Circadian Control of Histone Turnover During Cardiac Development and Growth.

During postnatal cardiac hypertrophy, cardiomyocytes undergo mitotic exit, relying on DNA replication-independent mechanisms of histone turnover to maintain chromatin organization and gene transcription. In other tissues, circadian oscillations in nucleosome occupancy influence clock-controlled gene expression, suggesting a role for the circadian clock in temporal control of histone turnover and coordinated cardiomyocyte gene expression. To elucidate roles for the master circadian transcription factor, Bmal1, in histone turnover, chromatin organization, and myocyte-specific gene expression and cell growth in the neonatal period. Bmal1 knockdown in neonatal rat ventricular myocytes (NRVM) decreased myocyte size, total cellular protein synthesis, and transcription of the fetal hypertrophic gene Nppb following treatment with serum or the α-adrenergic agonist phenylephrine (PE). Depletion of Bmal1 decreased expression of clock-controlled genes Per2 and Tcap, as well as Sik1, a Bmal1 target upregulated in adult versus embryonic hearts. Bmal1 knockdown impaired Per2 and Sik1 promoter accessibility as measured by MNase-qPCR and impaired histone turnover as measured by metabolic labeling of acid-soluble chromatin fractions. Sik1 knockdown in turn decreased myocyte size, while simultaneously inhibiting Nppb transcription and activating Per2 transcription. Linking these changes to chromatin remodeling, depletion of the replication-independent histone variant H3.3a inhibited myocyte hypertrophy and prevented PE-induced changes in clock-controlled gene transcription. Bmal1 is required for neonatal myocyte growth, replication-independent histone turnover, and chromatin organization at the Sik1 promoter. Sik1 represents a novel clock-controlled gene that coordinates myocyte growth with hypertrophic and clock-controlled gene transcription. Replication-independent histone turnover is required for transcriptional remodeling of clock-controlled genes in cardiac myocytes in response to growth stimuli.

Histone H1.0 couples cellular mechanical behaviors to chromatin structure.

Tuning of genome structure and function is accomplished by chromatin-binding proteins, which determine the transcriptome and phenotype of the cell. Here we investigate how communication between extracellular stress and chromatin structure may regulate cellular mechanical behaviors. We demonstrate that histone H1.0, which compacts nucleosomes into higher-order chromatin fibers, controls genome organization and cellular stress response. We show that histone H1.0 has privileged expression in fibroblasts across tissue types and that its expression is necessary and sufficient to induce myofibroblast activation. Depletion of histone H1.0 prevents cytokine-induced fibroblast contraction, proliferation and migration via inhibition of a transcriptome comprising extracellular matrix, cytoskeletal and contractile genes, through a process that involves locus-specific H3K27 acetylation. Transient depletion of histone H1.0 in vivo prevents fibrosis in cardiac muscle. These findings identify an unexpected role of linker histones to orchestrate cellular mechanical behaviors, directly coupling force generation, nuclear organization and gene transcription.

Posttraumatic Scrotal Reconstruction with a Pedicled "Extended" Superficial Circumflex Iliac Artery Perforator Flap: A Case Report.

The superficial circumflex iliac artery (SCIA) perforator (SCIP) flap has been used for scrotal reconstruction after Fournier's gangrene, skin cancer, or infections. However, there are few publications with regard to penoscrotal reconstruction after a traumatic injury with this flap. In this article, we propose a new SCIP flap variation, the "extended" or "direct" SCIP flap, to effectively reconstruct a wide scrotal defect after a traumatic injury. The "extended" SCIP flap is designed medial and cranial to the anterosuperior iliac spine (ASIS) using the superficial branch of the SCIA as the main pedicle.

Gender-specific genetic and epigenetic signatures in cardiovascular disease.

