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1.
A A Pract ; 18(8): e01837, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-39137122

RESUMEN

We report 2 cases of gastrointestinal bleeding and profound anemia in Jehovah's Witness patients (with nadir hemoglobin of 2.1 and 2.8 g/dL), both of whom survived until discharge to home. Management included supportive care, antifibrinolytics, and an aggressive erythropoietic regimen. Despite previous reports of high mortality with hemoglobin concentrations less than 5 to 6 g/dL, these patients illustrate that meticulous care in selected patients with severe anemia can lead to successful outcomes, without transfusion.


Asunto(s)
Hemorragia Gastrointestinal , Hemoglobinas , Testigos de Jehová , Humanos , Hemorragia Gastrointestinal/terapia , Hemoglobinas/análisis , Masculino , Persona de Mediana Edad , Femenino , Anemia/terapia , Anciano , Adulto
2.
Anesth Analg ; 2024 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-39037926

RESUMEN

BACKGROUND: While preoperative anemia is associated with adverse perioperative outcomes, the benefits of treatment with iron replacement versus red blood cell (RBC) transfusion remain uncertain. We used a national database to establish trends in preoperative iron-deficiency anemia (IDA) treatment and to test the hypothesis that treatment with preoperative iron may be superior to RBC transfusion. METHODS: This study is a propensity-matched retrospective cohort analysis from 2003 to 2023 using TriNetX Research Network, which included surgical patients diagnosed with IDA within 3 months preoperatively. After matching for surgery type and comorbidities, we compared a cohort of patients with preoperative IDA who were treated with preoperative intravenous (IV) iron but not RBCs (n = 77,179), with a cohort receiving preoperative RBCs but not IV iron (n = 77,179). Propensity-score matching was performed for age, ethnicity, race, sex, overweight and obesity, type 2 diabetes, hyperlipidemia, essential hypertension, heart failure, chronic ischemic heart disease, neoplasms, hypothyroidism, chronic kidney disease, nicotine dependence, surgery type, and lab values from the day of surgery including ferritin, transferrin, and hemoglobin split into low (<7 g/dL), medium (7-<12 g/dL), and high (≥12 g/dL) to account for anemia severity. The primary outcome was 30-day postoperative mortality with the secondary outcomes being 30-day morbidity, postoperative hemoglobin level, and 30-day postoperative RBC transfusion. RESULTS: Compared with RBC transfusion, preoperative IV iron was associated with lower risk of postoperative mortality (n = 2550/77,179 [3.3%] vs n = 4042/77,179 [5.2%]; relative risk [RR], 0.63, 95% confidence interval [CI], 0.60-0.66), and a lower risk of postoperative composite morbidity (n = 14,174/77,179 [18.4%] vs n = 18,632/77,179 [24.1%]; RR, 0.76, 95% CI, 0.75-0.78) (both P = .001 after Bonferroni adjustment). Compared with RBC transfusion, IV iron was also associated with a higher hemoglobin in the 30-day postoperative period (10.1 ± 1.8 g/dL vs 9.4 ± 1.7 g/dL, P = .001 after Bonferroni adjustment) and a reduced incidence of postoperative RBC transfusion (n = 3773/77,179 [4.9%] vs n = 12,629/77,179 [16.4%]; RR, 0.30, 95% CI, 0.29-0.31). CONCLUSIONS: In a risk-adjusted analysis, preoperative IDA treatment with IV iron compared to RBC transfusion was associated with a reduction in 30-day postoperative mortality and morbidity, a higher 30-day postoperative hemoglobin level, and reduced postoperative RBC transfusion. This evidence represents a promising opportunity to improve patient outcomes and reduce blood transfusions and their associated risk and costs.

