have focused on between-person associations rather than coupling of within-person changes in gaze behaviors and arousal. In addition, there is debate about whether prompts to maintain eye contact are beneficial for individuals with FXS. In a study of young females (ages 6-16), we used eye tracking to assess gaze behavior and pupil dilation during social interactions in a group with FXS (n = 32) and a developmentally similar comparison group (n = 23). Participants engaged in semi-structured conversations with a female examiner during blocks with and without verbal prompts to maintain eye contact. We identified a social-behavioral and psychophysiological profile that is specific to females with FXS; this group exhibited lower mean levels of eye contact, significantly increased mean pupil dilation during conversations that included prompts to maintain eye contact, and showed stronger positive coupling between eye contact and pupil dilation. Our findings strengthen support for the perspective that gaze aversion in FXS reflects negative reinforcement of social avoidance behavior. We also found that behavioral skills training may improve eye contact, but maintaining eye contact appears to be physiologically taxing for females with FXS.
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Early detection decreases breast cancer death. The ACR recommends annual screening beginning at age 40 for women of average risk and earlier and/or more intensive screening for women at higher-than-average risk. For most women at higher-than-average risk, the supplemental screening method of choice is breast MRI. Women with genetics-based increased risk, those with a calculated lifetime risk of 20% or more, and those exposed to chest radiation at young ages are recommended to undergo MRI surveillance starting at ages 25 to 30 and annual mammography (with a variable starting age between 25 and 40, depending on the type of risk). Mutation carriers can delay mammographic screening until age 40 if annual screening breast MRI is performed as recommended. Women diagnosed with breast cancer before age 50 or with personal histories of breast cancer and dense breasts should undergo annual supplemental breast MRI. Others with personal histories, and those with atypia at biopsy, should strongly consider MRI screening, especially if other risk factors are present. For women with dense breasts who desire supplemental screening, breast MRI is recommended. For those who qualify for but cannot undergo breast MRI, contrast-enhanced mammography or ultrasound could be considered. All women should undergo risk assessment by age 25, especially Black women and women of Ashkenazi Jewish heritage, so that those at higher-than-average risk can be identified and appropriate screening initiated.
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Neoplasias de la Mama , Femenino , Humanos , Adulto , Persona de Mediana Edad , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/genética , Detección Precoz del Cáncer , Mamografía/métodos , Mama/patología , Ultrasonografía , Tamizaje Masivo/métodos , Densidad de la MamaRESUMEN
The enteric nervous system (ENS) is a complex network of diverse molecularly defined classes of neurons embedded in the gastrointestinal wall and responsible for controlling the major functions of the gut. As in the central nervous system, the vast array of ENS neurons is interconnected by chemical synapses. Despite several studies reporting the expression of ionotropic glutamate receptors in the ENS, their roles in the gut remain elusive. Here, by using an array of immunohistochemistry, molecular profiling and functional assays, we uncover a new role for d-serine (d-Ser) and non-conventional GluN1-GluN3 N-methyl d-aspartate receptors (NMDARs) in regulating ENS functions. We demonstrate that d-Ser is produced by serine racemase (SR) expressed in enteric neurons. By using both in situ patch clamp recording and calcium imaging, we show that d-Ser alone acts as an excitatory neurotransmitter in the ENS independently of the conventional GluN1-GluN2 NMDARs. Instead, d-Ser directly gates the non-conventional GluN1-GluN3 NMDARs in enteric neurons from both mouse and guinea-pig. Pharmacological inhibition or potentiation of GluN1-GluN3 NMDARs had opposite effects on mouse colonic motor activities, while genetically driven loss of SR impairs gut transit and fluid content of pellet output. Our results demonstrate the existence of native GluN1-GluN3 NMDARs in enteric neurons and open new perspectives on the exploration of excitatory d-Ser receptors in gut function and diseases.
