Liver cancer development driven by the AP-1/c-Jun~Fra-2 dimer through c-Myc.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. HCC incidence is on the rise, while treatment options remain limited. Thus, a better understanding of the molecular pathways involved in HCC development has become a priority to guide future therapies. While previous studies implicated the Activator Protein-1 (AP-1) (Fos/Jun) transcription factor family members c-Fos and c-Jun in HCC formation, the contribution of Fos-related antigens (Fra-) 1 and 2 is unknown. Here, we show that hepatocyte-restricted expression of a single chain c-Jun~Fra-2 protein, which functionally mimics the c-Jun/Fra-2 AP-1 dimer, results in spontaneous HCC formation in c-Jun~Fra-2hep mice. Several hallmarks of human HCC, such as cell cycle dysregulation and the expression of HCC markers are observed in liver tumors arising in c-Jun~Fra-2hep mice. Tumorigenesis occurs in the context of mild inflammation, low-grade fibrosis, and Pparγ-driven dyslipidemia. Subsequent analyses revealed increased expression of c-Myc, evidently under direct regulation by AP-1 through a conserved distal 3' enhancer. Importantly, c-Jun~Fra-2-induced tumors revert upon switching off transgene expression, suggesting oncogene addiction to the c-Jun~Fra-2 transgene. Tumors escaping reversion maintained c-Myc and c-Myc target gene expression, likely due to increased c-Fos. Interfering with c-Myc in established tumors using the Bromodomain and Extra-Terminal motif inhibitor JQ-1 diminished liver tumor growth in c-Jun~Fra-2 mutant mice. Thus, our data establish c-Jun~Fra-2hep mice as a model to study liver tumorigenesis and identify the c-Jun/Fra-2-Myc interaction as a potential target to improve HCC patient stratification and/or therapy.

Hernia inguinal inusual en paciente de edad media: cuando el ovario y la trompa atraviesan el canal inguinal: a propósito de un caso / Unusual inguinal hernia in a middle-aged patient: when the ovary and fallopian tubepass through the inguinal canal: acase report / Hérnia inguinal incomum em paciente de meia-idade: quando o ovário e a trompauterina passam pelo canal inguinal: um relato de caso

La hernia inguinal supone la patología de pared abdominal más frecuente hoy en día. En el saco herniario podemos encontrar diferentes estructuras, como grasa preperitoneal, intestino delgado, colon o incluso la vejiga, resultando inusual la presencia de la trompa de Falopio y el ovario. El contenido tubo-ovárico supone un hallazgo frecuente en población pediátrica, mientras que resulta un hecho extremadamente raro en mujeres en edad reproductiva o menopáusica, siendo imprescindible su tratamiento con el fin de evitar complicaciones relacionadas con la fertilidad y la viabilidad de los anejos. Con el objetivo de revisar la bibliografía descrita al respecto dado la infrecuencia que supone este hallazgo en mujeres adultas, se presenta el siguiente caso clínico de forma resumida, con la consiguiente revisión de la literatura disponible. Se trata de una paciente mujer de 50 años, con antecedentes de mioma uterino, intervenida de forma programada de hernioplastia inguinal derecha, observando contenido tubo-ovárico en el saco herniario, en la cual se realiza hernioplastia inguinal según la técnica de Lichtenstein con preservación de anejos sin complicaciones postoperatorias. Como conclusiones finales, consideramos que los hallazgos intraoperatorios de contenido tubo-ovárico en la cirugía de hernia inguinal en mujeres adultas supone un hecho infrecuente, cuyo conocimiento y manejo resulta necesario para el cirujano general, precisando de un índice de alta sospecha con el fin de evitar complicaciones y otorgar el tratamiento quirúrgico más óptimo para el bienestar de los pacientes.

