Toward low-cost gene therapy: mRNA-based therapeutics for treatment of inherited retinal diseases.

Inherited retinal diseases (IRDs) stem from genetic mutations that result in vision impairment. Gene therapy shows promising therapeutic potential, exemplified by the encouraging initial results with voretigene neparvovec. Nevertheless, the associated costs impede widespread access, particularly in low-to-middle income countries. The primary challenge remains: how can we make these therapies globally affordable? Leveraging advancements in mRNA therapies might offer a more economically viable alternative. Furthermore, transitioning to nonviral delivery systems could provide a dual benefit of reduced costs and increased scalability. Relevant stakeholders must collaboratively devise and implement a research agenda to realize the potential of mRNA strategies in equitable access to treatments to prevent vision loss.

Lumbar paraspinal intramuscular myxoma: A case report.

Background: With an estimated incidence of about 1 case/million patients, paravertebral intramuscular myxomas represent a rare cause of lumbar pain. Rather, they typically occur in the heart and in bone tissues. Case Description: A 64-year-old female presented with a protracted course of nocturnal lumbar pain that radiated to the anterior aspect of the right thigh accompanied by numbness. She reported a slow-growing right paramedian lumbar mass in the previous months. The magnetic resonance (MR) showed a right lumbar paravertebral intramuscular mass at the L3 level (i.e., 70 × 50 mm) that had well-defined margins, and markedly enhanced with gadolinium. Following gross total "en bloc" tumor resection, the patient fully recovered. Pathologically, the myofibroblastic lesion proved to be an intramuscular myxoma without malignant changes. Conclusion: A 64-year-old female presented with a slow-growing MR-documented right paramedian lumbar L3 mass responsible for proximal right-thigh numbness. Following "en bloc" gross total removal of the benign intramuscular myxoma, the patient was asymptomatic.

Estilos de aprendizagem na graduação em Enfermagem: um caso no Nordeste brasileiro / Estilos de aprendizaje en el pregrado de Enfermería: estudio de caso en el noreste de Brasil / Learning styles in nursing graduation: A case study in northeastern Brazil

Objetivo: apresentar o perfil sociodemográfico e analisar os estilos de aprendizagem de acadêmicos de Enfermagem de uma universidade no Nordeste brasileiro. Materiais e método: estudo de caso, com abordagem quantitativa, cuja coleta foi realizada em dezembro de 2019, por meio de um questionário sociodemográfico e do Inventário de Estilos de Aprendizagem de Kolb. Os dados obtidos foram analisados por meio da estatística descritiva simples. Resultados: o perfil convergente (37%) apareceu como o mais prevalente na amostra, sendo predominante também no 4º, 6º e 7º períodos. Já o perfil assimilador (33%), segundo mais presente entre os estudantes analisados, apresentou maioria no 1º e 2º períodos. O 3º período obteve o mesmo percentual dos perfis convergente e assimilador. Por fim, o 5º período divergiu dos demais por apresentar maioria do perfil acomodador. Conclusões: a compreensão das preferências de aprendizagem dos acadêmicos de Enfermagem é capaz de potencializar as metodologias aplicadas em sala de aula conforme os objetivos e necessidades mapeados a partir dessa avaliação inicial. O alinhamento entre estilos de aprendizagem e métodos de ensino pode ainda subsidiar reformulações estratégicas que visem melhor desenvolver as competências formativas do estudante.

Objetivo: presentar el perfil sociodemográfico de los estudiantes de Enfermería de una universidad del noreste de Brasil y analizar sus estilos de aprendizaje. Materiales y método: estudio de caso con enfoque cuantitativo, cuya recolección de datos se realizó en diciembre de 2019 a través de un cuestionario sociodemográfico y el uso del Inventario de Estilos de Aprendizaje de Kolb. Los datos obtenidos fueron analizados mediante estadística descriptiva simple. Resultados: el perfil convergente (37 %) fue el más prevalente en la muestra, siendo también predominante en los semestres 4, 6 y 7. El perfil asimilador (33 %) fue el segundo más recurrente entre los estudiantes analizados, siendo prevalente en los semestres 1 y 2. El semestre 3 reportó el mismo porcentaje para los perfiles convergente y asimilador. Finalmente, el semestre 5 se diferenció de los demás, porque la mayoría de los estudiantes se identifica con el perfil acomodador. Conclusiones: la comprensión de las preferencias de aprendizaje de los estudiantes de Enfermería permite potenciar las metodologías aplicadas en el aula con base en los objetivos y las necesidades identificadas a partir de este diagnóstico inicial. La alineación entre los estilos de aprendizaje y los métodos de enseñanza puede contribuir a generar ajustes estratégicos para desarrollar las habilidades de formación de los estudiantes de una mejor manera.

