[Double aortic arch and aortotracheal fistula as cause of fatal massive bleeding: a rare and dangerous association]. / Doble arco aórtico y fistula aortotraqueal como causa de hemorragia masiva fatal: una asociación rara y peligrosa.

Vascular rings are unusual congenital malformations. Among them, double aortic arch (DAA) is often difficult to diagnose due to its low incidence of symptoms. DAA can be associated with tracheal or esophageal compression and, in severe cases, could require tracheal intubation or chronic use of a nasogastric tube. This scenario favors the development of aortotracheal fistulas (ATF) or aortoe-sophageal fistulas (AEF). OBJECTIVE: To present a clinical case with an unusual association of DAA with ATF and to reinforce the importance of maintaining high diagnostic suspicion in patients with massive aerodigestive bleeding without an obvious source. CLINICAL CASE: A 32-week preterm newborn who required prolonged mechanical ventilation and presented intermittent episodes of massive oropharyngeal bleeding with hemodynamic compromise associated with lower airway obstruction without pulmonary hemorrhage. The patient underwent upper endoscopy and exploratory laparotomy without evidence of bleeding. Flexible nasopharyngolaryngoscopy and direct laryngoscopy also showed no abnormalities. A CT angiography showed complete DAA with indentation of the left dominant arch over the trachea, without severe stenosis or evidence of a fistula. AEF was suspected, so exploratory surgery was considered. However, the patient died before surgery due to a massive pulmonary hemorrhage. The autopsy revealed the presence of ATF. CONCLUSIONS: In patients with massive aerodigestive bleeding without an obvious source, the presence of DAA and possible AEF/ ATF should be considered. Imaging studies have a poor performance for this diagnosis, so surgery should be considered for diagnosis and treatment in these patients.

Risk-stratified Results among Congenital Diaphragmatic Hernia Patients in Two Large Extracorporeal Membrane Oxygenation Centers in South America.

INTRODUCTION: Mortality related to CDH is high, but with great variability among centers. There are few studies on patients with this condition born in South America which show poor outcomes. The goal of this study is to present the outcome of CDH in several high-volume quaternary centers in South America, ascertain the factors associated with lower mortality in our population, and compare our outcomes to those of the CDH Study Group (CDHSG). METHODS: The data from two South American centers were retrospectively analyzed and compared with contemporary data from other CDHSG participating centers. Patient demographic and clinical characteristics were also evaluated and compared. RESULTS: Between 2013 and 2018, the two South American centers saw 335 patients with CDH with an overall survival rate of 73.1%. Survival for the high, intermediate, and low-risk groups as determined by the Brindle score was 50%, 70%, and 87%, respectively. In our cohort the strongest predictors of mortality were ECMO use and early PaCO2. There were no significant differences in mortality between the two South American centers and the other CDHSG centers when adjusted by risk score, however, the South American centers had higher use of ECMO in the intermediate-risk group. DISCUSSION: Quaternary South American centers had similar outcomes to CDHSG centers worldwide. The availability and coordination of centralized dedicated care allow more efficient use of scarce technical and professional resources in patients with CDH. LEVEL OF EVIDENCE: III.

Population pharmacokinetics of amikacin in suspected cases of neonatal sepsis.

AIMS: This study aimed to characterize the population pharmacokinetic parameters of intravenously administered amikacin in newborns and assess the effect of sepsis in amikacin exposure. METHODS: Newborns aged ≥3 days who received at least 1 dose of amikacin during their hospitalization period were eligible for the study. Amikacin was administered intravenously during a 60-min infusion period. Three venous blood samples were taken from each patient during the first 48 h. Population pharmacokinetic parameter estimates were obtained using a population approach with the programme NONMEM. RESULTS: Data from 329 drug assay samples were obtained from 116 newborn patients (postmenstrual age [PMA] 38.3, range 32-42.4 weeks; weight 2.8, range 1.6-3.8 kg). Measured amikacin concentrations ranged from 0.8 to 56.4 mg/L. A 2-compartment model with linear elimination produced a good fit of the data. Estimated parameters for a typical subject (2.8 kg, 38.3 weeks) were clearance (Cl = 0.16 L/h), intercompartmental clearance (Q = 0.15 L/h), volume of distribution of the central compartment (Vc = 0.98 L) and peripheral volume of distribution (Vp = 1.23 L). Total bodyweight, PMA and the presence of sepsis positively influenced Cl. Plasma creatinine concentration and circulatory instability (shock) negatively influenced Cl. CONCLUSION: Our main results confirm previous findings showing that weight, PMA and renal function are relevant factors influencing newborn amikacin pharmacokinetics. In addition, current results showed that pathophysiological states of critically ill neonates, such as sepsis and shock, were associated with opposite effects in amikacin clearance and should be considered in dose adjustments.