Inguinal hernia represents the most common pathology of the abdominal wall currently. In the hernia sac, various structures can be found, such as preperitonealphat, smallbowel, colon, oreventhe bladder, but the presence of the fall opiantube and ovaryisun common. Tubo-ovarian content is a frequent finding in pediatric population, while infection is extremely rare in women of reproductive or menopausal age, requiring essential treatment to prevent complications related to fertility and adnexal viability. In order to review the literature described in this regard, given the infrequency of this finding in adult women, we present the following clinical case, along with a review of the available literature. The patient is a 50-year-old woman with a history of uterine fibroids, who underwent surgery of a right inguinal hernioplasty, revealing tube-ovarian content in the hernia sac. Inguinal hernioplasty was performed using the Lichtenstein technique with preservation of adnexa, and there were no postoperative complications. In final conclusions, we consider that intraoperative finding of tube-ovarian content in inguinal hernia surgery in adult women are uncommon, and knowledge and management of this condition are necessary for the general surgeon. A high index of suspicion is required to avoid complications and provide the most optimal surgical treatment for the well-being of patients.

A hérnia inguinal representa uma patologia comum da parede abdominal nos dias seguintes. No saco herniário, podem ser encontradas diferentes estruturas, como gordura pré-peritoneal, intestino delgado, cólon propriamente dito com a bexiga, sendoincomum com presença da trompa de Falópio e do ovário. O conteúdo trompa-ovariano é muito comum em populações pediátricas, mas é extremamente raro em mulheres em saúde reprodutiva ou na menopausa, sendo essencial ou seutratamento para evitar complicações relacionadas à fertilidade e à viabilidade dos dois anexos. Com o objetivo de revisar a bibliografia descrita a esse respeito, dado pouco discutido em mulheres adultas, o seguinte caso clínico é apresentado de forma resumida, juntamente com uma revisão da literatura disponível. Trata-se de paciente do sexo feminino, 50 anos, com história de mioma uterino, submetida a hernioplastia inguinal direta programada, observando-se conteúdo da tuba ovariana e saco herniário. A hernioplastia inguinal foi realizada segundo a técnica de Lichtenstein, comprimindo dois anexos e sem complicações operatórias. Como conclusões finais, consideramos que a redução intraoperatória do conteúdo tubo-ovariano na cirurgia de hérnia inguinal em mulheres adultas é incomum, e o conhecimento e o manejo dos procedimentos necessários à cirurgia geral requerem um alto índice de suspeita para evitar complicações e proporcionar tratamento cirúrgico . maisadequado para ou bem-est dois pacientes.

Preclinical discovery and initial clinical data of WVT078, a BCMA × CD3 bispecific antibody.

B-cell maturation antigen (BCMA) is an ideal target in multiple myeloma (MM) due to highly specific expression in malignant plasma cells. BCMA-directed therapies including antibody drug conjugates, chimeric antigen receptor-T cells and bispecific antibodies (BsAbs) have shown high response rates in MM. WVT078 is an anti-BCMA× anti-CD3 BsAb that binds to BCMA with subnanomolar-affinity. It was selected based on potent T cell activation and anti-MM activity in preclinical models with favorable tolerability in cynomolgus monkey. In the ongoing first-in-human phase I dose-escalation study (NCT04123418), 33 patients received intravenous WVT078 once weekly at escalated dosing. At the active doses of 48-250 µg/kg tested to date (n = 26), the overall response rate (ORR) was 38.5% (90% CI: 22.6-56.4%) and the complete response rate (CRR, stringent complete response + complete response) was 11.5%, (90% CI: 3.2-27.2%). At the highest dose level tested, the ORR was 75% (3 of 4 patients). 26 (78.8%) patients reported at least one Grade ≥3 AE and 16 of these AEs were suspected to be drug related. 20 patients (60.6%) experienced cytokine release syndrome. WVT078 has an acceptable safety profile and shows preliminary evidence of clinical activity at doses tested to date.

Correction: Magallon et al. Oxidative Stress and Endoplasmic Reticulum Stress in Rare Respiratory Diseases. J. Clin. Med. 2021, 10, 1268.

Sara Pastor was not included as an author in the original publication [...].

Small extracellular vesicles from young adipose-derived stem cells prevent frailty, improve health span, and decrease epigenetic age in old mice.