Cardiac sex differences represent a pertinent focus in pursuit of the long-awaited goal of personalized medicine. Despite evident disparities in the onset and progression of cardiac pathology between sexes, historical oversight has led to the neglect of gender-specific considerations in the treatment of patients. This oversight is attributed to a predominant focus on male samples and a lack of sex-based segregation in patient studies. Recognizing these sex differences is not only relevant to the treatment of cisgender individuals; it also holds paramount importance in addressing the healthcare needs of transgender patients, a demographic that is increasingly prominent in contemporary society. In response to these challenges, various agencies, including the National Institutes of Health, have actively directed their efforts toward advancing our comprehension of this phenomenon. Epigenetics has proven to play a crucial role in understanding sex differences in both healthy and disease states within the heart. This review presents a comprehensive overview of the physiological distinctions between males and females during the development of various cardiac pathologies, specifically focusing on unraveling the genetic and epigenetic mechanisms at play. Current findings related to distinct sex-chromosome compositions, the emergence of gender-biased genetic variations, and variations in hormonal profiles between sexes are highlighted. Additionally, the roles of DNA methylation, histone marks, and chromatin structure in mediating pathological sex differences are explored. To inspire further investigation into this crucial subject, we have conducted global analyses of various epigenetic features, leveraging data previously generated by the ENCODE project.

Promoting cardiomyocyte proliferation for myocardial regeneration in large mammals.

From molecular and cellular perspectives, heart failure is caused by the loss of cardiomyocytes-the fundamental contractile units of the heart. Because mammalian cardiomyocytes exit the cell cycle shortly after birth, the cardiomyocyte damage induced by myocardial infarction (MI) typically leads to dilatation of the left ventricle (LV) and often progresses to heart failure. However, recent findings indicate that the hearts of neonatal pigs completely regenerated the cardiomyocytes that were lost to MI when the injury occurred on postnatal day 1 (P1). This recovery was accompanied by increases in the expression of markers for cell-cycle activity in cardiomyocytes. These results suggest that the repair process was driven by cardiomyocyte proliferation. This review summarizes findings from recent studies that found evidence of cardiomyocyte proliferation in 1) the uninjured hearts of newborn pigs on P1, 2) neonatal pig hearts after myocardial injury on P1, and 3) the hearts of pigs that underwent apical resection surgery (AR) on P1 followed by MI on postnatal day 28 (P28). Analyses of cardiomyocyte single-nucleus RNA sequencing data collected from the hearts of animals in these three experimental groups, their corresponding control groups, and fetal pigs suggested that although the check-point regulators and other molecules that direct cardiomyocyte cell-cycle progression and proliferation in fetal, newborn, and postnatal pigs were identical, the mechanisms that activated cardiomyocyte proliferation in response to injury may differ from those that regulate cardiomyocyte proliferation during development.

Repeated pancreatic resection for pancreatic metastases from renal cell Carcinoma: A Spanish multicenter study (PANMEKID).

BACKGROUND AND OBJECTIVES: Recurrent isolated pancreatic metastasis from Renal Cell Carcinoma (RCC) after pancreatic resection is rare. The purpose of our study is to describe a series of cases of relapse of pancreatic metastasis from renal cancer in the pancreatic remnant and its surgical treatment with a repeated pancreatic resection, and to analyse the results of both overall and disease-free survival. METHODS: Multicenter retrospective study of patients undergoing pancreatic resection for RCC pancreatic metastases, from January 2010 to May 2020. Patients were grouped into two groups depending on whether they received a single pancreatic resection (SPS) or iterative pancreatic resection. Data on short and long-term outcome after pancreatic resection were collected. RESULTS: The study included 131 pancreatic resections performed in 116 patients. Thus, iterative pancreatic surgery (IPS) was performed in 15 patients. The mean length of time between the first pancreatic surgery and the second was 48.9 months (95 % CI: 22.2-56.9). There were no differences in the rate of postoperative complications. The DFS rates at 1, 3 and 5 years were 86 %, 78 % and 78 % vs 75 %, 50 % and 37 % in the IPS and SPS group respectively (p = 0.179). OS rates at 1, 3, 5 and 7 years were 100 %, 100 %, 100 % and 75 % in the IPS group vs 95 %, 85 %, 80 % and 68 % in the SPS group (p = 0.895). CONCLUSION: Repeated pancreatic resection in case of relapse of pancreatic metastasis of RCC in the pancreatic remnant is justified, since it achieves OS results similar to those obtained after the first resection.