Functional consequences of SARS-CoV-2 infection in pregnant women, fetoplacental unit, and neonate.

The SARS-CoV-2 infection causes COVID-19 disease, characterized by acute respiratory distress syndrome, bilateral pneumonia, and organ failure. The consequences of maternal SARS-CoV-2 infection for the pregnant woman, fetus, and neonate are controversial. Thus, it is required to determine whether there is viral and non-viral vertical transmission in COVID-19. The disease caused by SARS-CoV-2 leads to functional alterations in asymptomatic and symptomatic pregnant women, the fetoplacental unit and the neonate. Several diseases of pregnancy, including COVID-19, affect the fetoplacental function, which causes in utero programming for young and adult diseases. A generalized inflammatory state and a higher risk of infection are seen in pregnant women with COVID-19. Obesity, diabetes mellitus, and hypertension may increase the vulnerability of pregnant women to infection by SARS-CoV-2. Alpha, Delta, and Omicron variants of SARS-CoV-2 show specific mutations that seem to increase the capacity of the virus to infect the pregnant woman, likely due to increasing its interaction via the virus S protein and angiotensin-converting enzyme 2 receptors. This review shows the literature addressing to what extent COVID-19 in pregnancy affects the pregnant woman, fetoplacental unit, and neonate. Prospective studies that are key in managing SARS-CoV-2 infection in pregnancy are discussed.

Treatment of HCC with claudin-1-specific antibodies suppresses carcinogenic signaling and reprograms the tumor microenvironment.

BACKGROUND & AIMS: Despite recent approvals, the response to treatment and prognosis of patients with advanced hepatocellular carcinoma (HCC) remain poor. Claudin-1 (CLDN1) is a membrane protein that is expressed at tight junctions, but it can also be exposed non-junctionally, such as on the basolateral membrane of the human hepatocyte. While CLDN1 within tight junctions is well characterized, the role of non-junctional CLDN1 and its role as a therapeutic target in HCC remains unexplored. METHODS: Using humanized monoclonal antibodies (mAbs) specifically targeting the extracellular loop of human non-junctional CLDN1 and a large series of patient-derived cell-based and animal model systems we aimed to investigate the role of CLDN1 as a therapeutic target for HCC. RESULTS: Targeting non-junctional CLDN1 markedly suppressed tumor growth and invasion in cell line-based models of HCC and patient-derived 3D ex vivo models. Moreover, the robust effect on tumor growth was confirmed in vivo in a large series of cell line-derived xenograft and patient-derived xenograft mouse models. Mechanistic studies, including single-cell RNA sequencing of multicellular patient HCC tumorspheres, suggested that CLDN1 regulates tumor stemness, metabolism, oncogenic signaling and perturbs the tumor immune microenvironment. CONCLUSIONS: Our results provide the rationale for targeting CLDN1 in HCC and pave the way for the clinical development of CLDN1-specific mAbs for the treatment of advanced HCC. IMPACT AND IMPLICATIONS: Hepatocellular carcinoma (HCC) is associated with high mortality and unsatisfactory treatment options. Herein, we identified the cell surface protein Claudin-1 as a treatment target for advanced HCC. Monoclonal antibodies targeting Claudin-1 inhibit tumor growth in patient-derived ex vivo and in vivo models by modulating signaling, cell stemness and the tumor immune microenvironment. Given the differentiated mechanism of action, the identification of Claudin-1 as a novel therapeutic target for HCC provides an opportunity to break the plateau of limited treatment response. The results of this preclinical study pave the way for the clinical development of Claudin-1-specific antibodies for the treatment of advanced HCC. It is therefore of key impact for physicians, scientists and drug developers in the field of liver cancer and gastrointestinal oncology.

A monoclonal antibody targeting nonjunctional claudin-1 inhibits fibrosis in patient-derived models by modulating cell plasticity.