Aging is associated with an increased risk of frailty, disability, and mortality. Strategies to delay the degenerative changes associated with aging and frailty are particularly interesting. We treated old animals with small extracellular vesicles (sEVs) derived from adipose mesenchymal stem cells (ADSCs) of young animals, and we found an improvement in several parameters usually altered with aging, such as motor coordination, grip strength, fatigue resistance, fur regeneration, and renal function, as well as an important decrease in frailty. ADSC-sEVs induced proregenerative effects and a decrease in oxidative stress, inflammation, and senescence markers in muscle and kidney. Moreover, predicted epigenetic age was lower in tissues of old mice treated with ADSC-sEVs and their metabolome changed to a youth-like pattern. Last, we gained some insight into the microRNAs contained in sEVs that might be responsible for the observed effects. We propose that young sEV treatment can promote healthy aging.

Utilidad de la neuromonitorización vagal continua en cirugía tiroidea: experiencia y resultados en un hospital de tercer nivel / The role of continuous vagal intraoperative nerve monitoring in thyroid surgery: experience and results in a third-level hospital

Resumen Objetivo: La lesión del nervio laríngeo recurrente es una grave complicación en cirugía tiroidea. El propósito del presente estudio es analizar la utilidad de la neuromonitorización vagal continua intraoperatoria en un hospital terciario. Materiales y Método: Estudio observacional, analítico y retrospectivo que recoge pacientes intervenidos de cirugía tiroidea con neuromonitorización en un período de 14 meses. La pérdida de señal se define como amplitud final nerviosa < 100 ^V, realizándose laringoscopia postquirúrgica ante la sospecha de lesión nerviosa. El análisis estadístico se realizó con el programa SPSS® V25,0, con p < 0,05. Resultados: Se incluyeron 120 pacientes intervenidos, registrándose en el 24,2% pérdida de señal. Factores de riesgo para lesión fueron bocio intratorácico (OR 5,31; IC 95% 1,56-17,99; p = 0,007), cirugía cervical previa (OR 5,76; IC 95% 0,64-51,97; p = 0,119) y patología maligna (OR 1,44; IC 95% 0,16-12,79; p = 0,743). Fue posible el cambio de estrategia quirúrgica en 7 casos. En el seguimiento posterior se cuantificó parálisis recurrencial transitoria en 27 pacientes y permanente en 4. Discusión: La neuromonitorización parece reducir la incidencia de parálisis laríngea porque aumenta la seguridad en la identificación del nervio recurrente y reduce su manipulación durante la cirugía. Conclusiones: La neuromonitorización intraoperatoria es útil para identificar el nervio laríngeo recurrente y advierte del riesgo potencial de lesión, permitiendo cambiar la estrategia quirúrgica para evitar la parálisis bilateral de cuerdas vocales.

Aim: Recurrent laryngeal nerve injury is a serious complication in thyroid surgery. The purpose of the present study is to analyze the use of intraoperative continuous vagal neuromonitoring in a tertiary hospital. Materials and Method: Observational, analytical and retrospective study that includes patients who underwent thyroid surgery with neuromonitoring in a period of 14 months. Loss of signal is defined as final nerve amplitude < 100 ^V, and postsurgical laryngoscopy is performed due to suspicion of nerve injury. Statistical analysis was performed with the SPSS® V25.0 program, with p < 0.05. Results: 120 operated patients were included, registering loss of signal in 24.2%. Risk factors for injury were intrathoracic goiter (OR 5.31; 95% CI 1.56-17.99; p = 0.007), previous cervical surgery (OR 5.76; 95% CI 0.64-51.97; p = 0.119) and malignant pathology (OR 1.44; 95% CI 0.16-12.79; p = 0.743). A change in surgical strategy was possible in 7 cases. In the subsequent follow-up, transient recurrent paralysis was quantified in 27 patients and permanent in 4. Discussion: Neuromonitoring seems to reduce the incidence of laryngeal paralysis because it increases the security in the identification of the recurrent nerve and reduces its manipulation during surgery. Conclusions: Intraoperative neuromonitoring is useful to identify the recurrent laryngeal nerve and warns of the potential risk of injury, allowing to change the surgical strategy to avoid bilateral vocal cord paralysis.