Endometrial cancer: predictors and oncological safety of tumor tissue manipulation.

PURPOSE: The main goal of this study is to assess the impact of tumor manipulation on the presence of lympho-vascular space invasion and its influence on oncological results. METHODS: We performed a retrospective multi-centric study amongst patients who had received primary surgical treatment for apparently early-stage endometrial cancer. A multivariate statistical analysis model was designed to assess the impact that tumor manipulation (with the use of uterine manipulator or preoperative hysteroscopy) has on lympho-vascular development (LVSI) in the final surgical specimen. RESULTS: A total of 2852 women from 15 centers were included and divided into two groups based on the lympho-vascular status in the final surgical specimen: 2265 (79.4%) had no LVSI and 587 (20.6%) presented LVSI. The use of uterine manipulator was associated with higher chances of lympho-vascular involvement regardless of the type used: Balloon manipulator (HR: 95% CI 4.64 (2.99-7.33); p < 0.001) and No-Balloon manipulator ([HR]: 95% CI 2.54 (1.66-3.96); p < 0.001). There is no evidence of an association between the use of preoperative hysteroscopy and higher chances of lympho-vascular involvement (HR: 95% CI 0.90 (0.68-1.19); p = 0.479). CONCLUSION: Whilst performing common gynecological procedures, iatrogenic distention and manipulation of the uterine cavity are produced. Our study suggests that the use of uterine manipulator increases the rate of LVSI and, therefore, leads to poorer oncological results. Conversely, preoperative hysteroscopy does not show higher rates of LVSI involvement in the final surgical specimen and can be safely used.

The relationship between sperm nuclear DNA fragmentation, mitochondrial DNA fragmentation, and copy number in normal and abnormal human ejaculates.

BACKGROUND: While it is common to clinically evaluate sperm nuclear DNA fragmentation, less attention has been given to sperm mitochondrial DNA. Recently, a digital PCR assay has allowed accurate estimation of the proportion of fragmented mtDNA molecules and relative copy number. OBJECTIVES: To determine the correlation of classical sperm parameters, average mtDNA copies per spermatozoon and the level of mtDNA fragmentation (SDF-mtDNA) to that of nuclear DNA fragmentation (SDF-nDNA), measured as the proportion of global, single-strand DNA (SDF-SSBs) and double-strand DNA breaks (SDF-DSBs). To determine whether the level of nuclear and mitochondrial DNA fragmentation and/or copy number can differentiate normozoospermic from non-normozoospermic samples. MATERIALS AND METHODS: Ejaculates from 29 normozoospermic and 43 non-normozoospermic were evaluated. SDF was determined using the sperm chromatin dispersion assay. mtDNA copy number and SDF-mtDNA were analyzed using digital PCR assays. RESULTS: Relative mtDNA copy increased as sperm concentration or motility decreased, or abnormal morphology increased. Unlike SDF-mtDNA, mtDNA copy number was not correlated with SDF-nDNA. SDF-mtDNA increased as the concentration or proportion of non-vital sperm increased; the higher the mtDNA copy number, the lower the level of fragmentation. Non-normozoospermic samples showed double the level of SDF-nDNA compared to normozoospermic (median 25.00 vs. 13.67). mtDNA copy number per spermatozoon was 3× higher in non-normozoospermic ejaculates (median 16.06 vs. 4.99). Although logistic regression revealed SDF-Global and mtDNA copy number as independent risk factors for non-normozoospermia, when SDF-Global and mtDNA copy number were combined, ROC curve analysis resulted in an even stronger discriminatory ability for predicting the probability of non-normozoospermia (AUC = 0.85, 95% CI 0.76-0.94, p < 0.001). CONCLUSION: High-quality ejaculates show lower nuclear SDF and retain less mtDNA copies, with approximately half of them fragmented, so that the absolute number of non-fragmented mtDNA molecules per spermatozoon is extremely low.