Tissue fibrosis is a key driver of end-stage organ failure and cancer, overall accounting for up to 45% of deaths in developed countries. There is a large unmet medical need for antifibrotic therapies. Claudin-1 (CLDN1) is a member of the tight junction protein family. Although the role of CLDN1 incorporated in tight junctions is well established, the function of nonjunctional CLDN1 (njCLDN1) is largely unknown. Using highly specific monoclonal antibodies targeting a conformation-dependent epitope of exposed njCLDN1, we show in patient-derived liver three-dimensional fibrosis and human liver chimeric mouse models that CLDN1 is a mediator and target for liver fibrosis. Targeting CLDN1 reverted inflammation-induced hepatocyte profibrogenic signaling and cell fate and suppressed the myofibroblast differentiation of hepatic stellate cells. Safety studies of a fully humanized antibody in nonhuman primates did not reveal any serious adverse events even at high steady-state concentrations. Our results provide preclinical proof of concept for CLDN1-specific monoclonal antibodies for the treatment of advanced liver fibrosis and cancer prevention. Antifibrotic effects in lung and kidney fibrosis models further indicate a role of CLDN1 as a therapeutic target for tissue fibrosis across organs. In conclusion, our data pave the way for further therapeutic exploration of CLDN1-targeting therapies for fibrotic diseases in patients.

Congenital diaphragmatic hernia: phosphodiesterase-5 and Arginase inhibitors prevent pulmonary vascular hypoplasia in rat lungs.

BACKGROUND: Severe pulmonary hypoplasia related to congenital diaphragmatic hernia (CDH) continues to be a potentially fatal condition despite advanced postnatal management strategies. OBJECTIVE: To evaluate the effect of the antenatal sildenafil and 2(S)-amino-6-boronohexanoic acid (ABH-Arginase inhibitor) on lung volume, pulmonary vascular development, and nitric oxide (NO) synthesis in a Nitrofen-induced CDH rat model. METHODS: Nitrofen-induced CDH rat model was used. Nitrofen was administrated on embryonic day(E) 9,5. At E14, five intervention groups were treated separately: Nitrofen, Nitrofen+Sildenafil, Nitrofen+ABH, Nitrofen+Sildenafil+ABH and Control. At term, offspring's lungs were weighed, some paraffin-embedded for histology, others snap-frozen to analyze eNOS, Arginase I-II expression, and activity. RESULTS: In CDH-bearing offsprings, ABH or Sildenafil+ABH preserved the total lung/body-weight index (p < 0.001), preventing pulmonary vascular smooth muscle cell hyperproliferation and improving lung morphometry. Sildenafil+ABH increased 1.7-fold the lung nitrite levels (p < 0.01) without changes in eNOS expression. Sildenafil and ABH improved the number of pulmonary vessels. CONCLUSION: These results suggest that in this CDH rat model, the basal activity of Arginase participates in the lung volume and, together with phosphodiesterase-5, regulates NOS activity in the term fetal lung. The combined treatment (Sildenafil+ABH) could revert some of the pulmonary features in CDH by improving the local NO synthesis and preventing smooth muscle cell hyperproliferation. IMPACT: This study presents Arginase inhibition as a new therapeutic target and the importance of the combined antenatal treatment to improve pulmonary vascular development in a congenital diaphragmatic hernia (CDH) rat model. This study shows that the action of an Arginase inhibitor (ABH) enhances the effects already described for sildenafil in this model. These results reinforce the importance of prenatal treatments' synergy in recovering the hypoplastic lung in the Nitrofen-induced CDH rat model.

Mortality in very low birth weight (VLBW) infants in South American NEOCOSUR Neonatal Network: timing and causes / Mortalidad en recién nacidos de muy bajo peso al nacer en la Red Neonatal NEOCOSUR: causalidad y temporalidad.

INTRODUCTION: Mortality in very low birth weight infants (VLBWIs) has remained at ~26% in the past 16 years in the NEOCOSUR Neonatal Network. OBJECTIVE: Mortality in very low birth weight infants (VLBWIs) has remained at ~26% in the past 16 years in the NEOCOSUR Neonatal Network. POPULATION AND METHODS: Observational, multicenter cohort study; retrospective analysis of data collected prospectively. Newborn infants born between 24 and 31+6 weeks of gestation age with a birth weight between 500 and 1500 g in the 26 sites of the NEOCOSUR Neonatal Network were included. The causes of death were analyzed depending on whether they occurred in the delivery room (DR) or in the neonatal intensive care unit (NICU). The postnatal age at time of death was determined using the KaplanMeier test. RESULTS: Observational, multicenter cohort study; retrospective analysis of data collected prospectively. Newborn infants born between 24 and 31+6 weeks of gestation age with a birth weight between 500 and 1500 g in the 26 sites of the NEOCOSUR Neonatal Network were included. The causes of death were analyzed depending on whether they occurred in the delivery room (DR) or in the neonatal intensive care unit (NICU). The postnatal age at time of death was determined using the KaplanMeier test. CONCLUSIONS: Important differences were observed in the causes of death of VLBWIs depending on their occurrence in the DR or the NICU. Infectious and respiratory conditions were the most relevant factors following admission to the NICU.

