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Pharmacological interventions that increase myofiber size counter the functional decline of dystrophic muscles 1 , 2 . We show that deacetylase inhibitors increase the size of myofibers in dystrophin-deficient (MDX) and α-sarcoglycan (α-SG)–deficient mice by inducing the expression of the myostatin antagonist follistatin 3 in satellite cells. Deacetylase inhibitor treatment conferred on dystrophic muscles resistance to contraction-coupled degeneration and alleviated both morphological and functional consequences of the primary genetic defect. These results provide a rationale for using deacetylase inhibitors in the pharmacological therapy of muscular dystrophies.

ObjectivesMelanoma accounts for 3% of skin neoplasms in Brazil, with an incidence of 1.7% in women in the year 2018, according to the National Institute of Cancer. It can appear in any part of the body, but the skin is the primary site in 90% of cases. In 2–3% of the cases, the primary site is unknown. In this context, the objective is to present a rare case of ovary metastatic melanoma.MethodsWe present a case report of a 36-year-old patient who underwent bilateral oophoroplasty and tubo-ovarian abscess drainage due to an acute inflammatory abdomen. Initially anatomopathological results of ovary dysgerminoma showed a 11 cm tumor with approximately 10% tumor necrosis and index mitotic 6/10. Histopathology study showed a superficial spreading melanoma, while immunohistochemistry discrimination was positive for S100, HMB-45, and Melan-A.ResultsThe case evolved with right inguinal lesion and bilateral adnexal tumors. Positron emission tomography showed multiple peritoneal implants, metastatic lesions in the lumen of the gastric body, peritoneal implants, and abdominopelvic lymph node enlargement. Biopsy of right inguinal lymph node and stomach biopsy returned positive for metastatic melanoma. The patient is currently being treated with immunotherapy.ConclusionsThe cutaneous melanoma dissemination to the gynecological tract is rare. The prognosis depends on the initial state and in advanced stages the prognosis declines, mainly due to the high rate of metastases, which are mostly lymphatic. Our case report demonstrates a diagnosis of ovarian malignant melanoma which simulated primary ovarian cancer. The differential diagnoses are sex cord-stromal tumors and germ cell tumors.

ObjectivesTo report a rare case of a patient with pelvic osteosarcoma after radiation therapy of uterine cervical cancer: a 58-year-old woman who received pelvic irradiation for stage IB2 uterine cervical cancer 7 years before was diagnosed with post-radiation osteossarcoma of the iliac right bone.MethodsThe necessary data was obtained by medical chart review, interview with the patient, image diagnose exams and literature review.ResultsThe development of osteosarcoma at the same time of another cancer is a rare fact. The risk factors and the origin of this tumor remains controversial. It is clearly that ionizing radiation can induce sarcoma. It is dificult to make systematic studies due to the rarity of these cases.For uterine cervical cancer stages IB2 to IVA radiotherapy associated with cisplatin for up to six cycles (chemoradiotherapy) has been the first line treatment choice with good results.The sarcomas post radiotherapy are rare. Usually appear 10 to 14.3 years post-treatment, the incidence comprises about 0.1% of all cancer cases and women are more affected because gynecological cancers are more frequently subjected to radiotherapy with a long-term survival.Abstract 164 Figure 1ConclusionsThis case is relevant due to the lenght of time over wich patients treated with radiotherapy may remain to be diagnosed with bone disease. A post-radiation sarcoma should be considered and differentiated from bone metastasis. To early diagnose is important to allow full treatment, providing a longer disease free survival.

