Reducing MYC's transcriptional footprint unveils a good prognostic gene signature in melanoma.

MYC's key role in oncogenesis and tumor progression has long been established for most human cancers. In melanoma, its deregulated activity by amplification of 8q24 chromosome or by upstream signaling coming from activating mutations in the RAS/RAF/MAPK pathway-the most predominantly mutated pathway in this disease-turns MYC into not only a driver but also a facilitator of melanoma progression, with documented effects leading to an aggressive clinical course and resistance to targeted therapy. Here, by making use of Omomyc, the most characterized MYC inhibitor to date that has just successfully completed a phase I clinical trial, we show for the first time that MYC inhibition in melanoma induces remarkable transcriptional modulation, resulting in severely compromised tumor growth and a clear abrogation of metastatic capacity independently of the driver mutation. By reducing MYC's transcriptional footprint in melanoma, Omomyc elicits gene expression profiles remarkably similar to those of patients with good prognosis, underlining the therapeutic potential that such an approach could eventually have in the clinic in this dismal disease.

The relative impact of parental and current environment on plant transcriptomes depends on type of stress and genotype.

Through developmental plasticity, an individual organism integrates influences from its immediate environment with those due to the environment of its parents. While both effects on phenotypes are well documented, their relative impact has been little studied in natural systems, especially at the level of gene expression. We examined this issue in four genotypes of the annual plant Persicaria maculosa by varying two key resources-light and soil moisture-in both generations. Transcriptomic analyses showed that the relative effects of parent and offspring environment on gene expression (i.e. the number of differentially expressed transcripts, DETs) varied both for the two types of resource stress and among genotypes. For light, immediate environment induced more DETs than parental environment for all genotypes, although the precise proportion of parental versus immediate DETs varied among genotypes. By contrast, the relative effect of soil moisture varied dramatically among genotypes, from 8-fold more DETs due to parental than immediate conditions to 10-fold fewer. These findings provide evidence at the transcriptomic level that the relative impacts of parental and immediate environment on the developing organism may depend on the environmental factor and vary strongly among genotypes, providing potential for the interplay of these developmental influences to evolve.

Mini-invasive technique of sclerotherapy with talc in chronic seroma after abdominoplasty - a case report and literature review.

The formation of a seroma after abdominoplasty is one of the most common complications faced by plastic surgeons. A 59-year-old man underwent lipoabdominoplasty and developed a large subcutaneous seroma that persisted for 7 months. Percutaneous sclerosis with talc was performed. We present the first report of chronic seroma after lipoabdominoplasty successfully treated with talc sclerosis.

Validation of Prediction Equations of Energy Values of a Single Ingredient or Their Combinations in Male Broilers.

A set of prediction equations to estimate the nitrogen-corrected apparent metabolizable energy (AMEn) of individual ingredients and diets used in the poultry feed industry was evaluated. The AMEn values of three energy ingredients (maize, sorghum and defatted maize germ meal), four protein ingredients (soybean meal, maize gluten meal 60% crude protein, integral micronized soy and roasted whole soybean) and four diets (three containing four feedstuffs, complex diets, and one containing only corn-soybean meal, basal diet) were determined using a metabolism assay with male broilers from 1 to 7, 8 to 21, 22 to 35, and 36 to 42 days old. These values were compared to the AMEn values presented in the tables of energy composition or estimated by equation predictions based on chemical composition data of feedstuffs. In general, the equation predictions more precisely estimated the AMEn of feedstuffs when compared to the tables of energy composition. The equation AMEn (dry matter [DM] basis) = 4,164.187+51.006 ether extract (% in DM basis)-197.663 ash-35.689 crude fiber (% in DM basis)-20.593 neutral detergent fiber (% in DM basis) (R(2) = 0.75) was the most applicable for the prediction of the energy values of feedstuffs and diets used in the poultry feed industry.

MYC: there is more to it than cancer.