Isquemia aguda del canal anal / Acute Ischemia of the Anal Canal

Introducción: La isquemia anal aguda con gangrena es una entidad infrecuente, con escasa literatura publicada al respecto, cuyas cifras de mortalidad descritas se sitúan en un 20 por ciento - 40 por ciento de los casos. Debe considerarse en ancianos con enfermedad aterosclerótica que presenten síntomas gastrointestinales inferiores y shock hipotensivo. Puede ser causada por oclusión vascular aguda, enfermedad vascular grave o un estado de bajo flujo, aunque en algunos casos se presenta sin enfermedad vascular preexistente. Objetivo: Presentar la literatura existente acerca del manejo diagnóstico y terapéutico de la isquemia de canal anal en base a un caso clínico diagnosticado y tratado de urgencia en el hospital "Marina Baixa". Caso clínico: Se presenta un caso de isquemia espontánea de canal anal en paciente de 76 años de edad con morbilidad cardiovascular asociada. Debuta como cuadro séptico sin evidencia de causa desencadenante. Conclusiones: Las pruebas endoscópicas y radiológicas deben realizarse con urgencia y la valoración quirúrgica está siempre justificada en estos pacientes debido a la alta tasa de mortalidad descrita en el manejo conservador del cuadro. En casos graves, la reanimación preoperatoria y cirugía urgente para resecar el segmento gangrenoso es necesaria. Sin embargo, el tratamiento de la proctitis isquémica aguda es controvertido y depende, en parte, del estado basal del paciente y los hallazgos clínicos, siendo importante examinar otras posibles etiologías de proctitis isquémica y así determinar qué pacientes necesitan intervención quirúrgica temprana en comparación con una actitud más conservadora(AU)

Introduction: Acute ischemic gangrene of the anus is an infrequent entity, with little published literature, whose reported mortality figures are 20-40 percent of cases. It should be considered in elderlies with atherosclerotic disease who present lower gastrointestinal symptoms and hypotensive shock. It can be caused by acute vascular occlusion, severe vascular disease, or a low-flow state, although in some cases it presents without pre-existing vascular disease. Objective: To present the existing literature on diagnostic and therapeutic management of ischemia of the anal canal upon the base of a clinical case diagnosed and treated as an urgency at Marina Baixa hospital. Clinical case: The case is presented of a 76-year-old patient with spontaneous ischemia of the anal canal and associated cardiovascular morbidity. It debuts as a septic condition without evidence of a triggering cause. Conclusions: Endoscopic and radiological tests should be performed urgently. Surgical assessment is always justified in these patients, due to the high mortality rate described in the conservative management of the condition. In severe cases, preoperative resuscitation and urgent surgery to resect the gangrenous segment is necessary. However, managment of acute ischemic proctitis is controversial and depends, in part, on the patient's baseline status and clinical findings, while it is important to examine other possible etiologies of ischemic proctitis and thus determine which patients need early surgical intervention compared to a more conservative attitude(AU)

PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer.

High-grade serous ovarian cancers (HGSOC) represent the most common subtype of ovarian malignancies. Due to the frequency of late-stage diagnosis and high rates of recurrence following standard of care treatments, novel therapies are needed to promote durable responses. We investigated the anti-tumor activity of CD3 T cell engaging bispecific antibodies (TCBs) directed against the PAX8 lineage-driven HGSOC tumor antigen LYPD1 and demonstrated that anti-LYPD1 TCBs induce T cell activation and promote in vivo tumor growth inhibition in LYPD1-expressing HGSOC. To selectively target LYPD1-expressing tumor cells with high expression while sparing cells with low expression, we coupled bivalent low-affinity anti-LYPD1 antigen-binding fragments (Fabs) with the anti-CD3 scFv. In contrast to the monovalent anti-LYPD1 high-affinity TCB (VHP354), the bivalent low-affinity anti-LYPD1 TCB (QZC131) demonstrated antigen density-dependent selectivity and showed tolerability in cynomolgus monkeys at the maximum dose tested of 3 mg/kg. Collectively, these data demonstrate that bivalent TCBs directed against LYPD1 have compelling efficacy and safety profiles to support its use as a treatment for high-grade serous ovarian cancers.

Management of symptomatic uterine fibroids after ulipristal acetate suspension and identification of high risk patients for surgery at 6-months of follow-up.