Prophylactic lymphedema surgery in lower limb soft tissue sarcomas: A clinical paradigm in a promising field.

INTRODUCTION: Oncological treatments, such as radiotherapy and surgery, are high-risk factors for the development of secondary lymphedema in the upper and lower limbs, as well as the genitalia. Prophylactic lymphedema surgery (PLS) has previously demonstrated promising results in reducing secondary lymphedema in breast cancer and urogenital cancer patients. We conducted a study to adapt this principle for patients with lower-extremity sarcomas. MATERIAL AND METHODS: Inclusion criteria included patients with tumors on the medial aspect of the thigh and leg and tumor size larger than 5 cm. Group A (19 patients) comprised a prospective cohort (2020-2023) in which a PLS protocol was executed. Lymphaticovenous anastomosis (LVA) was performed when lymphatic channels were interrupted due to tumor resection, intraoperatively verified by indocyanine green. Lymph node transfer was employed exclusively in cases involving preoperative radiotherapy and inguinal lymph node resection. Measurements were collected both preoperatively and at 1, 3, 6, and 12 months postoperatively. Group B (26 patients) constituted a retrospective cohort (2017-2020) without PLS reconstruction, where the prevalence of lymphedema was determined. RESULTS: In total, we enrolled 45 patients with soft tissue sarcomas located on the inner aspect of the thigh and leg (26 in the control group vs. 19 in the prophylactic group). In the control group, lymphedema was observed in 10 out of 27 patients (37.04%). In the prophylactic group, two patients exhibited signs of lower-extremity lymphedema (2/19, 10.52%) with a median follow-up of 14.15 months (6 months-33months), demonstrating statistically significant differences between the two groups (p = 0.02931). CONCLUSIONS: PLS for lower limb soft tissue sarcomas shows promising results, although it is premature to reach solid conclusions. Multicentre studies, standardization of criteria, larger sample sizes and longer-term follow-up are imperative for further validation.

Circadian Control of Histone Turnover During Cardiac Development and Growth.

Rationale: During postnatal cardiac hypertrophy, cardiomyocytes undergo mitotic exit, relying on DNA replication-independent mechanisms of histone turnover to maintain chromatin organization and gene transcription. In other tissues, circadian oscillations in nucleosome occupancy influence clock-controlled gene expression, suggesting an unrecognized role for the circadian clock in temporal control of histone turnover and coordinate cardiomyocyte gene expression. Objective: To elucidate roles for the master circadian transcription factor, Bmal1, in histone turnover, chromatin organization, and myocyte-specific gene expression and cell growth in the neonatal period. Methods and Results: Bmal1 knockdown in neonatal rat ventricular myocytes (NRVM) decreased myocyte size, total cellular protein, and transcription of the fetal hypertrophic gene Nppb following treatment with increasing serum concentrations or the α-adrenergic agonist phenylephrine (PE). Bmal1 knockdown decreased expression of clock-controlled genes Per2 and Tcap, and salt-inducible kinase 1 (Sik1) which was identified via gene ontology analysis of Bmal1 targets upregulated in adult versus embryonic hearts. Epigenomic analyses revealed co-localized chromatin accessibility and Bmal1 localization in the Sik1 promoter. Bmal1 knockdown impaired Per2 and Sik1 promoter accessibility as measured by MNase-qPCR and impaired histone turnover indicated by metabolic labeling of acid-soluble chromatin fractions and immunoblots of total and chromatin-associated core histones. Sik1 knockdown basally increased myocyte size, while simultaneously impairing and driving Nppb and Per2 transcription, respectively. Conclusions: Bmal1 is required for neonatal myocyte growth, replication-independent histone turnover, and chromatin organization at the Sik1 promoter. Sik1 represents a novel clock-controlled gene that coordinates myocyte growth with hypertrophic and clock-controlled gene transcription.