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BACKGROUND: Lenalidomide maintenance after autologous stem cell transplant (ASCT) in multiple myeloma (MM) results in superior progression-free survival and overall survival. However, patients with high-risk multiple myeloma (HRMM) do not derive the same survival benefit from lenalidomide maintenance compared with standard-risk patients. The authors sought to determine the outcomes of bortezomib-based maintenance compared with lenalidomide maintenance in patients with HRMM undergoing ASCT. METHODS: In total, the authors identified 503 patients with HRMM who were undergoing ASCT within 12 months of diagnosis from January 2013 to December 2018 after receiving triplet novel-agent induction in the Center for International Blood and Marrow Transplant Research database. HRMM was defined as deletion 17p, t(14;16), t(4;14), t(14;20), or chromosome 1q gain. RESULTS: Three hundred fifty-seven patients (67%) received lenalidomide alone, and 146 (33%) received bortezomib-based maintenance (with bortezomib alone in 58%). Patients in the bortezomib-based maintenance group were more likely to harbor two or more high-risk abnormalities and International Staging System stage III disease (30% vs. 22%; p = .01) compared with the lenalidomide group (24% vs. 15%; p < .01). Patients who were receiving lenalidomide maintenance had superior progression-free survival at 2 years compared with those who were receiving either bortezomib monotherapy or combination therapy (75% vs. 63%; p = .009). Overall survival at 2 years was also superior in the lenalidomide group (93% vs. 84%; p = .001). CONCLUSIONS: No superior outcomes were observed in patients with HRMM who received bortezomib monotherapy or (to a lesser extent) in those who received bortezomib in combination as maintenance compared with lenalidomide alone. Until prospective data from randomized clinical trials are available, post-transplant therapy should be tailored to each patient with consideration for treating patients in clinical trials that target novel therapeutic strategies for HRMM, and lenalidomide should remain a cornerstone of treatment.
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Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple , Humanos , Mieloma Múltiple/terapia , Lenalidomida/uso terapéutico , Bortezomib/uso terapéutico , Estudios Prospectivos , Trasplante de Células Madre Hematopoyéticas/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante Autólogo/métodos , Dexametasona/uso terapéuticoRESUMEN
The mechanisms underlying ETS-driven prostate cancer initiation and progression remain poorly understood due to a lack of model systems that recapitulate this phenotype. We generated a genetically engineered mouse with prostate-specific expression of the ETS factor, ETV4, at lower and higher protein dosage through mutation of its degron. Lower-level expression of ETV4 caused mild luminal cell expansion without histologic abnormalities, and higher-level expression of stabilized ETV4 caused prostatic intraepithelial neoplasia (mPIN) with 100% penetrance within 1 week. Tumor progression was limited by p53-mediated senescence and Trp53 deletion cooperated with stabilized ETV4. The neoplastic cells expressed differentiation markers such as Nkx3.1 recapitulating luminal gene expression features of untreated human prostate cancer. Single-cell and bulk RNA sequencing showed that stabilized ETV4 induced a previously unidentified luminal-derived expression cluster with signatures of cell cycle, senescence, and epithelial-to-mesenchymal transition. These data suggest that ETS overexpression alone, at sufficient dosage, can initiate prostate neoplasia.
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Neoplasia Intraepitelial Prostática , Neoplasias de la Próstata , Masculino , Ratones , Animales , Humanos , Próstata/metabolismo , Próstata/patología , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias de la Próstata/genética , Factores de Transcripción/metabolismo , Neoplasia Intraepitelial Prostática/genética , Transformación Celular Neoplásica/genética , Regulación Neoplásica de la Expresión Génica , Proteínas Proto-Oncogénicas c-ets/genéticaRESUMEN
Breast cancer is the most common cancer in women, with the incidence rising substantially with age. Older women are a vulnerable population at increased risk of developing and dying from breast cancer. However, women aged 75 years and older were excluded from all randomized controlled screening trials, so the best available data regarding screening benefits and risks in this age group are from observational studies and modeling predictions. Benefits of screening in older women are the same as those in younger women: early detection of smaller lower-stage cancers, resulting in less invasive treatment and lower morbidity and mortality. Mammography performs significantly better in older women with higher sensitivity, specificity, cancer detection rate, and positive predictive values, accompanied by lower recall rates and false positives. The overdiagnosis rate is low, with benefits outweighing risks until age 90 years. Although there are conflicting national and international guidelines about whether to continue screening mammography in women beyond age 74 years, clinicians can use shared decision making to help women make decisions about screening and fully engage them in the screening process. For women aged 75 years and older in good health, continuing annual screening mammography will save the most lives. An informed discussion of the benefits and risks of screening mammography in older women needs to include each woman's individual values, overall health status, and comorbidities. This article will review the benefits, risks, and controversies surrounding screening mammography in women 75 years old and older and compare the current recommendations for screening this population from national and international professional organizations. ©RSNA, 2023 Quiz questions for this article are available through the Online Learning Center.