4.
Anesth Analg ; 138(2): 465-474, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38175737

RESUMEN

BACKGROUND: Pediatric patients requesting bloodless care represent a challenging clinical situation, as parents cannot legally refuse lifesaving or optimal interventions for their children. Here, we report clinical outcomes for the largest series of pediatric inpatients requesting bloodless care and also discuss the ethical considerations. METHODS: We performed a single-institution retrospective cohort study assessing 196 pediatric inpatients (<18 years of age) who requested bloodless care between June 2012 and June 2016. Patient characteristics, transfusion rates, and clinical outcomes were compared between pediatric patients receiving bloodless care and those receiving standard care (including transfusions if considered necessary by the clinical team) (n = 37,271). Families were informed that all available measures would be undertaken to avoid blood transfusions, although we were legally obligated to transfuse blood if the child's life was threatened. The primary outcome was composite morbidity or mortality. Secondary outcomes included percentage of patients transfused, individual morbid events, length of stay, total hospital charges, and total costs. Subgroup analyses were performed after stratification into medical and surgical patients. RESULTS: Of the 196 pediatric patients that requested bloodless care, 6.1% (n = 12) received an allogeneic blood component, compared to 9.1% (n = 3392) for standard care patients ( P = .14). The most common indications for transfusion were perioperative bleeding and anemia of prematurity. None of the transfusions were administered under a court order. Overall, pediatric patients receiving bloodless care exhibited lower rates of composite morbidity compared to patients receiving standard care (2.6% vs 6.2%; P = .035). There were no deaths in the bloodless cohort. Individual morbid events, length of stay, and total hospital charges/costs were not significantly different between the 2 groups. After multivariable analysis, bloodless care was not associated with a significant difference in composite morbidity or mortality (odds ratio [OR], 0.37; 95% confidence interval [CI], 0.12-1.11; P = .077). CONCLUSIONS: Pediatric patients receiving bloodless care exhibited similar clinical outcomes compared to patients receiving standard care, although larger studies with adequate power are needed to confirm this finding. There were no mortalities among the pediatric bloodless cohort. Although a subset of our pediatric bloodless patients received an allogeneic transfusion, no patients required a court order. When delivered in a collaborative and patient-centered manner, blood transfusions can be safely limited among pediatric patients.


Asunto(s)
Anemia , Procedimientos Médicos y Quirúrgicos sin Sangre , Humanos , Niño , Estudios Retrospectivos , Pacientes Internos , Costos de Hospital
5.
PLoS One ; 18(8): e0290351, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37624779

RESUMEN

BACKGROUND: The national blood shortage and growing patient population who decline blood transfusions have created the need for bloodless medicine initiatives. This case series describes the management of gastrointestinal bleed patients who declined allogeneic blood transfusion. Understanding the effectiveness of bloodless techniques may improve treatment for future patients while avoiding the risks and cost associated with transfusion. STUDY DESIGN AND METHODS: A retrospective chart review identified 30 inpatient encounters admitted between 2016 to 2022 for gastrointestinal hemorrhage who declined transfusion due to religious or personal reasons. Clinical characteristics and patient blood management methods utilized during hospitalization were analyzed. Hemoglobin concentrations and clinical outcomes are reported. RESULTS: The most common therapy was intravenous iron (n = 25, 83.3%), followed by erythropoietin (n = 18, 60.0%). Endoscopy was the most common procedure performed (n = 23, 76.7%), and surgical intervention was less common (n = 4, 13.3%). Pre-procedure hemoglobin was <6 g/dL in 7 patients, and <5 g/dL in 4 patients. The median nadir hemoglobin was 5.6 (IQR 4.5, 7.0) g/dL, which increased post-treatment to 7.3 (IQR 6.2, 8.4) g/dL upon discharge. One patient (3.3%) with a nadir Hb of 3.7 g/dL died during hospitalization from sepsis. Nine other patients with nadir Hb <5 g/dL survived hospitalization. CONCLUSIONS: Gastrointestinal bleed patients can be successfully managed with optimal bloodless medicine techniques. Even patients with a nadir Hb <5-6 g/dL can be stabilized with aggressive anemia treatment and may safely undergo anesthesia and endoscopy or surgery for diagnostic or therapeutic purposes. Methods used for treating bloodless medicine patients may be used to improve clinical care for all patients.


Asunto(s)
Anestesiología , Transfusión Sanguínea , Humanos , Estudios Retrospectivos , Administración Intravenosa , Hemorragia Gastrointestinal/terapia
8.
Anesth Analg ; 136(2): e9-e10, 2023 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-36638522
9.
Anesth Analg ; 135(3): 576-585, 2022 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-35977366

