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The adaptor proteins NCK1 and NCK2 are well-established signalling nodes that regulate diverse biological processes including cell proliferation and actin dynamics in many tissue types. Here we have investigated the distribution and function of Nck1 and Nck2 in the developing mouse mammary gland. Using publicly available single-cell RNA sequencing data, we uncovered distinct expression profiles between the two paralogs. Nck1 showed widespread expression in luminal, basal, stromal and endothelial cells, while Nck2 was restricted to luminal and basal cells, with prominent enrichment in hormone-sensing luminal subtypes. Next, using mice with global knockout of Nck1 or Nck2, we assessed mammary gland development during and after puberty (5, 8 and 12 weeks of age). Mice lacking Nck1 or Nck2 displayed significant defects in ductal outgrowth and branching at 5 weeks compared to controls, and the defects persisted in Nck2 knockout mice at 8 weeks before normalizing at 12 weeks. These defects were accompanied by an increase in epithelial cell proliferation at 5 weeks and a decrease at 8 weeks in both Nck1 and Nck2 knockout mice. We also profiled expression of several key genes associated with mammary gland development at these timepoints and detected temporal changes in transcript levels of hormone receptors as well as effectors of cell proliferation and migration in Nck1 and Nck2 knockout mice, in line with the distinct phenotypes observed at 5 and 8 weeks. Together these studies reveal a requirement for NCK proteins in mammary gland morphogenesis, and suggest that deregulation of Nck expression could drive breast cancer progression and metastasis.
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Proteínas Adaptadoras de Transdução de Sinal , Glândulas Mamárias Animais , Animais , Camundongos , Camundongos Knockout , Camundongos Endogâmicos C57BL , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/crescimento & desenvolvimento , Glândulas Mamárias Animais/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proliferação de Células , Células Epiteliais/citologia , Expressão GênicaRESUMO
Tumor recurrence represents a significant clinical challenge in the treatment and management of breast cancer. To investigate whether copy number aberrations (CNAs) facilitate the re-emergence of tumor growth from residual disease, we performed array comparative genomic hybridization on primary and recurrent mammary tumors from an inducible mouse model of type-I insulin-like growth factor receptor driven breast cancer. This genome-wide analysis revealed primary and recurrent tumors harbored distinct CNAs with relapsed tumors containing an increased number of gene-level gains and losses. Remarkably, high-level CNAs detected in primary tumors were largely devoid of annotated cancer genes while the vast majority of recurrent tumors harbored at least one CNA containing a known oncogene or tumor suppressor. Specifically, 38% of recurrent tumors carried gains at 6qA2 and 9qA2 which encode the Met and Yap1 oncogenes, respectively. The most frequent CNA, occurring in 63% of recurrent tumors, was a focal deletion at 4qC5 involving the Cdkn2a/b tumor suppressor genes. Integrative analysis revealed positive correlations between gene copy number and mRNA expression suggesting Met, Yap1, and Cdkn2a/b may serve as potential drivers that promote tumor recurrence. Accordingly, cross-species analysis revealed gene-level murine CNAs were present in a subset of human breast cancers with high MET and YAP1 mRNA predictive of decreased relapse-free survival in basal-like breast cancers. Together, these findings indicate that tumor recurrence is facilitated by the acquisition of CNAs with oncogenic potential and provide a framework to dissect the molecular mechanisms that mediate tumor escape from dormancy.
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Carcinogênese/genética , Variações do Número de Cópias de DNA , Regulação Neoplásica da Expressão Gênica , Neoplasias Mamárias Experimentais/genética , Recidiva Local de Neoplasia/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Ciclo Celular , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Feminino , Neoplasias Mamárias Experimentais/patologia , Camundongos , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas de Sinalização YAPRESUMO
The miR-200 family of microRNAs consisting of miR-141, miR-200a, miR-200b, miR-200c and miR-429 are emerging as important regulators of breast cancer progression. This family of microRNAs maintain mammary epithelial identity and downregulation of miR-200 expression has been associated with epithelial-to-mesenchymal transition in mammary tumors. Therefore, re-expression of one or more miR-200 family members in mammary tumor cells with mesenchymal characteristics may restore an epithelial phenotype including growth and metastasis suppression. To test this hypothesis, the miR-200b/200a/429 cluster was re-expressed in a murine claudin-low cell line, RJ423. Re-expression of the miR-200b/200a/429 cluster in RJ423 cells significantly suppressed the expression of Vim, Snai1, Twist1, Twist2 and Zeb1, reverted RJ423 cells to a more epithelial morphology and significantly inhibited proliferation in vitro. Moreover, the miR-200b/200a/429 cluster prevented lung metastasis in an experimental metastasis model and although tumor initiation was not prevented, re-expression of the miR-200b/200a/429 cluster induced a dormancy-like state where mammary tumors failed to grow beyond ~150â¯mm3 or grew extremely slowly following intra-mammary injection. These dormant tumors contained elevated levels of collagen and were highly vascularized. Therefore, re-expression of the miR-200b/200a/429 cluster in the claudin-low mammary tumor cell line, RJ423, is sufficient to alter cell morphology, impair metastasis and induce tumor dormancy.
