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1.
Ann Surg ; 2024 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-38606552

RESUMEN

OBJECTIVE: The objective of this study is to explore the patient characteristics and practice patterns of non-certified surgeons who treat Medicare patients in the United States. SUMMARY BACKGROUND DATA: While most surgeons in the United States are board-certified, non-certified surgeons are permitted to practice in many locations. At the same time, surgical workforce shortages threaten access to surgical care for many patients. It is possible that non-certified surgeons may be able to help fill these access gaps. However, little is known about the practice patterns of non-certified surgeons. METHODS: A 100% sample of Medicare claims data from 2014-2019 were used to identify practicing general surgeons. Surgeons were categorized as certified or non-certified in general surgery​​ based on data from the American Board of Surgery. Surgeon practice patterns and patient characteristics were analyzed. RESULTS: A total of 2,097,206 patient cases were included in the study. These patients were treated by 16,076 surgeons, of which 6% were identified as non-certified surgeons. Compared to certified surgeons, non-certified surgeons were less frequently fellowship-trained (20.5% vs. 24.2%, P=0.008) and more likely to be a foreign medical graduate (14.5% vs. 9.2%, P<0.001). Non-certified surgeons were more frequently practicing in for-profit hospitals (21.2% vs. 14.2%, P<0.001) and critical access hospitals (2.2% vs. 1.3%, P<0.001), and were less likely to practice in a teaching hospital (63.2% vs. 72.4%, P<0.001). Compared to certified surgeons, non-certified surgeons treated more non-White patients (19.6% vs. 14%, P<0.001) as well as a higher percentage of patients in the two lowest socioeconomic status (SES) quintiles (36.2% vs. 29.2%, P<0.001). Operations related to emergency admissions were more common amongst non-certified surgeons (68.8% vs. 55.7%, P<0.001). There were no differences in gender or age of the patients treated by certified and non-certified surgeons. CONCLUSION: For Medicare patients, non-certified surgeons treated more patients who are non-White, of lower SES, and in more rural, critical-access hospitals.

2.
Pediatr Blood Cancer ; 71(5): e30933, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38430473

RESUMEN

INTRODUCTION: In complex pediatric surgical oncology, surgical planning is contingent upon data gathered from preoperative imaging. Three-dimensional (3D) modeling and printing has been shown to be beneficial for adult presurgical planning, though pediatric literature is less robust. The study reviews our institutional experience with the use of 3D image segmentation and printed models in approaching resection of extracranial solid tumors in children. METHODS: This is a single institutional series from 2021 to 2023. Models were based on computed tomography and magnetic resonance imaging studies, optimized for 3D imaging. The feasibility and creation of the models is reviewed, including specific techniques, software, and printing materials from our institution. Clinical implications for surgical planning are also described, along with detailed preoperative and intraoperative images. RESULTS: 3D modeling and printing was performed for four pediatric patients diagnosed with extracranial solid tumors. Diagnoses included Ewing sarcoma, hepatoblastoma, synovial sarcoma, and osteosarcoma. No intraoperative complications or discrepancies with the preoperative 3D-printed model were noted. No evidence of local recurrence was identified in any patient thus far. CONCLUSION: Our institutional series demonstrates a wide spectrum of clinical application for 3D modeling and printing technology within pediatric surgical oncology. This technology may aid in surgical planning for both resection and reconstruction, can be applied to a diverse breadth of diagnoses, and may potentially augment patient and/or family education about their condition.


Asunto(s)
Sarcoma de Ewing , Sarcoma Sinovial , Niño , Humanos , Imagenología Tridimensional/métodos , Imagen por Resonancia Magnética , Sarcoma de Ewing/diagnóstico por imagen , Sarcoma de Ewing/cirugía , Tomografía Computarizada por Rayos X
3.
J Surg Educ ; 81(4): 503-513, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38403502