RESUMEN

BACKGROUND: Providing bloodless medical care for patients who wish to avoid allogeneic transfusion can be challenging; however, previous studies have demonstrated favorable outcomes when appropriate methods are used. Here, we report one of the largest series of patients receiving bloodless care, along with the methods used to provide such care, and the resulting outcomes. METHODS: In a retrospective cohort study, 1111 adult inpatients (age ≥18 years) at a single institution who declined allogeneic transfusion for religious or personal reasons between June 2012 and June 2016 were included, and the patient blood management methods are described. Patient characteristics, laboratory data, and transfusion rates, as well as clinical outcomes (morbidity, mortality, and length of stay) were compared to all other patients in the hospital who received standard care, including transfusions if needed (n = 137,009). Medical and surgical patients were analyzed as subgroups. The primary outcome was composite morbidity (any morbid event: infectious, thrombotic, ischemic, renal, or respiratory). Secondary outcomes included individual morbid events, in-hospital mortality, length of stay, total hospital charges, and costs. RESULTS: The bloodless cohort had more females and a lower case mix index, but more preadmission comorbidities. Mean nadir hemoglobin during hospitalization was lower in the bloodless (9.7 ± 2.6 g/dL) compared to the standard care (10.1 ± 2.4 g/dL) group (P < .0001). Composite morbidity occurred in 14.4% vs 16.0% (P = .16) of the bloodless and standard care patients, respectively. Length of stay and in-hospital mortality were similar between the bloodless and standard care patients. After Bonferroni adjustment for multiple comparisons, hospital-acquired infection occurred less frequently in the bloodless compared to the standard care cohort (4.3% vs 8.3%) (P < .0001) in the medical patient subgroup, but not in the surgical subgroup. After propensity score adjustment in a multivariable model and adjustment for multiple comparisons, bloodless care was associated with less risk of hospital-acquired infection (OR, 0.56; 95% CI, 0.35-0.83; P = .0074) in the medical subgroup, but not in the surgical subgroup. Median total hospital charges (by 8.5%; P = .0017) and costs (by 8.7%; P = .0001) were lower in the bloodless compared to the standard care cohort, when all patients were included. CONCLUSIONS: Overall, adult patients receiving bloodless care had similar clinical outcomes compared to patients receiving standard care. Medical (but not surgical) bloodless patients may be at less risk for hospital-acquired infection compared to those receiving standard care. Bloodless care is cost-effective and should be considered as high-value practice.


Asunto(s)
Transfusión Sanguínea , Trasplante de Células Madre Hematopoyéticas , Adolescente , Adulto , Femenino , Hemoglobinas/análisis , Mortalidad Hospitalaria , Humanos , Masculino , Estudios Retrospectivos
10.
Blood ; 139(18): 2797-2815, 2022 05 05.
Artículo en Inglés | MEDLINE | ID: mdl-35286385

RESUMEN

Myeloproliferative neoplasms (MPNs) transform to myelofibrosis (MF) and highly lethal acute myeloid leukemia (AML), although the actionable mechanisms driving progression remain elusive. Here, we elucidate the role of the high mobility group A1 (HMGA1) chromatin regulator as a novel driver of MPN progression. HMGA1 is upregulated in MPN, with highest levels after transformation to MF or AML. To define HMGA1 function, we disrupted gene expression via CRISPR/Cas9, short hairpin RNA, or genetic deletion in MPN models. HMGA1 depletion in JAK2V617F AML cell lines disrupts proliferation, clonogenicity, and leukemic engraftment. Surprisingly, loss of just a single Hmga1 allele prevents progression to MF in JAK2V617F mice, decreasing erythrocytosis, thrombocytosis, megakaryocyte hyperplasia, and expansion of stem and progenitors, while preventing splenomegaly and fibrosis within the spleen and BM. RNA-sequencing and chromatin immunoprecipitation sequencing revealed HMGA1 transcriptional networks and chromatin occupancy at genes that govern proliferation (E2F, G2M, mitotic spindle) and cell fate, including the GATA2 master regulatory gene. Silencing GATA2 recapitulates most phenotypes observed with HMGA1 depletion, whereas GATA2 re-expression partially rescues leukemogenesis. HMGA1 transactivates GATA2 through sequences near the developmental enhancer (+9.5), increasing chromatin accessibility and recruiting active histone marks. Further, HMGA1 transcriptional networks, including proliferation pathways and GATA2, are activated in human MF and MPN leukemic transformation. Importantly, HMGA1 depletion enhances responses to the JAK2 inhibitor, ruxolitinib, preventing MF and prolonging survival in murine models of JAK2V617F AML. These findings illuminate HMGA1 as a key epigenetic switch involved in MPN transformation and a promising therapeutic target to treat or prevent disease progression.