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Claudinas/genética , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/patologia , MicroRNAs/fisiologia , Fase de Repouso do Ciclo Celular/genética , Animais , Linhagem Celular Tumoral , Claudinas/metabolismo , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor/fisiologia , Camundongos , MicroRNAs/genética , Família Multigênica/fisiologia , Metástase NeoplásicaRESUMO
BACKGROUND: Intraosseous (IO) access can be complicated by obesity. Successful placement of a 25 mm IO needle is unlikely when soft tissue depth exceeds 20 mm. OBJECTIVES: The authors examined the relationship between body mass index (BMI), the ability to palpate the tibial tuberosity (TT), and soft tissue depth at recommended IO insertion sites. METHODS: Obese emergency department patients were assessed for a palpable TT and received ultrasound measurement of the soft tissue depth at recommended IO insertion sites. Linear and logistic regression were used to determine cut-off BMI values predicting soft tissue depth >20 mm. RESULTS: Seventy-five patients were enrolled with a mean BMI of 47.2. The mean soft tissue depth at the proximal humerus, proximal tibial, and distal tibial were 29.6 [95% CI 27.5-31.7] mm, 11.0 [8.9-13.0] mm, and 10.7 [9.4-12.1] mm, respectively. In 5 patients without a palpable TT the soft tissue depth exceeded 20 mm at all three anatomic sites. A BMI ≥43 and BMI ≥60 predicted a soft tissue depth >20 mm at the proximal tibia and distal tibia, respectively, while no reliable BMI cut-off was identified at the proximal humerus. CONCLUSIONS: In obese adults with a palpable TT or BMI ≤43 a 25 mm IO needle is likely adequate at the proximal and distal tibial insertion sites. Empiric use of an extended 45 mm IO needle is advisable at the proximal humeral insertion site in obese patients.
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Infusões Intraósseas/instrumentação , Agulhas , Obesidade Mórbida/diagnóstico por imagem , Obesidade/diagnóstico por imagem , Tela Subcutânea/diagnóstico por imagem , Adulto , Braço , Índice de Massa Corporal , Humanos , Úmero , Perna (Membro) , Modelos Lineares , Tamanho do Órgão , Tíbia , UltrassonografiaRESUMO
BACKGROUND: Epidemiologic data indicates that Asian diets, which are high in soy protein, reduce a women's risk of developing breast cancer. However, it has been difficult to dissociate the benefits of soy from other variables including environmental and lifestyle factors. Since prospective studies in humans would take decades to complete, rodent models provide a valuable research alternative. METHODS: In this study, MTB-IGFIR transgenic mice, which develop mammary tumors resulting from overexpression of the type I insulin-like growth factor receptor (IGF-IR), were utilized. MTB-IGFIR mice were fed a soy-based or casein-based diet throughout all stages of development to reflect soy exposure in Asian cultures. Mammary tumors were initiated at 2 different developmental stages by commencing IGF-IR transgene expression either during puberty or in adult mice. RESULTS: MTB-IGFIR mice fed a soy-based diet displayed increased tumor incidence and accelerated tumor onset compared to MTB-IGFIR mice fed a casein diet. Two markers of estrogen receptor signaling, Pgr and Areg, were elevated in mammary tissue from mice fed the soy diet compared to mice fed the casein diet suggesting that high levels of soy may promote mammary tumor development through acting as an estrogen receptor agonist. Mammary tumors from mice fed a soy diet more frequently expressed metaplastic markers such as cytokeratins 5 and 14 as well as p63 and displayed reduced lung metastases compared to mammary tumors from mice fed a casein diet. CONCLUSIONS: Diets consisting of very high levels of soy protein promote mammary tumor development and decrease tumor latency possibly through activating estrogen receptor signaling. Additional studies are required to determine whether a more moderate amount of dietary soy can inhibit oncogene-induced mammary tumorigenesis.