RESUMEN

INTRODUCTION: While competency-based training is at the forefront of educational innovation in General Surgery, Pediatric Surgery training programs should not wait for downstream changes. There is currently no consensus on what it means for a pediatric surgery fellow to be "practice-ready". In this study, we aimed to provide a framework for better defining competency and practice readiness in a way that can support the Milestones system and allow for improved assessment of pediatric surgery fellows. METHODS: For this exploratory qualitative study, we developed an interview guide with nine questions focused on how faculty recognize competency and advance autonomy among pediatric surgery fellows. Demographic information was collected using an anonymous online survey platform. We iteratively reviewed data from each interview to ensure adequate information power was achieved to answer the research question. We used inductive reasoning and thematic analysis to determine appropriate codes. Additionally, the Dreyfus model was used as a framework to guide interpretation and contextualize the responses. Through this method, we generated common themes. RESULTS: A total of 19 pediatric surgeons were interviewed. We identified four major themes from 127 codes that practicing pediatric surgeons associate with practice-readiness of a fellow: skill-based competency, the recognition and benefits of struggle, developing expertise and facilitating autonomy, and difficulties in variability of evaluation. While variability in evaluation is not typically included in the concept of practice readiness, assessment and evaluation were described by study participants as essential aspects of how practicing pediatric surgeons perceive practice readiness and competency in pediatric surgery fellows. Competency was further divided into interpersonal versus technical skills. Sub-themes within struggle included personal and professional struggle, benefits of struggle and how to identify and assist those who are struggling. Autonomy was commonly stated as variable based on the attending. CONCLUSION: Our analysis yielded several themes associated with practice readiness of pediatric surgery fellows. We aim to further refine our list of themes using the Dreyfus Model as our interpretive framework and establish consensus amongst the community of pediatric surgeons in order to define competency and key elements that make a fellow practice-ready. Further work will then focus on establishing assessment metrics and educational interventions directed at achieving such key elements.


Asunto(s)
Especialidades Quirúrgicas , Cirujanos , Niño , Humanos , Becas , Competencia Clínica , Especialidades Quirúrgicas/educación , Encuestas y Cuestionarios
4.
J Surg Educ ; 81(2): 172-177, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38158276

RESUMEN

Competency-based medical education (CBME) is the future of medical education and relies heavily on high quality assessment. However, the current assessment practices employed by many general surgery graduate medical education training programs are subpar. Assessments often lack reliability and validity evidence, have low faculty engagement, and differ from program to program. Given the importance of assessment in CBME, it is critical that we build a better assessment system for measuring trainee competency. We propose that an ideal system of assessment is standardized, evidence-based, comprehensive, integrated, and continuously improving. In this article, we explore these characteristics and propose next steps to achieve such a system of assessment in general surgery.


Asunto(s)
Educación de Postgrado en Medicina , Educación Médica , Humanos , Reproducibilidad de los Resultados , Educación Basada en Competencias , Docentes Médicos , Competencia Clínica
5.
J Surg Res ; 293: 670-675, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37839098

RESUMEN

INTRODUCTION: Given the rapidly changing landscape of residency applications, many medical students struggle to identify guidance from faculty advisors. Additionally, faculty advisors may find it difficult to maintain up-to-date knowledge on changes such as the new supplemental application. These gaps could potentially lead to inequitable advising. The objective of this study was to identify both students' and faculty's perceived barriers and expectations for residency application advising. METHODS: Anonymous surveys were administered to both fourth-year medical students and faculty advisors at a single institution within 2 mo of the residency application deadline. Survey questions assessed student and faculty barriers to establishing the advisor-advisee relationships, as well as expectations of the advisor role. Surveys were analyzed using descriptive statistics. RESULTS: We identified that the majority of students (57%) did not have a faculty advisor within weeks of the application deadline, and an equal amount felt that finding an advisor was either somewhat difficult or extremely difficult. Of all the students, 60% felt their biggest barrier was not knowing how to find an advisor. Though faculty felt equipped to advise students, 75% of faculty in the participating specialties had advising concerns regarding the supplemental application or were unaware of the changes. CONCLUSIONS: We identified gaps in the residency application advising process from both student and faculty perspectives. Future work involves increasing awareness of the resources and opportunities available to students to improve advising relationships. Standardized training tools and resources for faculty will result in more consistent and reliable faculty advising.


Asunto(s)
Internado y Residencia , Estudiantes de Medicina , Humanos , Motivación , Docentes Médicos , Encuestas y Cuestionarios
6.
Ann Surg Open ; 4(3): e306, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37746606

RESUMEN

We are the multi-institutional organization known as the Collaboration of Surgical Education Fellows (CoSEF). We've collectively reflected on our range of experiences across the country and identified 3 principles which promote a successful intern experience: (1) Own your patients; (2) Treat people like people; and (3) Take care of yourself.