Objective: To present the sociodemographic profile of nursing students at a university in northeastern Brazil and analyze their learning styles. Materials and method: Case study under a quantitative approach, whose data were collected in December 2019 through a sociodemographic questionnaire and the Kolb Learning Styles Inventory. The data obtained were analyzed using simple descriptive statistics. Results: The convergent profile (37%) appears as the most prevalent in the sample, being also predominant in the 4th, 6th and 7th periods. The assimilator profile (33%) was the second most representative style among students, being more present in the 1st and 2nd periods. The 3rd period reported the same percentage for the converging and assimilating profiles. Finally, the 5th period diverged from the others since most students were classified in the accommodating profile. Conclusions: Understanding the learning preferences of nursing students allows enhancing in-class methodologies based on the objectives and needs mapped out from this initial assessment. The alignment between learning styles and teaching methods could support strategic reformulations in order to better develop student training skills.

Arteriovenous fistula of the filum terminale masqueraded as a failed back surgery syndrome - A case report and review of literature.

BACKGROUND: The filum terminale arteriovenous fistulas (FTAVFs) are a very rare type of spinal vascular malformation. Clinically, these lesions could present with a progressive ascending myelopathy also called FoixAlajouanine syndrome. Due to the rarity of these vascular malformation, some can be misdiagnosed, submitted to unnecessary spinal surgery, and even masqueraded as a failed back surgery syndrome. Based on the present case and related literature, we review all the cases with similar history and describe factors that should raise awareness for diagnosis of this spinal vascular malformation. CASE DESCRIPTION: We present a case of a patient with a FTAVF at the level of L5-S1 that presented with a FoixAlajouanine syndrome. He had been previously submitted to a lumbar decompressive laminectomy without sustained improvement. After the identification and surgical treatment of the vascular malformation, he had progressive neurological improvement. CONCLUSION: FTAVF is a very rare spinal intradural spinal vascular malformation that can be masqueraded as a failed back surgery syndrome. In these cases, signs of ascending myelopathy should prompt awareness and vascular voids must be carefully evaluated in MRI.

Cervical spine multiple myeloma and isolated radiotherapy.

Multiple myeloma is a hematologic malignancy frequently presenting with spinal lytic lesions. The authors report the case of a patient with an extensively destructive osteolytic MM lesion in the cervical spine treated exclusively with radiotherapy. Computed tomography and magnetic resonance imaging scans showed an arrest of further progression of instability and resolution of the lytic lesion, showing signs of new bone formation. Whereas surgery should be considered for cases of spinal instability and potential neurological injury, this case demonstrates that isolated radiotherapy can be used in select cases to treat MM lesions and restore the structural integrity of the spinal elements.

Postoperative Brown-Séquard syndrome: case report and review of the literature.

Brown-Séquard syndrome (BSS) is a rare neurological condition caused by a hemi-lesion of the spinal cord and was first described in the 1800s. BSS is characterized by an ipsilateral absence of motor control and discriminatory/proprioceptive/vibratory sensation at and below the spinal level involved, associated with loss of contralateral temperature and pain sensation a couple of vertebral segments below the lesion. BSS is commonly associated with trauma, but can also be iatrogenic. The authors report a case of a patient who presented with neoplastic dorsal spinal cord compression and developed a BSS after surgical decompression and review of the literature of postoperative BSS cases.

HIF-transcribed p53 chaperones HIF-1α.

Chronic hypoxia is associated with a variety of physiological conditions such as rheumatoid arthritis, ischemia/reperfusion injury, stroke, diabetic vasculopathy, epilepsy and cancer. At the molecular level, hypoxia manifests its effects via activation of HIF-dependent transcription. On the other hand, an important transcription factor p53, which controls a myriad of biological functions, is rendered transcriptionally inactive under hypoxic conditions. p53 and HIF-1α are known to share a mysterious relationship and play an ambiguous role in the regulation of hypoxia-induced cellular changes. Here we demonstrate a novel pathway where HIF-1α transcriptionally upregulates both WT and MT p53 by binding to five response elements in p53 promoter. In hypoxic cells, this HIF-1α-induced p53 is transcriptionally inefficient but is abundantly available for protein-protein interactions. Further, both WT and MT p53 proteins bind and chaperone HIF-1α to stabilize its binding at its downstream DNA response elements. This p53-induced chaperoning of HIF-1α increases synthesis of HIF-regulated genes and thus the efficiency of hypoxia-induced molecular changes. This basic biology finding has important implications not only in the design of anti-cancer strategies but also for other physiological conditions where hypoxia results in disease manifestation.