MYC is a pleiotropic transcription factor involved in multiple cellular processes. While its mechanism of action and targets are not completely elucidated, it has a fundamental role in cellular proliferation, differentiation, metabolism, ribogenesis, and bone and vascular development. Over 4 decades of research and some 10,000 publications linking it to tumorigenesis (by searching PubMed for "MYC oncogene") have led to MYC becoming a most-wanted target for the treatment of cancer, where many of MYC's physiological functions become co-opted for tumour initiation and maintenance. In this context, an abundance of reviews describes strategies for potentially targeting MYC in the oncology field. However, its multiple roles in different aspects of cellular biology suggest that it may also play a role in many additional diseases, and other publications are indeed linking MYC to pathologies beyond cancer. Here, we review these physiological functions and the current literature linking MYC to non-oncological diseases. The intense efforts towards developing MYC inhibitors as a cancer therapy will potentially have huge implications for the treatment of other diseases. In addition, with a complementary approach, we discuss some diseases and conditions where MYC appears to play a protective role and hence its increased expression or activation could be therapeutic.

Reverse abdominoplasty as a salvage procedure for infected bilateral implant-based breast reconstruction.

INTRODUCTION: Infection is one of the most feared complications of implant-based breast reconstruction and is difficult to manage in irradiated patients. We present the first case of bilateral breast reconstruction with infected expanders salvaged by performing a reverse abdominoplasty. PRESENTATION OF CASE: A 64-year-old woman with a history of locally advanced bilateral breast cancer underwent modified bilateral radical mastectomy and postmastectomy radiotherapy. We performed two-stage breast reconstruction with implants. However, the patient developed a mild infection of the expanders, which was treated with targeted oral antibiotic therapy. The response to treatment was favorable, allowing us to salvage the reconstruction with a reverse abdominoplasty. DISCUSSION: Traditionally, the management of infected breast prostheses has consisted of removal of the infected implant, a complication that forces a delay in the reconstructive process. Successful reports of salvage of infected prostheses have been described in the literature. On the other hand, we were able to salvage the reconstruction by performing a reverse abdominoplasty, which allowed us to resect the irradiated tissue and provide adequate non-irradiated soft tissue coverage for the replaced implants. CONCLUSION: Reverse abdominoplasty offers an acceptable aesthetic result with much less donor site morbidity and represents a valid alternative to other complex reconstruction techniques.

Venous thromboembolism after aesthetic surgeries in low-risk patients without hypercoagulability.

Venous thromboembolism (VTE) is a serious but rare complication of aesthetic surgery, with an incidence of 0.017% for liposuction and 0.01%-0.02% for augmentation mammoplasty. Despite the low incidence and appropriate patient selection, we present two cases of VTE in low-risk patients without hypercoagulability undergoing aesthetic procedures. In the first case, a 45-year-old woman with a history of anemia developed bilateral pulmonary embolism after ultrasound-assisted liposuction. In the second case, a 33-year-old woman with a history of oral contraceptive use developed deep vein thrombosis in the right upper extremity after augmentation mammoplasty. The patients were treated early and fully recovered after 12 months. This report highlights the importance of early diagnosis and treatment of VTE in aesthetic surgery, even in low-risk patients.

Intraoperative Fluorescence Imaging to Identify and Preserve the Fifth Anterior Intercostal Sensory Nerves during Inferior Pedicle Reduction Mammoplasty.

Postoperative sensitivity of the nipple-areola complex (NAC) is an important concern for women after reduction mammoplasty. Previous studies have demonstrated that sensory branches of the fifth anterior intercostal nerve are important for innervating the NAC and that using an inferior pedicle technique is associated with improved sensory retention. The significance of this case report is that it demonstrates the importance of the fifth anterior intercostal sensory nerve branches using a prototype fluorescent imaging camera. The benefit of this device is that it can detect intraoperative auto-fluorescence of nerves and facilitate their identification and preservation, potentially facilitating the retention of sensation in the NAC and surrounding skin. The goals of this article are, therefore, to demonstrate the importance of this neurovascular pedicle when the inferior pedicle technique is used for breast reduction; and to provide demonstrative evidence of the nerve's presence within the fifth anterior intercostal artery perforator pedicle. The case involved a woman with mammary hypertrophy who underwent bilateral reduction mammoplasty using the inferior pedicle technique. Full NAC sensation was demonstrated on postoperative day 3 with complete sensory recovery at 1- and 3-month follow-up confirmed. To our knowledge, this is the first reported instance of the fifth intercostal nerve being visualized during aesthetic breast surgery, demonstrating the importance of this neurovascular bundle for sensory preservation when an inferior pedicle reduction mammaplasty technique is used.