7.
J Surg Educ ; 80(11): 1516-1521, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37385931

RESUMEN

OBJECTIVE: Feedback is critical for learning, however, gender differences exist in the quality of feedback that trainees receive. For example, narrative feedback on surgical trainees' end-of-block rotations differs based on trainee-faculty gender dyads, with female faculty giving higher quality feedback and male trainees receiving higher quality feedback. Though this represents evidence of gender bias in global evaluations, there is limited understanding of how much bias might be present in operative workplace-based assessments (WBAs). In this study, we explore the quality of narrative feedback among trainee-faculty gender dyads in an operative WBA. DESIGN: A previously validated natural language processing model was used to examine instances of narrative feedback and assign a probability of being characterized as high quality feedback (defined as feedback which was relevant as well as corrective and/or specific). A linear mixed model was performed, with probability of high quality feedback as the outcome, and resident gender, faculty gender, PGY, case complexity, autonomy rating, and operative performance rating as explanatory variables. PARTICIPANTS: Analyses included 67,434 SIMPL operative performance evaluations (2,319 general surgery residents, 70 institutions) collected from September 2015 through September 2021. RESULTS: Of 36.3% evaluations included narrative feedback. Male faculty were more likely to provide narrative feedback compared to female faculty. Mean probabilities of receiving high quality feedback ranged from 81.6 (female faculty-male resident) to 84.7 (male faculty-female resident). Model-based results demonstrated that female residents were more likely to receive high quality feedback (p < 0.01), however, there was no significant difference in probability of high quality narrative feedback based on faculty-resident gender dyad (p = 0.77). CONCLUSIONS: Our study revealed resident gender differences in the probability of receiving high-quality narrative feedback following a general surgery operation. However, we found no significant differences based on faculty-resident gender dyad. Male faculty were more likely to provide narrative feedback compared to their female colleagues. Further research using general surgery resident-specific feedback quality models may be warranted.


Asunto(s)
Cirugía General , Internado y Residencia , Humanos , Masculino , Femenino , Retroalimentación , Competencia Clínica , Sexismo , Educación de Postgrado en Medicina/métodos , Cirugía General/educación
8.
J Surg Educ ; 80(11): 1493-1502, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37349156

RESUMEN

OBJECTIVE: Assessing surgical trainee operative performance is time- and resource-intensive. To maximize the utility of each assessment, it is important to understand which assessment activities provide the most information about a trainee's performance. The objective of this study is to identify the procedures that best differentiate performance for each general surgery postgraduate year (PGY)-level, leading to recommendations for targeted assessment. DESIGN: The Society for Improving Medical Professional Learning (SIMPL) operative performance ratings were modeled using a multilevel Rasch model which identified the highest and lowest performing trainees for each PGY-level. For each procedure within each PGY-level, a procedural performance discrimination index was calculated by subtracting the proportion of "practice-ready" ratings of the lowest performing trainees from the proportion of "practice-ready" ratings of the highest performing trainees. Four-quadrant plots were created using the median procedure volume and median discrimination index for each PGY-level. All procedures within the upper right quadrant were considered "highly differentiating, high volume" procedures. SETTING: This study was conducted across 70 general surgical residency programs who are members of the SIMPL collaborative. PARTICIPANTS: A total of 54,790 operative performance evaluations of categorical general surgery trainees were collected between 2015 and 2021. Trainees who had at least 1 procedure in common were included. Procedures with less than 25 evaluations per training year were excluded. RESULTS: The total number of evaluations per procedure ranged from 25 to 2,131. Discrimination values were generated for 51 (PGY1), 54 (PGY2), 92 (PGY3), 105 (PGY4), and 103 (PGY5) procedures. Using the above criteria, a total of 12 (PGY1), 15 (PGY2), 22 (PGY3), 21 (PGY4), and 28 (PGY5) procedures were identified as highly differentiating, high volume procedures. CONCLUSIONS: Our study draws on national data to identify procedures which are most useful in differentiating trainee operative performance at each PGY-level. This list of procedures can be used to guide targeted assessment and improve assessment efficiency.