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Neoplasias de la Mama , Femenino , Humanos , Anciano , Neoplasias de la Mama/diagnóstico por imagen , Mamografía , Detección Precoz del Cáncer/métodos , Valor Predictivo de las Pruebas , Factores de Riesgo , Tamizaje MasivoRESUMEN
BACKGROUND: Fragile X syndrome (FXS) is an X chromosome-linked genetic disorder characterized by increased risk for behavioral, social, and neurocognitive deficits. Because males express a more severe phenotype than females, research has focused largely on identifying neural abnormalities in all-male or both-sex populations with FXS. Therefore, very little is known about the neural alterations that contribute to cognitive behavioral symptoms in females with FXS. This cross-sectional study aimed to elucidate the large-scale resting-state brain networks associated with the multidomain cognitive behavioral phenotype in girls with FXS. METHODS: We recruited 38 girls with full-mutation FXS (11.58 ± 3.15 years) and 32 girls without FXS (11.66 ± 2.27 years). Both groups were matched on age, verbal IQ, and multidomain cognitive behavioral symptoms. Resting-state functional magnetic resonance imaging data were collected. RESULTS: Compared with the control group, girls with FXS showed significantly greater resting-state functional connectivity of the default mode network, lower nodal strength at the right middle temporal gyrus, stronger nodal strength at the left caudate, and higher global efficiency of the default mode network. These aberrant brain network characteristics map directly onto the cognitive behavioral symptoms commonly observed in girls with FXS. An exploratory analysis suggested that brain network patterns at a prior time point (time 1) were predictive of the longitudinal development of participants' multidomain cognitive behavioral symptoms. CONCLUSIONS: These findings represent the first examination of large-scale brain network alterations in a large sample of girls with FXS, expanding our knowledge of potential neural mechanisms underlying the development of cognitive behavioral symptoms in girls with FXS.
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Síndrome del Cromosoma X Frágil , Femenino , Humanos , Masculino , Síndrome del Cromosoma X Frágil/complicaciones , Estudios Transversales , Encéfalo , Síntomas Conductuales , Cognición , Imagen por Resonancia MagnéticaRESUMEN
Multiple myeloma (MM) is a disease of older people, yet factors relating to comorbidity and frailty may threaten treatment tolerability for many of this heterogenous group. There has been increasing interest in defining specific and clinically relevant frailty assessment tools within the MM population, with the goal of using these frailty scores, not just as a prognostic instrument, but also as a predictive tool to allow for a frailty-adapted treatment approach. This paper reviews the various frailty assessment frameworks used in the evaluation of patients with MM, including the International Myeloma Working Group Frailty Index (IMWG-FI), the Mayo Frailty Index and the simplified frailty scale. While the IMWG-FI remains the most widely accepted tool, the simplified frailty scale is the most user-friendly in busy day-to-day clinics based on its ease of use. This paper summarises the recommendations from the Myeloma Scientific Advisory Group (MSAG) of Myeloma Australia, on the use of frailty assessment tools in clinical practice and proposes a frailty-stratified treatment algorithm to aid clinicians in tailoring therapy for this highly heterogeneous patient population.