OBJECTIVE: The use of ulipristal acetate (UPA) was indicated for the treatment of uterine fibroids. Following UPA suspension in March 2020, some patients presented worsening and required surgery. We aimed to identify patients at high-risk for undergoing surgery after UPA suspension. METHODS: We evaluated 85 women receiving intermittent UPA treatment until March 2020. Following UPA suspension, patients received other medical treatments or surgery. The clinico-pathological features were recoded and a quality of life health survey was completed by patients at the time of UPA suspension and at 6-months thereafter. RESULTS: After the suspension of UPA, 17 of the 85 patients receiving intermittent UPA (20%) required surgery, and 68 (80%) required other medical treatments. Patients who underwent surgery were younger and had greater fibroid volume. CONCLUSIONS: In our series, 20% of clinically stable patients receiving intermittent UPA required surgery following UPA suspension. These women should be considered for future medical strategies.

Oxidative Stress and Endoplasmic Reticulum Stress in Rare Respiratory Diseases.

Several studies have shown that some rare respiratory diseases, such as alpha-1 antitrypsin deficiency (AATD), idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), and primary ciliary dyskinesia (PCD) present oxidative stress (OS) and endoplasmic reticulum (ER) stress. Their involvement in these pathologies and the use of antioxidants as therapeutic agents to minimize the effects of OS are discussed in this review.

Shorter telomere lengths in patients with severe COVID-19 disease.

The incidence of severe manifestations of COVID-19 increases with age with older patients showing the highest mortality, suggesting that molecular pathways underlying aging contribute to the severity of COVID-19. One mechanism of aging is the progressive shortening of telomeres, which are protective structures at chromosome ends. Critically short telomeres impair the regenerative capacity of tissues and trigger loss of tissue homeostasis and disease. The SARS-CoV-2 virus infects many different cell types, forcing cell turn-over and regeneration to maintain tissue homeostasis. We hypothesize that presence of short telomeres in older patients limits the tissue response to SARS-CoV-2 infection. We measure telomere length in peripheral blood lymphocytes COVID-19 patients with ages between 29 and 85 years-old. We find that shorter telomeres are associated to increased severity of the disease. Individuals within the lower percentiles of telomere length and higher percentiles of short telomeres have higher risk of developing severe COVID-19 pathologies.

Dynamics of telomeric repeat-containing RNA expression in early embryonic cleavage stages with regards to maternal age.

Telomeres are transcribed into long non-coding RNAs known as Telomeric Repeat-Containing RNA (TERRA). They have been shown to be essential regulators of telomeres and to act as epigenomic modulators at extra-telomeric sites. However the role of TERRA during early embryonic development has never been investigated. Here, we show that TERRA is expressed in murine and bovine early development following a wave pattern. It starts at 4-cell stage, reaching a maximum at the 16-cell followed by a decline at the morula and blastocyst stages. Moreover, TERRA expression is not affected by increasing oocyte donor age whereas telomere length does. This indicates that TERRA expression is independent of the telomere length in early development. Our findings anticipate an essential role of TERRA in early stages of development and this might be useful in the future for a better understanding of age related female infertility.

Social stress during adolescence activates long-term microglia inflammation insult in reward processing nuclei.

The experience of social stress during adolescence is associated with higher vulnerability to drug use. Increases in the acquisition of cocaine self-administration, in the escalation of cocaine-seeking behavior, and in the conditioned rewarding effects of cocaine have been observed in rodents exposed to repeated social defeat (RSD). In addition, prolonged or severe stress induces a proinflammatory state with microglial activation and increased cytokine production. The aim of the present work was to describe the long-term effects induced by RSD during adolescence on the neuroinflammatory response and synaptic structure by evaluating different glial and neuronal markers. In addition to an increase in the conditioned rewarding effects of cocaine, our results showed that RSD in adolescence produced inflammatory reactivity in microglia that is prolonged into adulthood, affecting astrocytes and neurons of two reward-processing areas of the brain (the prelimbic cortex, and the nucleus accumbens core). Considered as a whole these results suggest that social stress experience modulates vulnerability to suffer a loss of glia-supporting functions and neuronal functional synaptic density due to drug consumption in later life.

Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation.