A curricularização da extensão na graduação em saúde: a experiência de um curso de Enfermagem / The inclusion of university extension in the curriculum of health graduation course: the experience of a Nursing program

Este estudo tem como objetivo descrever o processo de curricularização da extensão em um curso de graduação em enfermagem. Modela ­se em um relato de experiência desenvolvido por meio da vivência dos autores no módulo curricular Práticas Interdisciplinares em Ensino Pesquisa e Extensão I, do 4º semestre do curso de graduação em enfermagem da Universidade Estadual Vale do Acaraú, Sobral, Ceará, estruturando ­se em dois eixos analíticos, a saber: "Organização didático­ pedagógica do PIEPE I" e "O PIEPE I e sua contribuição social e para a formação em enfermagem". O módulo perfaz uma carga ­ horária de 80h, onde, 12h são destinadas às atividades teóricas, que integram ensino e pesquisa e 68h destinadas às atividades de extensão, que se desenvolve de forma integrada ao currículo, proporcionando ao acadêmico vivências no âmbito da saúde do adolescente em território vivo e o desenvolvimento de habilidades e competências que ultrapassam o saber técnico. A l é m de agregar conhecimento para o autocuidado em saúde, os adolescentes passam a ter novas perspectivas se reconhecendo como agentes importantes na sociedade. Compreende ­ se que apesar dos desafios para a implementação da curricularização da extensão, o curso de Enfermagem da UVA tem buscado avançar nesse sendo, favorecendo a melhoria do ensino e o desenvolvimento do papel social da universidade.

The objective of this study is to describe the process of including university extension in the curriculum in a nursing graduation course. This is an experience report developed with the experience of 4th semester nursing students from Vale do Acaraú State University (UVA), in the city of Sobral, state of Ceará. The experience was obtained from the course module named Interdisciplinary Practices in Teaching, Research, and Extension I, being based on two analytical axes, namely: "PIEPE I didactic - pedagogical organization" and "PIEPE I and its social contribution for nursing education". The module has a workload of 80h, of which 12h are for the theoretical activities, which integrate teaching and research, and 68h are destined for extension activities. These activities are developed in an integrated way to the curriculum, offering the student experiences in the area of adolescent health in living territory and the development of skills and competences that go beyond technical knowledge. Besides adding knowledge for self ­ care in health, adolescents will have new perspectives recognizing themselves as important agents in society. Despite the challenges for the implementation of the extension curriculum, the nursing program at UVA has sought to advance in this direction, favoring the improvement of teaching and the development of the university's social role.

A Rare Case of Radiculopathy: Monostotic Fibrous Dysplasia of the Sacrum.

Fibrous dysplasia is a bone disease characterized by an osteoblastic dysfunction resulting in a fibrous replacement of the normal medullary bone. We describe the case of a 33-year-old who presented with low back pain irradiating to her right leg. Both the computed tomography scan and magnetic resonance imaging showed an osteolytic, multicystic lesion of the right hemi-sacrum with invasion of the right S1 foramen. She underwent foraminotomy and curettage of the lesion. Histological diagnosis was fibrous dysplasia, without features of malignant transformation. Three years after surgery the patient is asymptomatic and imaging is stable. This is the fifth known case of monostotic fibrous dysplasia involving the sacrum, a rare entity that must be considered in the differential diagnosis when approaching patients with sacral lesions.

A displasia fibrosa é uma doença óssea caracterizada por uma disfunção osteoblástica que resulta na substituição do osso medular normal por tecido fibroso. Descrevemos o caso de uma doente de 33 anos que se apresentou com lombalgia e ciatalgia direita. A tomografia computorizada e ressonância magnética lombares revelaram uma lesão osteolítica e multiquística no hemissacro direito com invasão do foramen de S1. A doente foi submetida a foraminotomia e curetagem da lesão. O diagnóstico histológico foi de displasia fibrosa, sem sinais de transformação maligna. Três anos após a cirurgia, a doente está assintomática e os estudos de imagem apresentam estabilidade da lesão. Este é o quinto caso conhecido na literatura de displasia fibrosa monostótica com atingimento do sacro, uma entidade rara que deve ser considerada no diagnóstico diferencial de doentes com lesões do sacro.