Asunto(s)
Cirugía General , Internado y Residencia , Humanos , Educación de Postgrado en Medicina/métodos , Competencia Clínica , Evaluación Educacional/métodos , Cirugía General/educación
9.
J Surg Res ; 282: 225-231, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36327704

RESUMEN

INTRODUCTION: The virtual residency application season posed numerous challenges for the 2021 residency match process. Many residency programs are exploring relationships between this novel format and the match process. The purpose of this study was to compare one of the largest general surgery residency program's applications and match data from preCOVID years to the 2021 virtual cycle. MATERIALS AND METHODS: A retrospective review was performed of applicants to a single general surgery residency program from 2017 to 2021. The primary outcome was the number of locally matched applicants. The secondary outcomes were the total number of applications, change in applicant demographics, and variability of the geographic spread during this study period. Chi-square tests of independence, Fisher's exact tests, and negative binomial regression were performed. RESULTS: 6819 applicants were included in the study. In 2021, an increase in applications was observed. The distribution of 2021 applications was statistically different from previous years regarding gender and race (P < 0.0001). The 2021 application cycle had a greater proportion of applicants from the United States (P < 0.0001) and southern US medical schools (P = 0.008). While the 2021 cycle had significantly more interviews (P = 0.013), there were no significant differences in the demographic composition of interviewees. During the 2021 application year, all 11 matches were from southern medical schools and there was a trend to more matched female applicants compared to previous years. CONCLUSIONS: During the 2021 COVID-19 virtual match cycle, an increase in both the number of applications and number of interviews for general surgery residency was identified. The characteristics of applicants who interviewed and matched were not different when compared to previous years. As virtual interviews may become more commonplace, it is important to assess all factors that may be involved in the dynamic residency application process.


Asunto(s)
COVID-19 , Cirugía General , Internado y Residencia , Femenino , Humanos , Estados Unidos , COVID-19/epidemiología , Facultades de Medicina , Estudios Retrospectivos , Cognición , Cirugía General/educación
10.
Development ; 149(23)2022 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-36504079

RESUMEN

There are fundamental differences in how neonatal and adult intestines absorb nutrients. In adults, macromolecules are broken down into simpler molecular components in the lumen of the small intestine, then absorbed. In contrast, neonates are thought to rely on internalization of whole macromolecules and subsequent degradation in the lysosome. Here, we identify the Maf family transcription factors MAFB and c-MAF as markers of terminally differentiated intestinal enterocytes throughout life. The expression of these factors is regulated by HNF4α and HNF4γ, master regulators of enterocyte cell fate. Loss of Maf factors results in a neonatal-specific failure to thrive and loss of macromolecular nutrient uptake. RNA-Seq and CUT&RUN analyses defined an endo-lysosomal program as being downstream of these transcription factors. We demonstrate major transcriptional changes in metabolic pathways, including fatty acid oxidation and increases in peroxisome number, in response to loss of Maf proteins. Finally, we show that loss of BLIMP1, a repressor of adult enterocyte genes, shows highly overlapping changes in gene expression and similar defects in macromolecular uptake. This work defines transcriptional regulators that are necessary for nutrient uptake in neonatal enterocytes.


Asunto(s)
Factores de Transcripción Maf , Nutrientes , Ratones , Animales , Transporte Biológico , Diferenciación Celular , Factores de Transcripción/genética , Proteínas Proto-Oncogénicas c-maf
11.
J Surg Res ; 277: 279-289, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35525210