Metastasis of invasive ductal breast cancer in the subcutaneous tissue of the back: Report of a relapse at 15 years.

INTRODUCTION AND IMPORTANCE: Soft tissue metastases from any primary malignant tumor are considered very rare and can be found in subcutaneous or muscle tissue. We present the fifth case of breast cancer (BC) metastasis in subcutaneous tissue of the back and with an interval of 15 years between its detection and the diagnosis of BC. CASE PRESENTATION: A 57-year-old woman with a history of left mastectomy with axillary lymphadenectomy and immediate breast reconstruction due to invasive ductal BC with positive hormone receptors and HER2 negative 15 years ago. She consulted for a mass on her back and elevated levels of CA15-3. Nuclear magnetic resonance showed a tumor in the subcutaneous tissue in contact with the muscular aponeurosis. Radical metastasectomy was performed with curative intent and intraoperative control of the margins by freezing. Histopathology and immunohistochemistry reported a lesion consistent with breast adenocarcinoma metastasis, with positive estrogen and progesterone receptors, positive GATA-3, negative HER2, and free margins. The patient is free of disease 4 years after surgery. CLINICAL DISCUSSION: The incidence of soft tissue metastasis of breast cancer is 0.2-0.8 %. To date, only four cases of BC metastasis in the subcutaneous tissue of the back have been reported. This is the case with the longest relapse time reported in the literature. CONCLUSION: Soft tissue metastases should be suspected in all patients with a history of breast cancer, even 15 years after diagnosis.

Breast Reconstruction after Blunt Breast Trauma: Systematic Review and Case Report Using the Ribeiro Technique.

Blunt breast trauma occurs in 2% of blunt chest injuries. This study aimed to evaluate the evidence on breast reconstruction after blunt trauma associated with the use of a seat belt. Also, we describe the first case of breast reconstruction using the Ribeiro technique. In November 2022, a systematic search of MEDLINE, EMBASE, and Google Scholar databases was conducted. The literature was screened independently by two reviewers, and the data was extracted. Our search terms included breast, mammoplasty, blunt injury, and seat belts. In addition, we present the case of a woman with a left breast deformity and her reconstruction using the inferior Ribeiro flap technique. Six articles were included. All included studies were published between 2010 and 2021. The studies recruited seven patients. According to the Teo and Song classification, seven class 2b cases were reported. In five cases a breast reduction was performed in the deformed breast with different types of pedicles (three superomedial flaps, one lower flap, one superior flap). Only one case presented complications. The case here presented was a type 2b breast deformity in which the lower Ribeiro pedicle was used successfully without complications during follow-up. Until now there has been no consensus on reconstructive treatment due to the rarity of this entity. However, we must consider surgical treatment individually for each patient. We believe that the Ribeiro technique is a feasible and safe alternative in the treatment of posttraumatic breast deformities, offering very good long-term results.

Role of a corrugated Dion-Jacobson 2D perovskite as an additive in 3D MAPbBr3 perovskite-based light emitting diodes.

Metal halide perovskites represent an intriguing class of materials, and a very promising approach to tune the properties of optoelectronic devices and improve their performance involves the implementation of architectures based on mixed 3D and 2D perovskites. In this work, we investigated the use of a corrugated 2D Dion-Jacobson perovskite as an additive to a classical 3D MAPbBr3 perovskite for applications in light-emitting diodes. Taking advantage of the properties of this emerging class of materials, we studied the effect of a 2D 2-(dimethylamino)ethylamine (DMEN)-based perovskite on the morphological, photophysical, and optoelectronic properties of 3D perovskite thin films. We used α-DMEN perovskite both in a mixture with MAPbBr3 creating mixed 2D/3D phases and as a passivating thin layer deposited on the top of a 3D perovskite polycrystalline film. We observed a beneficial modulation of the thin film surface, a blue shift in the emission spectrum, and enhanced device performance.