Fourth ventricle neurocysticercosis: A case report.

BACKGROUND: Neurocysticercosis (NCC) is the most common helminthic disease of the nervous system in humans and it is caused by the larvae of the pork tapeworm, Taenia solium. We present a case of microsurgical removal of a fourth ventricle NCC cyst combined with an endoscopic third ventriculostomy (ETV) to treat hydrocephalus. CASE DESCRIPTION: A 36-year-old woman presented to the emergency room with headache and decreased visual acuity over the last 4 months. A brain magnetic resonance imaging showed obstructive hydrocephalus apparently correlated to a mobile, cystic lesion of the fourth ventricle. In the same operative time, an ETV and a suboccipital craniotomy were performed in order to remove the lesion and to treat the hydrocephalus. The cyst was completely removed and pathologically identified as a T. solium cyst. The early postoperative course was uneventful and she was discharged asymptomatic and off anthelmintic medication. Five weeks later, the patient returned with hydrocephalus recurrence and was successfully retreated with an ETV. At 5-month follow-up, she remains asymptomatic and has no evidence of persistent disease or hydrocephalus recurrence. CONCLUSION: Intraventricular neurocysticercosis is, typically, a surgical disease. For cysts located on the fourth ventricle, a suboccipital craniotomy and a telovelar approach remains a valid option. Cyst removal does not necessarily resolve the hydrocephalus problem. ETV offers an option to the classic shunt placement approach and was shown to be effective even on hydrocephalus recurrence.

Acute Subdural Hematoma Evacuation: Predictive Factors of Outcome.

BACKGROUND: Acute subdural hematoma (aSDH) is a major cause of admission at Neurosurgical Emergency Department. Nevertheless, concerns regarding surgical indication in patients with multiple comorbidities, poor neurological status, antithrombotic therapy, and older age still persist. Therefore, a correct recognition of predictive outcome factors at hospital discharge is crucial to an appropriate neurosurgical treatment. METHODS: Eighty-nine medical records of consecutive patients with age ≥18 years old who were submitted to aSDH evacuation between January 2008 and May 2012 were reviewed. Demographic characteristics, neurological status on admission, anticoagulant or antiplatelet therapy, and outcome on discharge were collected. Patients with insufficient data concerning these variables were excluded from the study. RESULTS: Sixty-nine patients were included; 52% were male; 74% were older than 65 years; 41% were under oral antithrombotic therapy (OAT); at admission, 54% presented with Glasgow coma scale (GCS) ≤8; 23% were submitted to a craniectomy instead of a craniotomy; 26% of the patients died, 32% were dependent, and 42% were independent on discharge. Crude analysis revealed craniectomy, A/A pupils, GCS ≤8 at admission statistically significant related with the worst outcome (P < 0.05). In the adjusted evaluation only A/A pupils (P = 0.04) was associated to poor outcome (spontaneous etiology P = 0.052). Considering daily living independency at hospital discharge, either male gender (P = 0.044) and A/A pupils (P = 0.030) were related to the worst outcome. No effect of age in outcome was observed. CONCLUSIONS: Male gender and A/A pupils are associated with lower probability of achieving independency living at hospital discharge. A/A pupils, low GCS at admission, spontaneous etiology, and craniectomy were associated with the worst outcome. Age and OAT were not predictive factors in this series. Caution should be taken when considering these factors in the surgical decision.

Adult Supratentorial Extraventricular Anaplastic Ependymoma: Therapeutic Approach and Clinical Review.

We report a 69-year-old patient with left paresthesia and hemiparesis. Magnetic resonance imaging revealed a right frontoparietal cystic tumor. A subtotal surgical resection was performed, and an Ommaya reservoir was left in place. The pathological diagnosis was supratentorial extraventricular anaplastic ependymoma. Radiation therapy was administered, and Ommaya reservoir drainages were performed. Four months after, her clinical status deteriorated after a reservoir drainage and image revealed an acute hemorrhage. An additional resection was carried out, and chemotherapy was undergone. One month later the tumor relapsed and the patient died 18 months after initial diagnosis. Some poor prognostic factors have been suggested in the literature: Young age, incomplete tumor resection - eloquent area location, histological anaplasia, supratentorial, and extraventricular locations. Ommaya reservoirs may be used in cystic lesions as a temporary measure only. Surgery is the mainstay of therapy with adjuvant radiotherapy and/or chemotherapy.