RESUMEN

INTRODUCTION: Traumatic injury is the leading cause of pediatric mortality and morbidity in the United States. Pediatric trauma survivors requiring inpatient rehabilitation (IPR) require coordinated, multispecialty follow-up. Knowledge of the nature and level of disability is necessary for planning this continued care that is specific to the needs of pediatric trauma patients. This study aims to describe the outcomes of pediatric and adolescent trauma patients using measures of functional progression. MATERIALS AND METHODS: A retrospective review of trauma patients aged ≤18 y admitted to IPR between January 2018 and December 2020 at the only certified pediatric rehabilitation center in the region was performed. RESULTS: Ninety five children and adolescents were admitted to IPR after traumatic injury with diagnoses of multitrauma (MT, N = 18), traumatic brain injury (TBI, N = 59), and spinal cord injury (SCI, N = 18). School aged children returned to school at high rates for all injury types (MT: 86.7%, TBI: 97.4%, SCI: 93.8%, P = ns). All groups had similar hospital and rehabilitation length of stay, and most patients required a durable medical equipment at discharge (79%). Using pediatric functional independence measure scoring progression from admission to discharge from IPR, SCI patients made significant improvement in bladder function and the least improvement in stair function. Patients sustaining a TBI made significant improvement in memory and comprehension tasks. CONCLUSIONS: Pediatric and adolescent trauma patients admitted to IPR had a positive progression during their therapy but required variable ongoing care depending on the mechanism of injury. Excellent rates of returning to school were seen across the three injury types.


Asunto(s)
Experiencias Adversas de la Infancia , Lesiones Traumáticas del Encéfalo , Adolescente , Niño , Humanos , Pacientes Internos , Tiempo de Internación , Alta del Paciente , Recuperación de la Función , Centros de Rehabilitación , Estudios Retrospectivos , Resultado del Tratamiento , Estados Unidos
12.
Am Surg ; 88(5): 901-907, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-34727724

RESUMEN

PURPOSE/BACKGROUND: The role of minimally invasive surgery (MIS) for the surgical treatment of diverticular disease is evolving. The aim of this study is to compare the outcomes of MIS colectomy to those of open surgery for patients with acute diverticulitis requiring urgent surgery. METHODS: The American college of Surgeons National Surgical Quality Improvement Project database was queried for all patients undergoing an urgent colectomy for acute diverticulitis between 2013 and 2018. The patients were then divided into 2 groups: MIS and open. Baseline characteristics and short-term outcomes were compared using univariable and multivariable regression analyses. RESULTS/OUTCOMES: 3487 patients were included in the analysis. Of these, 1272 (36.5%) underwent MIS colectomy and 2215 (63.5%) underwent open colectomy. Patients undergoing MIS colectomy were younger (58.7 vs 61.9 years) and less likely to be American Society of Anesthesiologists Classification (ASA) III (52.5 vs 57.9%) or IV (6.3 vs 10.5%). After adjusting for baseline differences, the odds of mortality for MIS and open groups were similar. While there was no difference in short-term complications between groups, the odds of developing an ileus were lower following MIS colectomy (OR .61, 95% CI: .49, .76). Both total length of stay (LOS) (12.3 vs 13.9 days) and post-operative LOS (7.6 days vs 9.5 days) were shorter for MIS colectomy. Minimally invasive surgery colectomy added an additional 40 minutes of operative time (202.2 vs 160.1 min). CONCLUSION/DISCUSSION: Minimally invasive surgery colectomy appears to be safe for patients requiring urgent surgical management for acute diverticulitis. Decreased incidence of ileus and shorter LOS may justify any additional operative time for MIS colectomy in suitable candidates.


Asunto(s)
Diverticulitis , Ileus , Obstrucción Intestinal , Laparoscopía , Colectomía/efectos adversos , Diverticulitis/complicaciones , Humanos , Laparoscopía/efectos adversos , Tiempo de Internación , Procedimientos Quirúrgicos Mínimamente Invasivos/efectos adversos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Resultado del Tratamiento
13.
Mol Biol Cell ; 32(21): ar29, 2021 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-34432485

RESUMEN

Proper spindle orientation is required for asymmetric cell division and the establishment of complex tissue architecture. In the developing epidermis, spindle orientation requires a conserved cortical protein complex of LGN/NuMA/dynein-dynactin. However, how microtubule dynamics are regulated to interact with this machinery and properly position the mitotic spindle is not fully understood. Furthermore, our understanding of the processes that link spindle orientation during asymmetric cell division to cell fate specification in distinct tissue contexts remains incomplete. We report a role for the microtubule catastrophe factor KIF18B in regulating microtubule dynamics to promote spindle orientation in keratinocytes. During mitosis, KIF18B accumulates at the cell cortex, colocalizing with the conserved spindle orientation machinery. In vivo we find that KIF18B is required for oriented cell divisions within the hair placode, the first stage of hair follicle morphogenesis, but is not essential in the interfollicular epidermis. Disrupting spindle orientation in the placode, using mutations in either KIF18B or NuMA, results in aberrant cell fate marker expression of hair follicle progenitor cells. These data functionally link spindle orientation to cell fate decisions during hair follicle morphogenesis. Taken together, our data demonstrate a role for regulated microtubule dynamics in spindle orientation in epidermal cells. This work also highlights the importance of spindle orientation during asymmetric cell division to dictate cell fate specification.