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Ração Animal , Neoplasias Mamárias Animais/etiologia , Neoplasias Mamárias Animais/patologia , Receptor IGF Tipo 1/genética , Alimentos de Soja , Animais , Biomarcadores , Transformação Celular Neoplásica , Feminino , Expressão Gênica , Humanos , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/mortalidade , Camundongos , Camundongos Transgênicos , Metástase Neoplásica , Transdução de Sinais , Carga TumoralAssuntos
Artérias Carótidas/diagnóstico por imagem , Espessura Intima-Media Carotídea , Dor no Peito/diagnóstico por imagem , Serviço Hospitalar de Emergência , Adulto , Idoso , Unidades de Observação Clínica , Teste de Esforço , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de RiscoRESUMO
Recently, use of the synthetic cathinone (aka "bath salt") eutylone has risen in the United States and globally. Due to its novelty in drug markets, its affective properties remain largely uninvestigated. In this context, drugs of abuse have both rewarding and aversive effects and understanding these effects, their relative balance, and factors that impact each are important to understanding the likelihood of drug use and abuse. This investigation attempted to characterize eutylone's rewarding and aversive effects in a combined conditioned taste avoidance/place preference assay. Female Sprague-Dawley rats were given 20-min access to saccharin, injected with one of five doses of eutylone (0, 3, 10, 18, 32 mg/kg; intraperitoneally; IP), and placed on one side of a place conditioning apparatus. On the following day, subjects were given 20-min access to water, injected IP with vehicle, and placed on the other side of the apparatus. After five conditioning cycles, place preference and saccharin avoidance were assessed. Eutylone induced significant taste avoidance but did not significantly increase time spent on the drug-paired side (relative to controls). Excluding animals with high initial side preference, however, eutylone induced a preference at all doses with the high dose group displaying higher preference than controls. There was no significant correlation between eutylone's aversive and rewarding effects. These data indicate that eutylone (like other synthetic cathinones) induces both rewarding and aversive effects and highlight the need to assess the impact of various factors on its affective properties (and their balance) and on their use and abuse. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
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Catinona Sintética , Paladar , Humanos , Ratos , Animais , Feminino , Ratos Sprague-Dawley , Sacarina/farmacologia , Aprendizagem da EsquivaRESUMO
BACKGROUND: Drugs of abuse have rewarding and aversive effects that, in balance, impact abuse potential. Although such effects are generally examined in independent assays (e.g., CPP and CTA, respectively), a number of studies have examined these effects concurrently in rats in a combined CTA/CPP design. The present study assessed if similar effects can be produced in mice which would allow for determining how each is affected by subject and experiential factors relevant to drug use and abuse and the relationship between these affective properties. METHODS: Male and female C57BL/6 mice were exposed to a novel saccharin solution, injected (IP) with saline or 5.6, 10 or 18 mg/kg of the synthetic cathinone, methylone, and placed on one side of the place conditioning apparatus. The following day, they were injected with saline, given access to water and placed on the other side of the apparatus. After four conditioning cycles, saccharin avoidance and place preferences were assessed in a final two-bottle CTA test and a CPP Post-Test, respectively. RESULTS: In the combined CTA/CPP design, mice acquired a significant dose-dependent CTA (p = 0.003) and a significant CPP (p = 0.002). These effects were independent of sex (all ps > 0.05). Further, there was no significant relationship between the degree of taste avoidance and place preference (p > 0.05). CONCLUSIONS: Similar to rats, mice displayed significant CTA and CPP in the combined design. It will be important to extend this design in mice to other drugs and to examine the impact of different subject and experiential factors on these effects to facilitate predictions of abuse liability.