Pituitary Apoplexy: Should Endoscopic Surgery Be the Gold Standard?

BACKGROUND: Pituitary apoplexy is an uncommon, potentially fatal condition due to spontaneous ischemia or hemorrhage in a pituitary adenoma. The treatment of this disorder has long been a matter of debate. METHODS: Retrospective cohort study including all patients admitted with pituitary apoplexy in our department between 2005 and 2015 was undertaken. Clinical symptoms and signs on admission, treatment (conservative vs. surgical), neurologic deficit on discharge and at 6 months' follow-up, and endocrinologic evaluation at 6 months' follow-up were analyzed. The statistical analysis was performed with STATA 13.0. Endocrinologic and visual outcomes at 6 months in the different groups according to treatment were compared by applying an independent multinomial probit regression test. Outcomes between the conservative and the surgical (endoscopic and microscopic considered together) groups also were compared and the differences between surgical treated groups were analyzed with logistic regression analysis. P values <0.05 were considered significant. RESULTS: Twenty-three patients were included in this study; 60.9% (n = 14) were treated surgically (5 microsurgically; 9 endoscopically) and 39.1% (n = 9) conservatively. Statistical analysis revealed no significant differences in the visual function between the 3 treatment groups in both univariate and multivariate analysis (P > 0.05). The endocrinologic outcome was better in the surgical group (P = 0.017; adjusted P = 0.027), with a significant difference between the conservative group and the endoscopic group (P = 0.004; adjusted P = 0.005). When we compared both surgical groups, the endoscopic group has a better endocrinologic outcome (P = 0.020; adjusted P = 0.012). CONCLUSIONS: Our results support endoscopic intranasal transsphenoidal surgery as a treatment of pituitary apoplexy patients, as it probably decreases the need for long-term hormonal replacement.

T1-T2 Herniated Disk Presenting with Horner Syndrome.

BACKGROUND: The incidence of thoracic disk herniation is estimated to be 1000 to 1,000,000. Upper thoracic disk herniation is an exceedingly rare pathology with unique neurologic features. We report a case of a young patient who presented with Horner syndrome caused by a T1-T2 disk herniation. CASE DESCRIPTION: A 34-year-old female patient was admitted to the emergency department presenting a sudden-onset history of ptosis and miosis on the left eye (Horner syndrome). She reported a 2-month history of neck, scapular, and medial left arm and forearm pain and numbness. The cervical magnetic resonance image showed a T1-T2 left disk herniation with intraforaminal compression of the T1 nerve root. A microdiskectomy was performed, and both left arm pain and Horner syndrome have completely regressed. CONCLUSIONS: Symptomatic T1-T2 disk herniation is an uncommon condition in a spine surgeon daily routine. The differential diagnosis for patients presenting upper limb pain and Horner's Syndrome should include upper thoracic disk herniation. Patients' outcomes can be excellent if an adequate surgical treatment is timely provided.

A purely extradural lumbar nerve root cavernoma mimicking acute myeloid leukemia recurrence: Case report and literature review.

BACKGROUND: Myeloid sarcoma (MS) is a malignant tumor that usually occurs concomitantly with or following acute myeloid leukemia (AML). Cavernomas are benign congenital malformations that are unusual in the spine and exceedingly rare in pure extradural locations. CASE DESCRIPTION: We report a 73-year-old female with a previous medical history of AML in remission for 3 years who presented with symptoms of low back pain and right lower extremity radiculopathy. A magnetic resonance scan showed an extradural, foraminal lesion centered at the L2 level involving the right L2 nerve root. In view of the history of AML, this lesion was potentially considered MS, a form of AML relapse. Surgery consisting of a right L1 and L2 hemilaminectomy facilitated gross total resection of the purely extradural lesion the proved histologically to be a cavernoma. CONCLUSION: In patients with a history of leukemia, MS must be considered in the differential diagnosis for any epidural or nerve root lesion that appears following treatment. Although rare, cavernomas must be considered among the differential diagnoses for epidural nerve root lesions in the setting of AML.

Whole-Brain Radiation to Treat a Recurrent Malignant Subdural Effusion.