Addendum to: The relationship between sperm nuclear DNA fragmentation, mitochondrial DNA fragmentation and copy number in normal and abnormal human ejaculates.

BACKGROUND: While the kinetics of human sperm nuclear DNA fragmentation (SDF-nDNA) following ejaculation have been described, the dynamics and relationships of mitochondrial DNA copy number per spermatozoon (mtDNAcn) and fragmentation (SDF-mtDNA) remain unexplored. OBJECTIVES: To compare post-ejaculatory kinetics of mtDNAcn, SDF-mtDNA and SDF-nDNA, global, single-strand DNA breaks (SDF-SSBs) and double-strand DNA breaks (SDF-DSBs) in normozoospermic and non-normozoospermic samples. MATERIALS AND METHODS: 28 normozoospermic and 43 non-normozoospermic ejaculates were evaluated at 0, 6, 24 and 48 h of incubation in vitro. SDF-nDNA was determined by sperm chromatin dispersion (SCD) assays. mtDNAcn and SDF-mtDNA were analysed by dPCR. RESULTS: SDF-nDNA-global values increased as a consequence of quadratic SDF-SSBs and linear SDF-DSBs kinetics. Non-normozoospermic samples showed a slower SDF-global rate between 6-24 h, due to lesser SSBs production. Regarding SDF-DSBs, non-normozoospermic samples exhibited a faster initial increase rate, followed by a slower final increment. The mtDNAcn median value decreased linearly, being 3.2× higher in non-normozoospermics at all time points; mtDNAcn in both cohorts reduced to half of the baseline by 48 h. mtDNAcn was identified as a risk factor for discriminating non-normozoospermia, a finding that was further strengthen when combined with SDF-Global or SDF-DSBs values. SDF-mtDNA frequencies were identical, increasing over time correspondingly in both cohorts. The mtDNA fragmentation rate was initially fast, decreasing progressively with time for both cohorts; half of the initially unfragmented copies were fragmented after 48 h. Rates of mtDNAcn loss and SDF-mtDNA increase were only marginally correlated with the rates of nuclear fragmentation. CONCLUSION: mtDNA fragmentation and loss occur post ejaculation. Their dynamics are likely to be associated with different and/or uncoupled mechanisms to that which cause nuclear DNA fragmentation. Our results indicate that while mtDNA fragmentation is not influenced by the sperm quality, the number of copies of sperm mtDNAcn can potentially serve as a risk factor for predicting non-normozoospermia.

Accuracy and Survival Outcomes after National Implementation of Sentinel Lymph Node Biopsy in Early Stage Endometrial Cancer.

BACKGROUND: Sentinel lymph node (SLN) biopsy has recently been accepted to evaluate nodal status in endometrial cancer at early stage, which is key to tailoring adjuvant treatments. Our aim was to evaluate the national implementation of SLN biopsy in terms of accuracy to detect nodal disease in a clinical setting and oncologic outcomes according to the volume of nodal disease. PATIENTS AND METHODS: A total of 29 Spanish centers participated in this retrospective, multicenter registry including patients with endometrial adenocarcinoma at preoperative early stage who had undergone SLN biopsy between 2015 and 2021. Each center collected data regarding demographic, clinical, histologic, therapeutic, and survival characteristics. RESULTS: A total of 892 patients were enrolled. After the surgery, 12.9% were suprastaged to FIGO 2009 stages III-IV and 108 patients (12.1%) had nodal involvement: 54.6% macrometastasis, 22.2% micrometastases, and 23.1% isolated tumor cells (ITC). Sensitivity of SLN biopsy was 93.7% and false negative rate was 6.2%. After a median follow up of 1.81 years, overall surivial and disease-free survival were significantly lower in patients who had macrometastases when compared with patients with negative nodes, micrometastases or ITC. CONCLUSIONS: In our nationwide cohort we obtained high sensitivity of SLN biopsy to detect nodal disease. The oncologic outcomes of patients with negative nodes and low-volume disease were similar after tailoring adjuvant treatments. In total, 22% of patients with macrometastasis and 50% of patients with micrometastasis were at low risk of nodal metastasis according to their preoperative risk factors, revealing the importance of SLN biopsy in the surgical management of patients with early stage EC.