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Condicionamento Psicológico , Paladar , Ratos , Camundongos , Masculino , Feminino , Animais , Sacarina/farmacologia , Camundongos Endogâmicos C57BL , Recompensa , Aprendizagem da Esquiva , Relação Dose-Resposta a DrogaRESUMO
Acute lower extremity deep venous thrombosis (DVT) is a serious vascular disorder that requires accurate and early diagnosis to prevent life-threatening sequelae. While whole leg compression ultrasound with color and spectral Doppler is commonly performed in radiology and vascular labs, point-of-care ultrasound (POCUS) is becoming more common in the acute care setting. Providers appropriately trained in focused POCUS can perform a rapid bedside examination with high sensitivity and specificity in critically ill patients. This paper describes a simplified yet validated approach to POCUS by describing a three-zone protocol for lower extremity DVT POCUS image acquisition. The protocol explains the steps in obtaining vascular images at six compression points in the lower extremity. Beginning at the level of the proximal thigh and moving distally to the popliteal space, the protocol guides the user through each of the compression points in a stepwise manner: from the common femoral vein to the femoral and deep femoral vein bifurcation, and, finally, to the popliteal vein. Further, a visual aid is provided that may assist providers during real-time image acquisition. The goal in presenting this protocol is to help make proximal lower extremity DVT exams more accessible and efficient for POCUS users at the patient's bedside.
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Sistemas Automatizados de Assistência Junto ao Leito , Trombose Venosa , Humanos , Trombose Venosa/diagnóstico por imagem , Veia Femoral , Veia Poplítea/diagnóstico por imagem , Extremidade Inferior/diagnóstico por imagem , Ultrassonografia/métodosRESUMO
Vascular access is one of the most commonly performed invasive procedures in medicine. Ultrasound-guided vascular access has been shown to improve patient safety, decrease associated complications and increase first attempt success rates, however, the risk for a posterior venous wall puncture (PVWP) still exists. To reduce this complication, needle guides have been used, though, current methods have limited accessibility and generalizability. Thus, the aim of this article is to describe how a self-made needle block constructed with materials present in a central line kit can reduce the incidence of PVWP and its associated complications in novice POCUS users.
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Cateterismo Venoso Central , Lesões do Sistema Vascular , Cateterismo Venoso Central/efeitos adversos , Cateterismo Venoso Central/métodos , Humanos , Agulhas , Punções , Ultrassonografia de Intervenção/métodos , VeiasRESUMO
OBJECTIVE: Ultrasound-guided peripheral intravenous (USPIV) catheters are being placed in emergency department (ED) patients with increasing frequency. USPIV catheters have been shown to improve the success rates of cannulation. It is unknown what the long-term effect of USPIV placement will be on fistula creation in chronic kidney disease (CKD) patients considering these ultrasound-guided peripheral lines often target the same deeper vessels used for fistulas. This study aimed to survey whether emergency medicine programs place restrictions on USPIV placement in patients with CKD stages 3-5. METHODS: This was a survey study encompassing all 110 emergency ultrasound fellowship directors in the United States at the time the survey was conducted. Data was collected on an anonymous and voluntary basis. The primary outcome was the number of programs with restrictions on USPIV placement in patients with CKD stage 3 or greater. RESULTS: Of the 56 programs that responded, 21% reported having policies limiting which patients were appropriate for USPIV. Despite this, only one program reported placing restrictions on USPIV in CKD stage 3 or greater (p < 0.0001). CONCLUSIONS: Emergency departments do not have or follow restrictions placed on USPIV placement in patients with CKD stage 3 or greater. The use of these veins in the ED may result in thrombosis as well as inflammation and permanent scarring which could negatively impact the ability to utilize those vessels for fistula creation. Future studies are needed to further characterize the impact of USPIV on fistula creation.
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Cateterismo Periférico , Insuficiência Renal Crônica , Administração Intravenosa , Cateterismo Periférico/efeitos adversos , Serviço Hospitalar de Emergência , Humanos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/terapia , Ultrassonografia de IntervençãoRESUMO
BACKGROUND: Polydrug use is well documented in synthetic cathinone users, although the consequences of such use are not well characterized. In pre-clinical research, a pre-exposure to a drug has been reported to attenuate the aversive effects of other drugs which has implications for their abuse potential. The goal of the present study was to investigate the impact of pre-exposure to the synthetic cathinone methylone on the aversive effects of MDPV and MDMA. METHOD: Male and female Sprague-Dawley rats were exposed to 10 mg/kg of methylone every 4th day (for a total of five injections) prior to taste avoidance training with 1.8 mg/kg of MDPV or 1 mg/kg of MDMA. RESULTS: MDPV and MDMA induced taste avoidance in males and females (all p's < 0.05). In males, methylone pre-exposure attenuated the avoidance induced by MDPV and MDMA (all p's < 0.05) with the attenuation greater with MDPV. In females, methylone pre-exposure attenuated avoidance induced by MDPV (all p's < 0.05), but it had no effect on those induced by MDMA (all p's > 0.05). CONCLUSIONS: The effects of exposure to methylone on taste avoidance induced by MDPV and MDMA were drug- (MDPV > MDMA) and sex- (MDMA only in males) dependent. The attenuating effects of methylone pre-exposure on MDPV and MDMA were discussed in terms of their shared neurochemical action. These findings suggest that a history of methylone use may reduce the aversive effects of MDPV and MDMA which may have implications for polydrug use involving the synthetic cathinones.