The aggressiveness of murine lymphomas selected in vivo by growth rate correlates with galectin-1 expression and response to cyclophosphamide.

Although lymphomas account for almost half of blood-derived cancers that are diagnosed each year, the causes of new cases are poorly understood, as reflected by the relatively few risk factors established. Galectin-1, an immunoregulatory ß-galactoside-binding protein, has been widely associated with tumor-immune escape. The aim of the present work was to study the relationship between tumor growth rate, aggressiveness, and response to cyclophosphamide (Cy) therapy with regard to Gal-1 expression in murine T-cell lymphoma models. By means of a disruptive selection process for tumor growth rate, we generated two lymphoma variants from a parental T-cell lymphoma, which have unique characteristics in terms of tumor growth rate, spontaneous regression, metastatic capacity, Gal-1 expression and sensitivity to Cy therapy. Here, we show that Gal-1 expression strongly correlates with tumor growth rate, metastatic capacity and response to single-dose Cy therapy in T-cell lymphoma models; this association might have important consequences for evaluating prognosis and treatments of this type of tumors.

Influence of VicRK and CovR on the interactions of Streptococcus mutans with phagocytes.

OBJECTIVE: Streptococcus mutans are members of the oral microbiota that are implicated in dental caries and infective endocarditis. To adapt to environmental stresses encountered during host colonization, these bacteria employ two-component regulatory systems, which modulate global changes in gene expression. These include the systems VicRK and CovR. In this study, we investigate the influence of VicRK and CovR in S. mutans interactions with mononuclear and polymorphonuclear (PMN) phagocytes. METHODS: Patterns of S. mutans uptake by murine macrophages were determined in strains, which differ in the production of proteins regulated by VicRK and CovR. Bacterial uptake by murine macrophages and by PMN in human blood was analyzed in vicK and covR knockout mutants obtained in strains UA159 and LT11. RESULTS: Inactivation of covR did not affect uptake by macrophages, while vicK inactivation transiently reduced uptake only in LT11 (P < 0.05). In the two strains, inactivation of vicK and covR impaired uptake by PMN for a period of 1 h or more (P < 0.01-0.05). Mutant complementation with vicK or covR restored the PMN uptake phenotypes. CONCLUSION: This study indicates that VicRK and CovR regulate functions that influence bacterial susceptibility to phagocytosis, suggesting a novel role for these systems in the virulence of S. mutans.

[Immunomodulation and antiangiogenesis in cancer therapy. From basic to clinical research]. / Inmunomodulación y antiangiogénesis en la terapéutica oncológica. De la investigación básica a la clínica.

Basic and pre-clinic research in cellular and molecular oncology are the main supports accounting for the advancement in cancer therapeutics. The findings achieved, and their implementation in clinical practice are responsible for the permanent improvement in the treatment of the neoplastic disease. Our present objective is to summarize and discuss the pre-clinical findings in immunomodulation and anti-angiogenesis for the treatment of several types of tumors obtained in our Institute during the last 15 years, and the subsequent translation and application of the acquired experimental knowledge in a Phase I/II Clinical Trial. We present the results and mechanisms of action of antimetastatic immunomodulation with cyclophosphamide, the metronomic chemotherapy with different single drugs and their combinations, and finally the design and preliminary results of a clinical trial with metronomic chemotherapy for patients with advanced breast cancer.

Usefulness of Glucose Measurement To Assess Tissue Perfusion of the Nipple-Areola Complex in Conservative Mastectomy: A Prospective Cohort Study Protocol.