We report the first case of a recurrent malignant subdural effusion that was treated with whole-brain radiation therapy. A 72-year-old man presented with headaches and de novo left central facial palsy and right upper extremity weakness. His past medical history was remarkable for a prostatic adenocarcinoma diagnosed in 1999 (T4N0M0) with no metastatic disease diagnosed to date. Brain magnetic resonance imaging with gadolinium showed carcinomatous meningitis and a 1.5-cm thick left hemisphere subdural collection causing a mass effect. Left-side frontal and parietal burr holes were created and a clear effusion was successfully drained under high pressure. A biopsy od the dura mater was also taken. Analysis of the effusion showed a protein concentration of 1233 mg/dL. Histopathological examination of the dura matter showed adenocarcinomatous cells. Despite the clinical improvement, serial postoperative computed tomography scans of the head showed massive recurrence of the subdural effusion. The patient was offered radiation therapy as a palliative treatment for effusion control. Whole-brain radiation therapy was performed from day 10 to 17 after surgery at a palliative dose of 20 Gy in 5 fractions. No treatment-associated complications were reported. Thirty days after radiotherapy, the computed tomography scan of the head showed total resolution of the malignant effusion.

Cholesterol-derived glucocorticoids control early fate specification in embryonic stem cells.

Aside from its role in cell membrane integrity, cholesterol is a key component in steroid hormone production. The vital functions of steroid hormones such as estrogen, testosterone, glucocorticoids (Gcrts) and mineralocorticoids (Mnrts) in perinatal and adult life are well understood; however, their role during early embryonic development remains largely unexplored. Here we show that siRNA-mediated perturbation of steroid hormone production during mesoderm formation has important consequences on cardiac differentiation in mouse embryonic stem cells (mESC). Both Gcrts and Mnrts are capable of driving cardiac differentiation in mESC. Interestingly, the Gcrt receptor is widely expressed during gastrulation in the mouse, and is exclusively localized in the nuclei-and thus active-in visceral endoderm cells, suggesting that it functions much earlier than previously anticipated. We therefore studied Gcrt signaling in mESC as a model of the gastrulating embryo, and found that Gcrt signaling regulates expression of the transcription factor Hnf4a and the secreted Nodal and BMP inhibitor Cer1 in the early visceral endoderm. RNAi-mediated knockdown of Gcrt function blocked cardiomyocyte differentiation, with limited effects on other cardiovascular cell types including vascular endothelial cells and smooth muscle. Furthermore, the cardiogenic effect of Gcrts required Hnf4a and paracrine Cer1. These results establish a novel function for cholesterol-derived steroid hormones and identify Gcrt signaling in visceral endoderm cells as a regulator of Cer1 and cardiac fate.

Small molecule-mediated TGF-ß type II receptor degradation promotes cardiomyogenesis in embryonic stem cells.

The cellular signals controlling the formation of cardiomyocytes, vascular smooth muscle, and endothelial cells from stem cell-derived mesoderm are poorly understood. To identify these signals, a mouse embryonic stem cell (ESC)-based differentiation assay was screened against a small molecule library resulting in a 1,4-dihydropyridine inducer of type II TGF-ß receptor (TGFBR2) degradation-1 (ITD-1). ITD analogs enhanced proteasomal degradation of TGFBR2, effectively clearing the receptor from the cell surface and selectively inhibiting intracellular signaling (IC(50) ~0.4-0.8 µM). ITD-1 was used to evaluate TGF-ß involvement in mesoderm formation and cardiopoietic differentiation, which occur sequentially during early development, revealing an essential role in both processes in ESC cultures. ITD-1 selectively enhanced the differentiation of uncommitted mesoderm to cardiomyocytes, but not to vascular smooth muscle and endothelial cells. ITD-1 is a highly selective TGF-ß inhibitor and reveals an unexpected role for TGF-ß signaling in controlling cardiomyocyte differentiation from multipotent cardiovascular precursors.

Isoxazolyl-serine-based agonists of peroxisome proliferator-activated receptor: design, synthesis, and effects on cardiomyocyte differentiation.

The peroxisome proliferator-activated receptors (PPARs) are important molecular targets for the development of drugs for the treatment of human metabolic diseases, inflammation, and cancer. They are known to be activated by a variety of structurally diverse compounds. Using a structure-based drug design approach, we designed and synthesized a series of novel isoxazolyl-serine-based PPAR ligands possessing moderate affinities. Some of the new PPAR ligands were able to stimulate cardiomyocyte differentiation from murine ES cells. Ligand 1a was the most active one tested at concentrations between 1.25 to 20 muM between days 2-6, coinciding with the period when mesodermal cells can be recruited to become cardiomyocytes. Notably, the known PPARalpha, gamma, and delta agonists tested, e.g., fenofibrate, rosiglitazone, and GW501516, were inactive in this assay.