ObjectivesTo report a rare histopathological diagnosis of adnexal mass.MethodsWe describe a case of a patient referred to our Gynecology Oncology service to investigate an adnexal mass found in routine exams.ResultsA 58-year-old woman was referred to our service due to an adnexal mass associated with hypogastric pain. Physical examination revealed a hardened mass bulging the anterior-right vaginal wall, discreetly painful by the touch. A magnetic resonance imaging (MRI) of the pelvis revealed a right adnexal heterogeneous mass measuring 9,5 x 4,5 x 6,5 cm adjacent to the iliac vessels. There were no altered tumoral markers. She underwent to exploratory laparotomy, and a mass in the right broad ligament was found. Bilateral salpingoophorectomy and total hysterectomy was performed, as well as the excision of the tumor (wich was adhered to the right iliac vein, pelvic wall and obturator fossa) and homolateral pelvic lymphadenectomy. The intraoperatory pathologic evaluation of the lesion suggested a Carcinoma. The anatomopathologycal study of the retroperitoneal tumor was consistent with poorly differentiated malignant neoplasm. The immunohistochemical analysis showed a strong and diffuse expression of CD23 and negative expression of other markers, ruling out the previous diagnosis and bringing to light the actual histology of the tumor, follicular dendritic cell sarcoma (FDCS).ConclusionsIt is known that FDCS is an uncommon lymphoid neoplasm, especially in pelvic location, with low incidence and indolent growth, difficult to diagnose, but with high rates of local recurrence and eventually distant metastases. There is no standard treatment established and adjuvant therapy is still controversial.

Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although it is responsible for approximately one-third of cancer deaths, no effective therapies are available and the underlying mechanisms have not been fully elucidated. We previously identified the bromodomain and extra-terminal domain (BET) protein BRD4 as an epigenetic regulator of muscle mass. Here we show that the pan-BET inhibitor (+)-JQ1 protects tumor-bearing mice from body weight loss and muscle and adipose tissue wasting. Remarkably, in C26-tumor-bearing mice (+)-JQ1 administration dramatically prolongs survival, without directly affecting tumor growth. By ChIP-seq and ChIP analyses, we unveil that BET proteins directly promote the muscle atrophy program during cachexia. In addition, BET proteins are required to coordinate an IL6-dependent AMPK nuclear signaling pathway converging on FoxO3 transcription factor. Overall, these findings indicate that BET proteins may represent a promising therapeutic target in the management of cancer cachexia. Cachexia is a metabolic syndrome leading to muscle and adipose tissue loss in majority of cancer patients. Here the authors show that, in a mouse model, BET inhibitor JQ1 counteracts muscle and adipose tissue wasting tempering cachexia and prolonging survival through a mechanism unrelated to tumour growth.

The transcriptional coactivator p300 is a histone acetyltransferase (HAT) whose function is critical for regulating gene expression in mammalian cells. However, the molecular events that regulate p300 HAT activity are poorly understood. We evaluated autoacetylation of the p300 HAT protein domain to determine its function. Using expressed protein ligation, the p300 HAT protein domain was generated in hypoacetylated form and found to have reduced catalytic activity. This basal catalytic rate was stimulated by autoacetylation of several key lysine sites within an apparent activation loop motif. This post-translational modification and catalytic regulation of p300 HAT activity is conceptually analogous to the activation of most protein kinases by autophosphorylation. We therefore propose that this autoregulatory loop could influence the impact of p300 on a wide variety of signaling and transcriptional events.

The cardiac α-actin gene is expressed in both heart and skeletal muscle. In skeletal myogenic cells, the 177-base-pair promoter of the human cardiac α-actin (HCA) gene requires three transcription factors for activation: Sp1, serum response factor (SRF), and MyoD. However, MyoD is undetectable in heart. To search for a functional equivalent of MyoD, we analyzed the transcriptional regulation of the HCA promoter in primary cultures of rat cardiac myocytes. The same DNA sequence elements recognized by SRF, Sp1, and MyoD and required for HCA transcription in skeletal muscle cells were also found to be necessary for expression in cardiomyocytes. Overexpression of Id, a negative regulator of basic helix-loop-helix proteins, selectively attenuated expression of the HCA promoter. Cardiomyocyte nuclei contain a protein complex that specifically interacts with the same required sequence (E box) in the HCA promoter that is bound by MyoD in skeletal myogenic cells. Furthermore, these complexes contain a peptide that is a member of the E2A family of basic helix-loop-helix proteins. Cardiomyocyte nuclei appear to be enriched for a protein that can bind to the E-box site as dimers with the E12 protein. These results suggest that a member of the basic helix-loop-helix family, together with SRF and Sp1, activates the HCA promoter in heart. Alternative strategies for myocardial transcription of HCA are discussed.