In recent decades, the mastectomy technique has undergone progressive adaptations in order to preserve the integrity of the breast structure and the nipple-areola complex (NAC), allowing reconstruction to be performed immediately after ablation. However, mastectomy flap necrosis or NAC has become a common complication, with an incidence between 2% and 22.3%. Blood glucose measurement to monitor microsurgical flaps has been reported as a simple method for the early detection of venous compromise. In this scenario, we propose the need to use an alternative, cost-effective method to assess the vitality of NAC in conservative oncological mastectomies. This protocol describes a prospective cohort study and was approved by the Research Protocols Ethics Committee of our institution. Patients will be included after signing informed consent. The anonymity and confidentiality of the information collected will be respected according to the Declaration of Helsinki and according to local and national guidelines. Highlights: The rate of flap necrosis or nipple-areola complex (NAC) after mastectomy with reconstruction ranges from 2% to 22.3%.Glucose measurement has been reported in microsurgical flaps.This protocol seeks to determine the use of glucose as an early predictor of NAC necrosis.Participants will be recruited from a high-volume breast pathology hospital.

Assessment of surgeon communication skills from the patient perspective: A national evaluation using the Communication Assessment Tool.

OBJECTIVE: The Communication Assessment Tool (CAT) has previously been translated and adapted to the Italian context. This national study aimed to validate the CAT and evaluate communication skills of practicing surgeons from the patient perspective. METHODS: CAT consists of 14 items associated with a 5-point scale (5 = excellent); results are reported as the percent of ''excellent'' scores. It was administered to 920 consenting outpatients aged 18-84 in 26 Italian surgical departments. RESULTS: The largest age group was 45-64 (43.8%); 52.2% of the sample was male. Scores ranged from 44.6% to 66.6% excellent. The highest-scoring items were "Treated me with respect" (66.6%), "Gave me as much information as I wanted" (66.3%) and "Talked in terms I could understand" (66.0%); the lowest was "Encouraged me to ask questions" (44.6%). Significant differences were associated with age (18-24 year old patients exhibited the lowest scores) and geographical location (Northern Italy had the highest scores). CONCLUSION: CAT is a valid tool for measuring communication in surgical settings. PRACTICE IMPLICATIONS: Results suggest that expectations of young people for communication in surgical settings are not being met. While there is room to improve communication skills of surgeons across Italy, patients highlighted the greatest need in the Central and Southern regions.

MYC Inhibition Halts Metastatic Breast Cancer Progression by Blocking Growth, Invasion, and Seeding.

MYC's role in promoting tumorigenesis is beyond doubt, but its function in the metastatic process is still controversial. Omomyc is a MYC dominant negative that has shown potent antitumor activity in multiple cancer cell lines and mouse models, regardless of their tissue of origin or driver mutations, by impacting on several of the hallmarks of cancer. However, its therapeutic efficacy against metastasis has not been elucidated yet. Here we demonstrate for the first time that MYC inhibition by transgenic Omomyc is efficacious against all breast cancer molecular subtypes, including triple-negative breast cancer, where it displays potent antimetastatic properties both in vitro and in vivo. Importantly, pharmacologic treatment with the recombinantly produced Omomyc miniprotein, recently entering a clinical trial in solid tumors, recapitulates several key features of expression of the Omomyc transgene, confirming its clinical applicability to metastatic breast cancer, including advanced triple-negative breast cancer, a disease in urgent need of better therapeutic options. Significance: While MYC role in metastasis has been long controversial, this manuscript demonstrates that MYC inhibition by either transgenic expression or pharmacologic use of the recombinantly produced Omomyc miniprotein exerts antitumor and antimetastatic activity in breast cancer models in vitro and in vivo, suggesting its clinical applicability.

Impairment of F1F0-ATPase, adenine nucleotide translocator and adenylate kinase causes mitochondrial energy deficit in human skin fibroblasts with chromosome 21 trisomy.