Asunto(s)
Factor de Transcripción GATA2 , Proteína HMGA1a , Leucemia Mieloide Aguda , Trastornos Mieloproliferativos , Mielofibrosis Primaria , Animales , Proliferación Celular , Cromatina/genética , Factor de Transcripción GATA2/genética , Redes Reguladoras de Genes , Proteína HMGA1a/genética , Proteína HMGA1a/metabolismo , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Leucemia Mieloide Aguda/genética , Ratones , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/metabolismo , Mielofibrosis Primaria/genética
12.
Pediatr Blood Cancer ; 68(3): e28888, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33381905

RESUMEN

Myeloproliferative neoplasms (MPN) are rare disorders in young patients, and because of this, standardized treatment recommendations are not available. Pediatric patients are more frequently treated with hydroxyurea than interferon, yet there are no data suggesting this is the best practice. Current treatment guidelines for adults suggest using interferon as upfront therapy in young patients. We reviewed the cases of 13 young patients with polycythemia vera or essential thrombocythemia, who were treated with interferon. Extreme thrombocytosis was well controlled and the medication was tolerated by many. Our work shows the need for prospective studies evaluating interferon in our youngest patients with MPN.


Asunto(s)
Antivirales/uso terapéutico , Interferón alfa-2/uso terapéutico , Interferón-alfa/uso terapéutico , Policitemia Vera/tratamiento farmacológico , Polietilenglicoles/uso terapéutico , Trombocitemia Esencial/tratamiento farmacológico , Adolescente , Adulto , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Masculino , Policitemia Vera/patología , Pronóstico , Proteínas Recombinantes/uso terapéutico , Trombocitemia Esencial/patología , Adulto Joven
14.
Breast Cancer Res Treat ; 179(1): 25-35, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31531802

RESUMEN

PURPOSE: The high mobility group A1 (HMGA1) chromatin remodeling protein is required for metastatic progression and cancer stem cell properties in preclinical breast cancer models, although its role in breast carcinogenesis has remained unclear. To investigate HMGA1 in primary breast cancer, we evaluated immunoreactivity score (IRS) in tumors from a large cohort of Asian women; HMGA1 gene expression was queried from two independent Western cohorts. METHODS: HMGA1 IRS was generated from breast tumors in Korean women as the product of staining intensity (weak = 1, moderate = 2, strong = 3) and percent positive cells (< 5% = 0, 5-30% = 1, 30-60% = 2, > 60% = 3), and stratified into three groups: low (< 3), intermediate (3-6), high (> 6). We assessed HMGA1 and estrogen receptor (ESR1) gene expression from two large databases (TCGA, METABRIC). Overall survival was ascertained from the METABRIC cohort. RESULTS: Among 540 primary tumors from Korean women (181 ER-negative, 359 ER-positive), HMGA1 IRS was < 3 in 89 (16.5%), 3-6 in 215 (39.8%), and > 6 in 236 (43.7%). High HMGA1 IRS was associated with estrogen receptor (ER)-negativity (χ2 = 12.07; P = 0.002) and advanced nuclear grade (χ2 = 12.83; P = 0.012). In two large Western cohorts, the HMGA1 gene was overexpressed in breast cancers compared to non-malignant breast tissue (P < 0.0001), including Asian, African American, and Caucasian subgroups. HMGA1 was highest in ER-negative tumors and there was a strong inverse correlation between HMGA1 and ESR1 gene expression (Pearson r = - 0.60, P < 0.0001). Most importantly, high HMGA1 predicted decreased overall survival (P < 0.0001) for all women with breast cancer and further stratified ER-positive tumors into those with inferior outcomes. CONCLUSIONS: Together, our results suggest that HMGA1 contributes to estrogen-independence, tumor progression, and poor outcomes. Moreover, further studies are warranted to determine whether HMGA1 could serve as a prognostic marker and therapeutic target for women with breast cancer.