Lymphovascular Space Invasion in Early-Stage Endometrial Cancer (LySEC): Patterns of Recurrence and Predictors. A Multicentre Retrospective Cohort Study of the Spain Gynecologic Oncology Group.

The main aim is to compare oncological outcomes and patterns of recurrence of patients with early-stage endometrioid endometrial cancer according to lymphovascular space invasion (LVSI) status. The secondary objective is to determine preoperative predictors of LVSI. We performed a multicenter retrospective cohort study. A total of 3546 women diagnosed with postoperative early-stage (FIGO I-II, 2009) endometrioid endometrial cancer were included. Co-primary endpoints were disease-free survival (DFS), overall survival (OS), and pattern of recurrence. Cox proportional hazard models were used for time-to-event analysis. Univariate and multivariate logistical regression models were employed. Positive LVSI was identified in 528 patients (14.6%) and was an independent prognostic factor for DFS (HR 1.8), OS (HR 2.1) and distant recurrences (HR 2.37). Distant recurrences were more frequent in patients with positive LVSI (78.2% vs. 61.3%, p < 0.01). Deep myometrial invasion (OR 3.04), high-grade tumors (OR 2.54), cervical stroma invasion (OR 2.01), and tumor diameter ≥ 2 cm (OR 2.03) were independent predictors of LVSI. In conclusion, in these patients, LVSI is an independent risk factor for shorter DFS and OS, and distant recurrence, but not for local recurrence. Deep myometrial invasion, cervical stroma invasion, high-grade tumors, and a tumor diameter ≥ 2 cm are independent predictors of LVSI.

Doble estimulación durante la fase folicular y lútea: una herramienta útil para bajas respondedoras / Dual stimulation during the follicular and luteal phase: a useful tool for low responders

Introducción: La baja respuesta ovárica tiene una incidencia del 5% al 24% y constituye un desafío para el profesional y puede ser motivo de frustración para los pacientes. El concepto de DuoStim o de doble estimulación en un mismo ciclo surge de implementar una estimulación durante la fase lútea a la convencional en fase folicular, con el objetivo de conseguir mayor respuesta ovárica y mayor número de ovocitos sin aumentar las tasas de complicaciones.Material y métodos: búsqueda bibliográfica en la literatura publicada sobre el protocolo de doble estimulación ovárica, enfocado sobre todo a aquellas mujeres que cumplen los criterios de Bolonia, publicados en los últimos 10 años; es decir, desde 2011 a 2021.Resultados: tabla de elaboración propia que recopila algunos de los artículos más interesantes sobre el tema tratado.Discusión: el protocolo DuoStim nos permite limitar el riesgo de cancelación del ciclo y maximiza el número de ovocitos por estimulación, siendo por tanto un procedimiento más costo-efectivo.Conclusiones: El protocolo de Shanghai proporciona una opción aceptable con un régimen de tratamiento más eficiente en el tiempo y menos costoso para los pacientes con baja respuesta ovárica. (AU)