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Estimulantes do Sistema Nervoso Central , Metanfetamina , N-Metil-3,4-Metilenodioxianfetamina , Transtornos Relacionados ao Uso de Substâncias , Animais , Benzodioxóis/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Relação Dose-Resposta a Droga , Feminino , Masculino , Metanfetamina/análogos & derivados , Metanfetamina/farmacologia , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Pirrolidinas/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Objective Auscultation of bowel sounds has been taught as a component of the physical examination since the beginning of the 20th century. However, there has been little research or consensus on the significance of listening in different quadrants. Some textbooks indicate that bowel sounds are the result of peristalsis in that region, while others state that bowel sounds can be generalized over the entire abdominal wall. With ultrasonography, peristalsis can be visualized in a dynamic and non-invasive manner. The purpose of this study was to determine the relationship between auscultation of bowel sounds and visualization of peristalsis with ultrasound, to understand whether or not bowel sounds and peristalsis are compartmentalized. Methods Study participants quietly lay supine, while one investigator positioned an ultrasound probe on the abdomen visualizing the small intestine, and a second investigator placed an EKO Digital Stethoscope (Eko Devices, Inc., Oakland, CA) directly adjacent to the probe auscultate for bowel sounds. During a two-minute interval, a third investigator noted every time a bowel sound was heard (A+), peristalsis was seen (U+), or a combined event (C+) occurred, recording the total number of events. Measurements were recorded from four quadrants (right upper quadrant {RUQ}, left upper quadrant {LUQ}, right lower quadrant {RLQ}, left lower quadrant {LLQ}) and the periumbilical region (PUR). Fisher Exact test was used to determine whether there were significant differences between the number of bowel sounds heard but not seen (A+) and those seen but not heard (U+) with sounds that were both seen and heard (C+). Significance was determined with p < 0.05. Results A total of 16 participants were included, with a combined 973 discrete bowel events, both auscultated and visualized. No quadrant showed a significant correlation between an isolated sound (A+) or peristalsis (U+) and a combined event (C+), indicating there were many events where an auscultated sound failed to correlate with observed peristalsis, and vice versa. The average p-value was 0.544, with a range of 0.052-1.00. Conclusion This study showed that there is no significant correlation between auscultated bowel sounds and peristalsis within a given region. This study calls into question whether auscultation of all four quadrants provides more meaningful information than auscultation of one central point of the abdomen.
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Introduction: Gamification engages learners and has successfully taught point-of-care ultrasound (POCUS) to residents and fellows. Yet ultrasound (US) curricula in undergraduate medical education remains limited. This study assessed a gamification model integrating US, anatomy, physiology, physical examination, and radiology created for preclinical medical students as compared with traditional didactic education. Methods: Twenty first-year medical students participated in a session on neck and thyroid material. Students were randomly assigned to a game or non-game group. Game students participated in games incorporating thyroid US with exam maneuvers, other imaging modalities, physiology, and pathology. Non-game students were taught the same material with an instructor. Students were assessed with a pretest and immediate and delayed post-tests. Group differences and scores were assessed using t-tests. A Likert scale evaluated learners' opinions of the educational experience. Results: The game group performed better than the non-game group on the immediate post-test (p = 0.007, CI = [0.0305, ∞]). There was no significant difference between the groups on the delayed post-test (p = 0.726, CI = [-0.120, ∞]). Students in both groups felt more confident in their knowledge of the material, and all students in the game group agreed that the games encouraged teamwork. Most (9/10) stated the games allowed them to learn the material more effectively and would like to see more gamification (8/10). Conclusion: This US education model incorporating gamification for preclinical medical students promotes teamwork and is as effective for learning material than a traditional learning model. Students additionally convey a positive attitude towards gamification.