Asunto(s)
Neoplasias de la Mama/metabolismo , Proteína HMGA1a/genética , Proteína HMGA1a/metabolismo , Receptores de Estrógenos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/genética , Progresión de la Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Pronóstico , República de Corea , Análisis de Supervivencia , Regulación hacia Arriba , Adulto Joven
15.
Hematol Oncol Clin North Am ; 33(5): 857-871, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31466609

RESUMEN

Providing optimal care to surgical oncology patients who cannot be transfused for religious or other reasons can be challenging. However, with careful planning, using a combination of blood-conserving methods, these "bloodless" patients have clinical outcomes that are similar to other patients who can be transfused. Bloodless surgery can be accomplished safely for most patients, including those undergoing technically challenging oncologic surgery. This article reviews best practices used in a bloodless program during the preoperative, intraoperative, and postoperative periods, with the aim of achieving optimal outcomes when transfusion is not an option for surgical oncology patients.


Asunto(s)
Procedimientos Médicos y Quirúrgicos sin Sangre , Oncología Médica , Neoplasias/cirugía , Anestesia/métodos , Anestesia/normas , Procedimientos Médicos y Quirúrgicos sin Sangre/ética , Procedimientos Médicos y Quirúrgicos sin Sangre/métodos , Procedimientos Médicos y Quirúrgicos sin Sangre/normas , Manejo de la Enfermedad , Personal de Salud , Humanos , Cuidados Intraoperatorios , Oncología Médica/ética , Oncología Médica/métodos , Oncología Médica/normas , Neoplasias/metabolismo , Aceptación de la Atención de Salud , Grupo de Atención al Paciente , Cuidados Preoperatorios , Resultado del Tratamiento
16.
Transfusion ; 59(8): 2551-2558, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31063596

RESUMEN

BACKGROUND: Although females have a lower baseline hemoglobin (Hb) compared to males, it is unknown whether females have a greater tolerance for anemia when hospitalized. We tested the hypothesis that females tolerate severe anemia better than males, with decreased inpatient mortality in this setting. STUDY DESIGN AND METHODS: We conducted a retrospective cohort study in 230,644 adult patients admitted to Johns Hopkins Hospital from January 2009 to June 2016. The relationships between nadir Hb and percentage change in Hb with inpatient mortality were assessed for nontransfused males and females. A multivariable logistic regression was used to determine risk-adjusted differences between males and females for the likelihood of inpatient mortality at nadir Hb levels of 5, 6, and 7 g/dL. RESULTS: Males had increased mortality when nadir Hb was 6.0 g/dL or less (p < 0.05), whereas females did not. The risk-adjusted likelihood for inpatient mortality was greater for males compared to females at a nadir Hb of 6 g/dL or less (odds ratio, 1.84; 95% confidence interval, 1.09-3.16) (p = 0.02), but this sex-related difference was not significant at a nadir Hb of 5 or 7 g/dL or less. Inpatient mortality increased significantly in both males and females when the percentage decrease in Hb was greater than 50% from baseline (p < 0.05). CONCLUSIONS: Compared to males, females tolerate a lower nadir Hb, but a similar percentage change in Hb, before an increase in inpatient mortality is recognized. The findings suggest that females may be "preconditioned" to tolerate anemia better than males.


Asunto(s)
Anemia/sangre , Anemia/mortalidad , Hemoglobinas/metabolismo , Mortalidad Hospitalaria , Hospitalización , Caracteres Sexuales , Adulto , Anciano , Anemia/terapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos
17.
J Vis Exp ; (147)2019 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-31132065

RESUMEN

Intestinal organoid cultures provide a unique opportunity to investigate intestinal stem cell and crypt biology in vitro, although efficient approaches to manipulate gene expression in organoids have made limited progress in this arena. While CRISPR/Cas9 technology allows for precise genome editing of cells for organoid generation, this strategy requires extensive selection and screening by sequence analysis, which is both time-consuming and costly. Here, we provide a detailed protocol for efficient viral transduction of intestinal organoids. This approach is rapid and highly efficient, thus decreasing the time and expense inherent in CRISPR/Cas9 technology. We also present a protocol to generate frozen sections from intact organoid cultures for further analysis with immunohistochemical or immunofluorescent staining, which can be used to confirm gene expression or silencing. After successful transduction of viral vectors for gene expression or silencing is achieved, intestinal stem cell and crypt function can be rapidly assessed. Although most organoid studies employ in vitro assays, organoids can also be delivered to mice for in vivo functional analyses. Moreover, our approaches are advantageous for predicting therapeutic responses to drugs because currently available therapies generally function by modulating gene expression or protein function rather than altering the genome.