A central role for mitochondrial dysfunction has been proposed in the pathogenesis of DS (Down's syndrome), a multifactorial disorder caused by trisomy of human chromosome 21. To explore whether and how abnormalities in mitochondrial energy metabolism are involved in DS pathogenesis, we investigated the catalytic properties, gene expression and protein levels of certain proteins involved in mitochondrial ATP synthesis, such as F1F0-ATPase, ANT (adenine nucleotide translocator) and AK (adenylate kinase), in DS-HSF (human skin fibroblasts with trisomic karyotype), comparing them with euploid fibroblasts. In DS-HSF, we found a strong impairment of mitochondrial ATP synthesis due to a reduction in the catalytic efficiency of each of the investigated proteins. This impairment occurred in spite of unchanged gene expression and an increase in ANT and AK protein content, whereas the amount of ATPase subunits was selectively reduced. Interestingly, exposure of DS-HSF to dibutyryl-cAMP, a permanent derivative of cAMP, stimulated ANT, AK and ATPase activities, whereas H89, a specific PKA (protein kinase A) inhibitor, suppressed this cAMPdependent activation, indicating an involvement of the cAMP/PKA-mediated signalling pathway in the ATPase, ANT and AK deficit. Consistently, DS-HSF showed decreased basal levels of cAMP and reduced PKA activity. Despite the impairment of mitochondrial energy apparatus, no changes in cellular energy status, but increased basal levels of L-lactate, were found in DS-HSF, which partially offset for the mitochondrial energy deficit by increasing glycolysis and mitochondrial mass.These results provide new insight into the molecular basis for mitochondrial dysfunction in DS and might provide a molecular explanation for some clinical features of the syndrome.

The Wnt signaling receptor Fzd9 is essential for Myc-driven tumorigenesis in pancreatic islets.

The huge cadre of genes regulated by Myc has obstructed the identification of critical effectors that are essential for Myc-driven tumorigenesis. Here, we describe how only the lack of the receptor Fzd9, previously identified as a Myc transcriptional target, impairs sustained tumor expansion and ß-cell dedifferentiation in a mouse model of Myc-driven insulinoma, allows pancreatic islets to maintain their physiological structure and affects Myc-related global gene expression. Importantly, Wnt signaling inhibition in Fzd9-competent mice largely recapitulates the suppression of proliferation caused by Fzd9 deficiency upon Myc activation. Together, our results indicate that the Wnt signaling receptor Fzd9 is essential for Myc-induced tumorigenesis in pancreatic islets.

Ca2+-dependent K+ efflux regulates deoxycholate-induced apoptosis of BHK-21 and Caco-2 cells.

BACKGROUND & AIMS: Deoxycholate (DC) has proapoptotic and tumorigenic effects in different cell types of the gastrointestinal tract. Exposure of BHK-21 (stromal) cells to DC induces Ca(2+) entry at the plasma membrane, which affects intracellular Ca(2+) signaling. We assessed whether DC-induced increases in [Ca(2+)] can impinge on plasma membrane properties (eg, ionic conductances) involved in cell apoptosis. METHODS: Single- and double-barreled microelectrodes were used to measure membrane potential (V(m)) and extracellular [K(+)] in BHK-21 fibroblasts and Caco-2 colon carcinoma cells. Apoptosis was assessed by Hoechst labeling, propidium iodide staining, and caspase-3 and caspase-7 assays. RESULTS: DC-induced cell membrane hyperpolarization was directly measured with intracellular microelectrodes in both cell lines. Diverse Ca(2+) mobilizing agents, such as membrane receptor agonists, an inhibitor of the sarco/endoplasmic reticulum Ca(2+) adenosine triphosphatase and a Ca(2+) ionophore, also induced increases in V(m). Removal of extracellular Ca(2+) reduced the agonist- and DC-induced membrane hyperpolarization by approximately 15% and 60%, respectively. These findings indicate a prominent role for Ca(2+) entry at the plasma membrane in the action of this bile salt. Blockade of Ca(2+)-activated K(+) conductances by charybdotoxin and apamin reduced DC-induced hyperpolarization by 75% and 64% in BHK-21 and Caco-2 cells, respectively. These inhibitors also reduced the DC-induced increase in extracellular [K(+)] by 75% and cell apoptosis by approximately 50% in both cell lines. CONCLUSIONS: Ca(2+)-dependent K(+) conductance is an important regulator of DC-induced apoptosis in stromal and colon cancer cells.