Human hepatocellular carcinomas (HCCs), which arise on a background of chronic liver damage and inflammation, express c-Fos, a component of the AP-1 transcription factor. Using mouse models, we show that hepatocyte-specific deletion of c-Fos protects against diethylnitrosamine (DEN)-induced HCCs, whereas liver-specific c-Fos expression leads to reversible premalignant hepatocyte transformation and enhanced DEN-carcinogenesis. c-Fos-expressing livers display necrotic foci, immune cell infiltration, and altered hepatocyte morphology. Furthermore, increased proliferation, dedifferentiation, activation of the DNA damage response, and gene signatures of aggressive HCCs are observed. Mechanistically, c-Fos decreases expression and activity of the nuclear receptor LXRα, leading to increased hepatic cholesterol and accumulation of toxic oxysterols and bile acids. The phenotypic consequences of c-Fos expression are partially ameliorated by the anti-inflammatory drug sulindac and largely prevented by statin treatment. An inverse correlation between c-FOS and the LXRα pathway was also observed in human HCC cell lines and datasets. These findings provide a novel link between chronic inflammation and metabolic pathways important in liver cancer.

Long-acting protein drugs for the treatment of ocular diseases.

Protein drugs that neutralize vascular endothelial growth factor (VEGF), such as aflibercept or ranibizumab, rescue vision in patients with retinal vascular diseases. Nonetheless, optimal visual outcomes require intraocular injections as frequently as every month. Here we report a method to extend the intravitreal half-life of protein drugs as an alternative to either encapsulation or chemical modifications with polymers. We combine a 97-amino-acid peptide of human origin that binds hyaluronan, a major macromolecular component of the eye's vitreous, with therapeutic antibodies and proteins. When administered to rabbit and monkey eyes, the half-life of the modified proteins is increased ∼3-4-fold relative to unmodified proteins. We further show that prototype long-acting anti-VEGF drugs (LAVAs) that include this peptide attenuate VEGF-induced retinal changes in animal models of neovascular retinal disease ∼3-4-fold longer than unmodified drugs. This approach has the potential to reduce the dosing frequency associated with retinal disease treatments.

Percepción de los graduados de la carrera de medicina de la Universidad de Cuenca 2003-2012, sobre la formación en la relación y comunicación médico-paciente / Perception of the medical career graduates of the University of Cuenca 2003 - 2012, on training in the relationship medical communication ­ patient

Objetivo: Identificar la percepción de los médicos graduados en la Facultad de Ciencias Médicas, respecto a su formación en el tema de Relación y Comunicación Médico Paciente.Diseño: es un estudio descriptivo transversal. Metodología: A través de encuesta a los médicos graduados en la Facultad de Ciencias Médicas de la Universidad de Cuenca.Se utilizó una base de datos del programa de Monitoreo de los graduados de la carrera de Medicina de la Universidad de Cuenca, 2003- 2012. Azuay. Resultados: Se realizaron 208 encuestas, 116 varones (56%) y 92 mujeres (44%), cuyas edades oscilan entre los 23 y 42 años, todos graduados de la Escuela de Medicina de la Universidad de Cuenca entre los años 2003 a 2012. El 98% de ellos residentes en el Ecuador. Respecto a la percepción sobre su formación en relación médico paciente y comunicación: para comunicación escrita, comunicación oral, entrega de noticias negativas, relación afectiva con los pacientes y participación comunitaria: la percepción es que su formación fue adecuada, en tanto aprecian como poco adecuado en manejo de situaciones de conflicto, al igual que en la aplicación del consentimiento informado

Objective. To identify the perception of the graduated doctors from Medical Faculty, regarding to their formation in the Relationship and Communication with patients.Design: It is a cross-sectional study.Methodology: A survey to graduated doctors from Medical Faculty in the University of Cuenca was conducted.A database of the monitoring program for graduated people from Medicine School in the University of Cuenca, Azuay 2003-2012 was used. Results: A total of 208 surveys, 116 males with a 56% and 92 women with a 44%, aged between 23 and 42, all graduated people from Medicine School in the University of Cuenca from 2003 to 2013. The 98% are living in Ecuador.Regarding the perception of training in communication and doctor-patient relationship: to written communication, oral communication, delivering bad news, emotional relationship with patients and community participation: the perception is that their training was adequate, while it is appreciated as little suitable for handling conflict situations, as well as in the application of the informed consent.