Asunto(s)
Cinesinas/metabolismo , Microtúbulos/fisiología , Huso Acromático/fisiología , Animales , Complejo Dinactina/metabolismo , Dineínas/metabolismo , Células Epidérmicas/metabolismo , Epidermis/metabolismo , Femenino , Queratinocitos/metabolismo , Cinesinas/fisiología , Masculino , Ratones , Ratones Noqueados , Microtúbulos/metabolismo , Mitosis , Cultivo Primario de Células , Huso Acromático/metabolismo
14.
Curr Biol ; 30(4): R144-R149, 2020 02 24.
Artículo en Inglés | MEDLINE | ID: mdl-32097634

RESUMEN

In this Primer, Moreci and Lechler follow the lifetime of an epidermal cell from its birth to its ultimate death, and detail how this journey is necessary for epidermal function.


Asunto(s)
Diferenciación Celular , Células Epidérmicas/fisiología , Epidermis/fisiología , Animales , Epidermis/crecimiento & desarrollo
15.
Trauma Case Rep ; 22: 100211, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31338406

RESUMEN

INTRODUCTION: Splenic rupture after laparoscopic surgery is a very rare complication. In this study, we report a case of a splenic laceration that occurred during a laparoscopic gastrostomy tube placement. The theorized mechanism in this case was acute disruption of a peri-splenic hematoma. CASE REPORT: A 64-year-old African-American male presented after a motor vehicle accident with multiple injuries and was admitted to a surgical intensive care unit, where he declined from ICU days 6 through 11. The patient underwent tracheostomy and laparoscopic gastrostomy tube placement given his significant neurologic deficits. Intraoperatively, the patient developed hypotension, leading to the discovery of hemoperitoneum and necessitating an emergent open splenectomy. CONCLUSION: Splenic rupture following laparoscopic procedures is a very rare phenomenon. In this case, we believe the splenic rupture was secondary to an acute disruption of a previously hemostatic splenic hematoma involving the abdominal wall during creation of capnoperitoneum.

16.
Sci Rep ; 9(1): 4452, 2019 03 14.
Artículo en Inglés | MEDLINE | ID: mdl-30872705

RESUMEN

The elevated level of Steroidogenic Factor 1 (Nr5a1, Sf-1) expression in the male gonadal development pathway, post sex determination, implies a vital role in testis gonadal differentiation. In this study we generated Sertoli cell-specific Nr5a1 KO mice (SC-SF-1-/-) at E14.5, which coincides with testis development post sex determination, using the Amh-Cre mouse model. Analysis of SC-SF-1-/- (Sertoli cell specific Nr5a1 knockout) testes demonstrated apoptosis as early as E15. Further analysis revealed that SC-SF-1-/- gonads displayed lower MDM2 levels resulting in elevated TP53 levels, which we believe may lead to apoptosis of the Sertoli cell population, inferring the possibility that NR5A1 directly regulates MDM2 expression. By E15.5, the Sertoli cell and germ cell population declined in SC-SF-1-/- mice resulting in the disruption of seminiferous cords with limited cord structure remaining at E18.5. Due to the loss of Sertoli and germ cells, the testis weights of SC-SF-1-/- mice at 6-weeks were much reduced; however, SC-SF-1-/- seminal vesicles weights were comparable suggesting intact Leydig cell androgen production. We conclude that NR5A1 regulates the TP53 pathway during development, is essential for fetal Sertoli cell survival and controls the cell cycle of Sertoli cells during differentiation.