Asunto(s)
Secciones por Congelación , Ingeniería Genética/métodos , Vectores Genéticos/metabolismo , Intestinos/fisiología , Nanopartículas de Magnetita/química , Organoides/metabolismo , Transducción Genética , Animales , ADN/genética , Edición Génica/métodos , Células HEK293 , Humanos , Campos Magnéticos , Ratones
19.
Prostate ; 78(7): 547-559, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29520928

RESUMEN

BACKGROUND: There are few tissue-based biomarkers that can accurately predict prostate cancer (PCa) progression and aggressiveness. We sought to evaluate the clinical utility of prostate and breast overexpressed 1 (PBOV1) as a potential PCa biomarker. METHODS: Patient tumor samples were designated by Grade Groups using the 2014 Gleason grading system. Primary radical prostatectomy tumors were obtained from 48 patients and evaluated for PBOV1 levels using Western blot analysis in matched cancer and benign cancer-adjacent regions. Immunohistochemical evaluation of PBOV1 was subsequently performed in 80 cancer and 80 benign cancer-adjacent patient samples across two tissue microarrays (TMAs) to verify protein levels in epithelial tissue and to assess correlation between PBOV1 proteins and nuclear architectural changes in PCa cells. Digital histomorphometric analysis was used to track 22 parameters that characterized nuclear changes in PBOV1-stained cells. Using a training and test set for validation, multivariate logistic regression (MLR) models were used to identify significant nuclear parameters that distinguish Grade Group 3 and above PCa from Grade Group 1 and 2 PCa regions. RESULTS: PBOV1 protein levels were increased in tumors from Grade Group 3 and above (GS 4 + 3 and ≥ 8) regions versus Grade Groups 1 and 2 (GS 3 + 3 and 3 + 4) regions (P = 0.005) as assessed by densitometry of immunoblots. Additionally, by immunoblotting, PBOV1 protein levels differed significantly between Grade Group 2 (GS 3 + 4) and Grade Group 3 (GS 4 + 3) PCa samples (P = 0.028). In the immunohistochemical analysis, measures of PBOV1 staining intensity strongly correlated with nuclear alterations in cancer cells. An MLR model retaining eight parameters describing PBOV1 staining intensity and nuclear architecture discriminated Grade Group 3 and above PCa from Grade Group 1 and 2 PCa and benign cancer-adjacent regions with a ROC-AUC of 0.90 and 0.80, respectively, in training and test sets. CONCLUSIONS: Our study demonstrates that the PBOV1 protein could be used to discriminate Grade Group 3 and above PCa. Additionally, the PBOV1 protein could be involved in modulating changes to the nuclear architecture of PCa cells. Confirmatory studies are warranted in an independent population for further validation.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Análisis de Matrices Tisulares
20.
Nat Commun ; 8: 15008, 2017 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-28452345

RESUMEN

High-mobility group A1 (Hmga1) chromatin remodelling proteins are enriched in intestinal stem cells (ISCs), although their function in this setting was unknown. Prior studies showed that Hmga1 drives hyperproliferation, aberrant crypt formation and polyposis in transgenic mice. Here we demonstrate that Hmga1 amplifies Wnt/ß-catenin signalling to enhance self-renewal and expand the ISC compartment. Hmga1 upregulates genes encoding both Wnt agonist receptors and downstream Wnt effectors. Hmga1 also helps to 'build' an ISC niche by expanding the Paneth cell compartment and directly inducing Sox9, which is required for Paneth cell differentiation. In human intestine, HMGA1 and SOX9 are positively correlated, and both become upregulated in colorectal cancer. Our results define a unique role for Hmga1 in intestinal homeostasis by maintaining the stem cell pool and fostering terminal differentiation to establish an epithelial stem cell niche. This work also suggests that deregulated Hmga1 perturbs this equilibrium during intestinal carcinogenesis.


Asunto(s)
Proteína HMGA1a/metabolismo , Mucosa Intestinal/metabolismo , Células de Paneth/metabolismo , Células Madre/metabolismo , Vía de Señalización Wnt , Animales , Diferenciación Celular/genética , Proliferación Celular/genética , Células Cultivadas , Proteína HMGA1a/genética , Humanos , Mucosa Intestinal/citología , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Confocal , Células de Paneth/citología , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/metabolismo , Nicho de Células Madre , Células Madre/citología , Imagen de Lapso de Tiempo
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