Introduction:Low ovarian response has an incidence of 5% to 24% and is a challenge for the professio-nal and can be a source of frustration for patients. The concept of DuoStim or double stimulation in the same cycle arises from implementing a stimulation during the luteal phase to the conventional one in the follicular phase, with the aim of achieving greater ovarian response and a greater number of oocytes without increasing reaction rates.•Material and methods:bibliographic research in the literature published on the double ovarian stimulation protocol, focused on all those women who meet the Bologna criteria, published in the last 10 years; that is, from 2011 to 2021.•Results:self-made table that compiles some of the most interesting articles on the subject matter.•Discussion:the DuoStim protocol allows us to limit the risk of cycle cancellation and maximizes the number of oocytes per stimulation, thus being a more cost-effective procedure.•Conclusions: The Shanghai protocol provides an acceptable option with a more time-efficient and less expensive treatment regimen for patients with poor ovarian response. (AU)

Comparative analysis of the cardiomyocyte differentiation potential of induced pluripotent stem cells reprogrammed from human atrial or ventricular fibroblasts.

Background: We had shown that cardiomyocytes (CMs) were more efficiently differentiated from human induced pluripotent stem cells (hiPSCs) when the hiPSCs were reprogrammed from cardiac fibroblasts rather than dermal fibroblasts or blood mononuclear cells. Here, we continued to investigate the relationship between somatic-cell lineage and hiPSC-CM production by comparing the yield and functional properties of CMs differentiated from iPSCs reprogrammed from human atrial or ventricular cardiac fibroblasts (AiPSC or ViPSC, respectively). Methods: Atrial and ventricular heart tissues were obtained from the same patient, reprogrammed into AiPSCs or ViPSCs, and then differentiated into CMs (AiPSC-CMs or ViPSC-CMs, respectively) via established protocols. Results: The time-course of expression for pluripotency genes (OCT4, NANOG, and SOX2), the early mesodermal marker Brachyury, the cardiac mesodermal markers MESP1 and Gata4, and the cardiovascular progenitor-cell transcription factor NKX2.5 were broadly similar in AiPSC-CMs and ViPSC-CMs during the differentiation protocol. Flow-cytometry analyses of cardiac troponin T expression also indicated that purity of the two differentiated hiPSC-CM populations (AiPSC-CMs: 88.23% ± 4.69%, ViPSC-CMs: 90.25% ± 4.99%) was equivalent. While the field-potential durations were significantly longer in ViPSC-CMs than in AiPSC-CMs, measurements of action potential duration, beat period, spike amplitude, conduction velocity, and peak calcium-transient amplitude did not differ significantly between the two hiPSC-CM populations. Yet, our cardiac-origin iPSC-CM showed higher ADP and conduction velocity than previously reported iPSC-CM derived from non-cardiac tissues. Transcriptomic data comparing iPSC and iPSC-CMs showed similar gene expression profiles between AiPSC-CMs and ViPSC-CMs with significant differences when compared to iPSC-CM derived from other tissues. This analysis also pointed to several genes involved in electrophysiology processes responsible for the physiological differences observed between cardiac and non-cardiac-derived cardiomyocytes. Conclusion: AiPSC and ViPSC were differentiated into CMs with equal efficiency. Detected differences in electrophysiological properties, calcium handling activity, and transcription profiles between cardiac and non-cardiac derived cardiomyocytes demonstrated that 1) tissue of origin matters to generate a better-featured iPSC-CMs, 2) the sublocation within the cardiac tissue has marginal effects on the differentiation process.

Chimeric SCIP flap with iliac bone for reconstruction of foot first ray in a radiated surgical bed: A case report.