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OBJECTIVES: Point-of-care ultrasound (POCUS) has become increasingly integrated into medical education given the growing role of evaluative and procedural techniques in practice today. Tele-ultrasound is a new and promising venture that aims to expand medical knowledge and education to previously unreached or underserved areas. This study aimed to determine the non-inferiority of teaching ultrasound remotely using tele-ultrasound via the Philips Lumify (Philips Medical Systems, Bothell, WA) system, which utilizes video conferencing technology and real-time imaging that can be viewed by the operator and educator simultaneously. METHODS: Three commonly used ultrasound exams were taught and evaluated in 56 ultrasound-naive medical participants: Focused Assessment with Sonography in Trauma (FAST), Lower Extremity Deep Venous Thrombosis (LEDVT) screening, and ultrasound-guided vascular access. The participants were randomized into either in-person traditional learning or tele-ultrasound learning with the Philips Lumify (Philips Medical Systems, Bothell, WA) units. The primary outcome of interest was the ability to perform certain tasks for each exam RESULTS: Competency on each exam was tested across all exams and no inferiority was found between in-person and remote learning (p < 0.05). CONCLUSIONS: Our findings support the use of tele-ultrasound in beginner ultrasound education.
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The importance of type I insulin-like growth factor receptor (IGF-IR) overexpression in mammary tumorigenesis was recently shown in two separate transgenic models. One of these models, the MTB-IGFIR transgenics, was generated in our lab to overexpress IGF-IR in mammary epithelial cells in a doxycycline (Dox)-inducible manner. To complement this transgenic model, primary cells that retained Dox-inducible expression of IGF-IR were isolated from a transgenic mammary tumor. This cell line, RM11A, expressed high levels of IGF-IR, phosphorylated Akt, and phosphorylated extracellular signal-regulated kinase 1/2 in the presence of Dox. IGF-IR overexpression provided the primary tumor cells with a survival advantage in serum-free media and seemed to induce ligand-independent activation of the IGF-IR because RM11A cells cultured in the presence of Dox were largely nonresponsive to exogenous IGFs. IGF-IR overexpression also augmented the growth of RM11A cells in vivo because injection of these cells into mammary glands of wild-type mice produced palpable tumors in 15.8 +/- 3.4 days when the mice were administered Dox, compared with 57.8 +/- 6.3 days in the absence of Dox. DNA microarray analysis revealed a number of genes regulated by IGF-IR, one of which was cyclin D1. Suppression of IGF-IR expression in vitro or in vivo was associated with a decrease in cyclin D1 protein, suggesting that at least some of the proliferative actions of IGF-IR are mediated through cyclin D1. Therefore, this article characterizes the first primary murine mammary tumor cell line with inducible IGF-IR expression. These cells provide a powerful in vitro/in vivo model to examine the function of IGF-IR in mammary tumorigenesis.
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Linhagem Celular Tumoral , Ciclina D1/biossíntese , Regulação Neoplásica da Expressão Gênica , Neoplasias Mamárias Animais/metabolismo , Receptor IGF Tipo 1/metabolismo , Animais , Proliferação de Células , Sobrevivência Celular , Ligantes , Camundongos , Camundongos Transgênicos , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação , RNA Mensageiro/metabolismo , Fatores de TempoRESUMO
Insulin-like growth factor-I and -II (IGF-I and IGF-II) and/or the type I insulin-like growth factor receptor (IGF-IR) have been implicated in a number of human tumors including breast cancer. However, despite being implicated in breast cancer for approximately 25 years and given that transgenic technology has been available for about the same period of time, it is surprising that transgenic mice overexpressing the IGF-IR in the mammary gland have only recently been characterized. This review will describe the effects of IGF-IR overexpression on mammary ductal morphogenesis and mammary tumorigenesis in the two available transgenic models.
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Neoplasias da Mama/metabolismo , Transformação Celular Neoplásica/metabolismo , Glândulas Mamárias Animais/crescimento & desenvolvimento , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Humanas/crescimento & desenvolvimento , Glândulas Mamárias Humanas/metabolismo , Receptor IGF Tipo 1/metabolismo , Animais , Neoplasias da Mama/genética , Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Receptor IGF Tipo 1/genéticaRESUMO
Femoral vein access is often required during resuscitation efforts and when other routes of intravenous access are difficult. This study evaluated by ultrasound the effect of abduction/external rotation of the hip on venous accessibility. This was a prospective repeated measurement study. The common femoral veins of 25 volunteers were scanned transversely inferior to the inguinal ligament with the leg straight and in external rotation/abduction. The diameter of the vein and percent accessible (not posterior to the femoral artery) were determined. Data were analyzed using repeated measures analysis of variance. The mean percentage of the femoral vein accessible with the leg in external rotation/abduction was greater than with the leg straight (82.6 +/- 20.3 vs. 70.4 +/- 26.3, respectively); p < 0.03. External rotation/abduction of the hip may improve the success rate of femoral vein cannulation by increasing the percentage of the femoral vein accessible.