The p53 protein plays a pivotal role in determining the quality of the response to DNA damage through its transcriptional activity. Upon DNA damage, p53 is activated by post-translational modifications, binds its cognate sequences on the promoters of its target genes and stimulates transcription. In proliferating keratinocytes, the activity of p53 is blunted by its inhibitor ΔNp63 α . Here, we describe a novel mechanism through which ΔNp63 functions in order to prevent the survival and propagation of ultraviolet (UV)-damaged keratinocytes. We found that UVB stimulation induces the rapid phosphorylation of ΔNp63, which precedes ΔNp63 transcriptional downregulation and protein degradation, which is mediated by the p38 MAPK. Phosphorylated ΔNp63 has a lower affinity for p53REs and detaches from cell cycle arrest and apoptotic promoters, thus allowing the rapid activation of p53-dependent transcriptional apoptotic program.

The balance between acetylation and deacetylation of histone and nonhistone proteins controls gene expression in a variety of cellular processes, with transcription being activated by acetyltransferases and silenced by deacetylases. We report here the formation and enzymatic characterization of a complex between the acetyltransferase p300 and histone deacetylases. The C/H3 region of p300 was found to co-purify deacetylase activity from nuclear cell extracts. A prototype of class I histone deacetylases, HDAC1, interacts with p300 C/H3 domain in vitro and in vivo . The p300-binding protein E1A competes with HDAC1 for C/H3 binding; and, like E1A, HDAC1 overexpression interferes with either activation of Gal4p300 fusion protein or p300-dependent co-activation of two C/H3-binding proteins, MyoD and p53. The exposure to deacetylase inhibitors could reverse the dominant-negative effect of a C/H3 fragment insulated from the rest of the molecule, on MyoD- and p53-dependent transcription, whereas inhibition by E1A was resistant to trichostatin A. These data support the hypothesis that association between acetyltransferases and deacetylases can control the expression of genes implicated in cellular growth and differentiation, and suggest that the dominant-negative effect of the p300 C/H3 fragment relies on deacetylase recruitment.

Objective: Our aim was to estimate prevalence of metabolic syndrome (MS), obesity and comorbidities in a cohort of 120 children (3–18 years) with biopsy-proven non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) and to evaluate correlations between clinical or biochemical variables and liver histology. Research methods and procedures: MS was diagnosed according to the adapted National Cholesterol Education Program criteria. Homeostatic model assessment of insulin resistance (HOMA-IR), quantitative insulin-sensitivity check index (QUICKI); and ISI composite, insulin secretion (insulin response at 30 min after a glucose load; HOMA-β cell; insulinogenic index) were all estimated. BMI z -score and total body fat (dual-energy X-ray absorptiometry) were evaluated as indexes of obesity. Results: MS was diagnosed in 66% of children. About 92% had weight above the 85th percentile, of which 42% were obese with weight above 97th percentile. Prevalence of hypertriglyceridaemia was 63%, low HDL cholesterol 45%, hypertension 40% and impaired glucose tolerance 10%. Levels of aminotransferases were higher as the number of comorbidities increased, the highest values being found in subjects with MS ( P ⩽0.05). Prevalence of a grade of steatosis ⩾2 ( P =0.05) and fibrosis ( P ⩽0.01) was higher in subjects with MS. Histology was associated significantly with higher values of a number of clinical and biochemical parameters (steatosis ⩾2 with BMI z -score ( P =0.04), fasting insulin ( P =0.02), HOMA-IR ( P =0.03), β-cell secretion ( P =0.04); necroinflammation with BMI z -score ( P =0.007), glucose ( P ⩽0.0001), cholesterol ( P ⩽0.04) and white blood cells ( P =0.025); fibrosis with body weight ( P =0.05), BMI z -score ( P =0.03), cholesterol ( P =0.05), triglycerides ( P =0.05), fasting insulin ( P ⩽0.0001) and mean values of the hormone at the OGTT ( P =0.03), HOMA-IR ( P ⩽0.0001)). Conclusion: Presence of MS or clinical and biochemical variables associated with the syndrome seems to be strictly related to histological features of NASH in paediatric fatty liver disease. Thus, routinely liver biopsy should be encouraged in these children.