Surgical management of sarcoma has evolved from amputation to limb salvage. Nevertheless, subsequent resections in previously irradiated feet are still challenging to reconstruct. First foot ray functional reconstruction is relevant due to its function in weight-bearing and gait. The reconstruction should include a thin, pliable and non-shearing skin paddle with vascularized long cortical bone to mimic the first metatarsal. A clinical case of a 37-year-old patient with a second sarcoma recurrence of the first metatarsal is presented. The patient was irradiated before this new recurrence and had a previous reconstruction with fibula allograft, but subsequently developed a first metatarsal pseudoarthrosis. A wide resection was performed (3.5 cm bone defect) and immediate soft tissue and bone reconstruction with a chimeric SCIP flap with a 17 × 8 cm skin paddle and 3.5 × 1.5 cm iliac bone (cSCIP-IB). At 7 months post-operatively, the patient was able to resumed full weight-bearing. Three years later, remains without disease progression. CSCIP-IB is a good option for foot first ray reconstruction in irradiated beds. This flap has low donor site morbidity and a higher ossification success rate compared to bone allografts.

Lesión ovárica compleja. Localización infrecuente de metástasis de cáncer medular de tiroides. Reporte de caso y revisión de la bibliografía / Complex ovarian lesion. Infrequent localization of metastasis of medullary thyroid cancer. Case report and review of the literature

Resumen ANTECEDENTES: El carcinoma medular de tiroides es un tumor maligno poco frecuente que se origina en las células parafoliculares tiroideas productoras de calcitonina. Si bien puede aparecer espontáneamente, la asociación familiar pocas veces es excepcional. Aunque la supervivencia en estadios iniciales es considerable, es frecuente la posibilidad de metástasis al momento del diagnóstico. CASO CLÍNICO: Paciente de 72 años, con un abultamiento en la región anterior del cuello y una adenopatía cervical izquierda de 15 días de evolución. La TAC, la ecografía y la biopsia reportaron: carcinoma bilateral de ovario poco diferenciado. Se procedió a la cirugía radical (histerectomía, doble anexectomía, linfadenectomía pélvica y para aórtica, omentectomía y apendicectomía) con la que se consiguió una citorreducción completa. En el estudio definitivo se encontraron metástasis de carcinoma medular de tiroides en ambos ovarios, miometrio y peritoneo. Enseguida se inició la quimioterapia con vandetanib. Después de 25 ciclos de tratamiento, la paciente continuó con el ácido zoledrónico y asintomática. Un mes después de finalizarlo comenzó con crisis comiciales que se trataron con quetiapina, con respuesta satisfactoria. Posteriormente, la paciente tuvo una celulitis facial que se trató con antibiótico y corticosteroide; tres semanas después falleció debido a insuficiencia multiorgánica. CONCLUSIONES: El carcinoma medular de tiroides es una rara localización de metástasis que aún requiere investigación que permita establecer protocolos de diagnóstico, tratamiento y estimación de la supervivencia.

Abstract BACKGROUND: Medullary thyroid carcinoma is a rare malignant tumor originating in the calcitonin-producing parafollicular thyroid cells. Although it can occur spontaneously, familial association is rarely exceptional. Although survival in early stages is considerable, the possibility of metastasis at the time of diagnosis is frequent. CLINICAL CASE: 72-year-old patient with a lump in the anterior neck region and left cervical adenopathy of 15 days of evolution. CT, ultrasound, and biopsy reported: bilateral poorly differentiated ovarian carcinoma. Radical surgery (hysterectomy, double adnexectomy, pelvic and para-aortic lymphadenectomy, omentectomy and appendectomy) was performed and complete cytoreduction was achieved. In the definitive study, metastases of medullary thyroid carcinoma were found in both ovaries, myometrium and peritoneum. Chemotherapy with vandetanib was then started. After 25 cycles of treatment, the patient continued with zoledronic acid and was asymptomatic. One month after the end of the treatment, she began to have comic crises that were treated with quetiapine, with satisfactory response. Subsequently, the patient had a facial cellulitis that was treated with antibiotics and corticosteroids; three weeks later she died due to multiorgan failure. CONCLUSIONS: Medullary thyroid carcinoma is a rare site of metastasis that still requires research to establish diagnostic and treatment protocols and to estimate survival.