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Cateterismo Venoso Central/métodos , Veia Femoral/anatomia & histologia , Articulação do Quadril/fisiologia , Ressuscitação/métodos , Adulto , Análise de Variância , Serviço Hospitalar de Emergência , Feminino , Veia Femoral/diagnóstico por imagem , Humanos , Masculino , Postura , Amplitude de Movimento Articular , Rotação , UltrassonografiaRESUMO
Mouse models of cancer play an important role in elucidating the molecular mechanisms that contribute to tumorigenesis. The extent to which these models resemble one another and their human counterparts at the molecular level is critical in understanding tumorigenesis. In this study, we carried out a comparative gene expression analysis to generate a detailed molecular portrait of a transgenic mouse model of IGFIR-driven lung cancer. IGFIR-driven tumors displayed a strong resemblance with established mouse models of lung adenocarcinoma, particularly EGFR-driven models highlighted by elevated levels of the EGFR ligands Ereg and Areg. Cross-species analysis revealed a shared increase in human lung adenocarcinoma markers including Nkx2.1 and Napsa as well as alterations in a subset of genes with oncogenic and tumor suppressive properties such as Aurka, Ret, Klf4 and Lats2. Integrated miRNA and mRNA analysis in IGFIR-driven tumors identified interaction pairs with roles in ErbB signaling while cross-species analysis revealed coordinated expression of a subset of conserved miRNAs and their targets including miR-21-5p (Reck, Timp3 and Tgfbr3). Overall, these findings support the use of SPC-IGFIR mice as a model of human lung adenocarcinoma and provide a comprehensive knowledge base to dissect the molecular pathogenesis of tumor initiation and progression.
Assuntos
Neoplasias Pulmonares/genética , MicroRNAs/genética , RNA Mensageiro/genética , Receptores de Somatomedina/genética , Animais , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Fator 4 Semelhante a Kruppel , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Transgênicos , Anotação de Sequência Molecular , Receptores de Somatomedina/metabolismo , Especificidade da Espécie , TranscriptomaRESUMO
STUDY OBJECTIVE: Visualization of the vocal cords and end-tidal capnography are the usual standards in confirming endotracheal tube placement. Vocal cord visualization is, however, not always possible, and capnography is not 100% reliable and requires ventilation of the lungs to confirm placement. The goal of this study is to determine the accuracy of ultrasonography for detecting endotracheal tube placement into the trachea and esophagus in real time. METHODS: This was a prospective, randomized, controlled study. Eligible patients were adults undergoing elective surgery requiring intubation. Exclusion criteria were a history of difficult intubation, abnormal airway anatomy, aspiration risk factors, and esophageal disease. Thirty-three patients were enrolled. After induction of anesthesia and neuromuscular blockade, the anesthesiologist placed the endotracheal tube in the trachea and esophagus in random order with direct laryngoscopy. During the intubations, a high-frequency, linear transducer was placed transversely on the neck at the suprasternal notch. Two emergency physicians, blinded to the order and performance of the intubations, independently recorded the location of the endotracheal tube according to the real-time ultrasonographic image. A 2-by-2 table was used to calculate sensitivity and specificity of the emergency physicians' ability to detect placement of the endotracheal tube. RESULTS: For each physician, the sensitivity for identifying the first intubation as tracheal was 100% (95% confidence interval [CI] 77% to 100%) with a specificity of 100% (95% CI 82% to 100%). One endotracheal tube was unintentionally placed twice in the esophagus, but both tube placements were identified as esophageal by the emergency physicians. CONCLUSION: In this pilot study, 2 emergency physicians experienced in ultrasonography accurately detected placement of endotracheal tubes during intubation with ultrasonography in select patients in the controlled environment of the operating room. Future studies should examine the use of ultrasonography to visualize endotracheal tube placement in real time by emergency physicians with less ultrasonographic training; use of the technique in the emergency department on a wider range of patients, including patients with difficult airways; and assessment of the utility of ultrasonography in confirmation of endotracheal tube position in already intubated patients.