Asunto(s)
Células de Sertoli/citología , Factor Esteroidogénico 1/metabolismo , Testículo/citología , Testículo/embriología , Animales , Hormona Antimülleriana/metabolismo , Apoptosis/genética , Supervivencia Celular , Femenino , Regulación del Desarrollo de la Expresión Génica , Integrasas/genética , Masculino , Ratones Noqueados , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Factor de Transcripción SOX9/genética , Células de Sertoli/fisiología , Procesos de Determinación del Sexo , Factor Esteroidogénico 1/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo
17.
Cell Rep ; 22(6): 1509-1521, 2018 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-29425506

RESUMEN

To fulfill bioenergetic demands of activation, T cells perform aerobic glycolysis, a process common to highly proliferative cells in which glucose is fermented into lactate rather than oxidized in mitochondria. However, the signaling events that initiate aerobic glycolysis in T cells remain unclear. We show T cell activation rapidly induces glycolysis independent of transcription, translation, CD28, and Akt and not involving increased glucose uptake or activity of glycolytic enzymes. Rather, TCR signaling promotes activation of pyruvate dehydrogenase kinase 1 (PDHK1), inhibiting mitochondrial import of pyruvate and facilitating breakdown into lactate. Inhibition of PDHK1 reveals this switch is required acutely for cytokine synthesis but dispensable for cytotoxicity. Functionally, cytokine synthesis is modulated via lactate dehydrogenase, which represses cytokine mRNA translation when aerobic glycolysis is disengaged. Our data provide mechanistic insight to metabolic contribution to effector T cell function and suggest that T cell function may be finely tuned through modulation of glycolytic activity.


Asunto(s)
Linfocitos T CD8-positivos/metabolismo , Glucólisis/inmunología , Activación de Linfocitos/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Animales , Linfocitos T CD8-positivos/inmunología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Serina-Treonina Quinasas/inmunología , Proteínas Serina-Treonina Quinasas/metabolismo , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , Receptores de Antígenos de Linfocitos T/inmunología , Transducción de Señal/inmunología
19.
Immunity ; 45(2): 374-88, 2016 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-27496732

RESUMEN

Although tumor-specific T cells recognize cancer cells, they are often rendered dysfunctional due to an immunosuppressive microenvironment. Here we showed that T cells demonstrated persistent loss of mitochondrial function and mass when infiltrating murine and human tumors, an effect specific to the tumor microenvironment and not merely caused by activation. Tumor-infiltrating T cells showed a progressive loss of PPAR-gamma coactivator 1α (PGC1α), which programs mitochondrial biogenesis, induced by chronic Akt signaling in tumor-specific T cells. Reprogramming tumor-specific T cells through enforced expression of PGC1α resulted in superior intratumoral metabolic and effector function. Our data support a model in which signals in the tumor microenvironment repress T cell oxidative metabolism, resulting in effector cells with metabolic needs that cannot be met. Our studies also suggest that modulation or reprogramming of the altered metabolism of tumor-infiltrating T cells might represent a potential strategy to reinvigorate dysfunctional T cells for cancer treatment.


Asunto(s)
Neoplasias del Colon/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Mitocondrias/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Linfocitos T/inmunología , Animales , Línea Celular Tumoral , Reprogramación Celular , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neoplasias Experimentales , Proteína Oncogénica v-akt/metabolismo , Estrés Oxidativo , PPAR gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Transducción de Señal , Microambiente Tumoral
20.
J Vis Exp ; (111)2016 05 27.
Artículo en Inglés | MEDLINE | ID: mdl-27286290

RESUMEN

Gene expression in different tissues is often controlled by alternative promoters that result in the synthesis of mRNA with unique - usually untranslated - first exons. Bcrp1 (Abcg2), the murine orthologue of the ABC transporter Breast Cancer Resistance Protein (BCRP, ABCG2), has at least four alternative promoters that are designated by the corresponding four alternative first exons produced: E1U, E1A, E1B, and E1C. Herein, in-silico protocols are presented to predict alternative promoter usage for Bcrp1. Furthermore, reporter assay methods are described to produce reporter constructs for alternative promoters and to determine the functionality of putative promoters upstream of the alternative first exons that are identified.


Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Regiones Promotoras Genéticas , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/biosíntesis , Animales , Secuencia de Bases , Exones , Regulación de la Expresión Génica , Humanos , Ratones , ARN Mensajero/biosíntesis , ARN Mensajero/genética
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