Introducción. La mortalidad de los recién nacidos de muy bajo peso de nacimiento (RNMBPN) se ha mantenido en ~26 % en los últimos 16 años en la Red Neonatal NEOCOSUR. Objetivo. Determinar la causa de muerte de los RNMBPN y su temporalidad en el período 20072016 en la Red Neonatal NEOCOSUR. Población y métodos. Estudio observacional de cohorte multicéntrica; análisis retrospectivo de datos obtenidos prospectivamente. Se incluyeron recién nacidos entre 24 y 31+6 semanas de edad gestacional y peso de nacimiento de 500-1500 g, en 26 centros de la Red Neonatal NEOCOSUR. Las causas de muerte se analizaron según ocurriera en sala de partos (SP) o durante la estadía en la unidad de cuidados intensivos neonatales (UCIN). La edad posnatal de muerte se determinó a través de análisis de Kaplan-Meier. Resultados. Se incluyeron un total de 11753 RNMBPN con una mortalidad global del 25,6 %. Las causas de muerte predominantes en SP fueron malformaciones congénitas (43,3 %), enfermedades respiratorias (14,3 %) y prematuridad (11,4 %). Las causas de muerte predominantes en UCIN fueron las respiratorias (24,2 %) e infecciosas (24,1 %). La edad promedio de muerte fue de 10,2 días y mediana de 4 días. El 10,2 % de las muertes ocurrieron en SP; el 21,5 %, durante el primer día; el 52 % ocurrió en los primeros 4 días y el 63,8 %, durante la primera semana de vida. , A través de los años, la mortalidad de los recién nacidos de muy bajo peso de nacimiento (RNMBPN) se ha mantenido estable, en torno al 26 % en la Red Neonatal NEOCOSUR.1 Esta mortalidad es mayor que la reportada por otras redes neonatales de países desarrollados. Así, los datos de la Red Suiza dan cuenta de una mortalidad de solo un 11 % entre los años 2012 a 2014 para el mismo grupo de recién nacidos.2 La red internacional iNEO, que agrupa 10 redes a lo largo del mundo, describe una mortalidad global del 9,1 % en RNMBPN de entre 24 a 32 semanas de edad gestacional entre los años 2007 y 2015.3 Por otra parte, la Red Neonatal Brasilera informa una mortalidad de 30 % en RNMBPN.4 f. Red Neonatal del Cono Sur (www. neocosur.org). Correspondencia: Alberto Toso: aatoso@ uc.cl Financiamiento: Ninguno. Conflicto de intereses: Ninguno que declarar. Recibido: 12-8-2021 Aceptado: 12-1-2022 Conclusiones. Se encuentran importantes diferencias en las causas de muerte de RNMBPN según ocurra en SP o en UCIN. Las infecciosas y respiratorias son las más relevantes luego del ingreso a la unidad de cuidados intensivos.

Mortalidad en recién nacidos de muy bajo peso al nacer en la Red Neonatal NEOCOSUR: causalidad y temporalidad / Mortality in very low birth weight (VLBW) infants in South American NEOCOSUR Neonatal Network: timing and causes

Introducción. La mortalidad de los recién nacidos de muy bajo peso de nacimiento (RNMBPN) se ha mantenido en ~26 % en los últimos 16 años en la Red Neonatal NEOCOSUR. Objetivo. Determinar la causa de muerte de los RNMBPN y su temporalidad en el período 20072016 en la Red Neonatal NEOCOSUR. Población y métodos. Estudio observacional de cohorte multicéntrica; análisis retrospectivo de datos obtenidos prospectivamente. Se incluyeron recién nacidos entre 24 y 31+6 semanas de edad gestacional y peso de nacimiento de 500-1500 g, en 26 centros de la Red Neonatal NEOCOSUR. Las causas de muerte se analizaron según ocurriera en sala de partos (SP) o durante la estadía en la unidad de cuidados intensivos neonatales (UCIN). La edad posnatal de muerte se determinó a través de análisis de Kaplan-Meier. Resultados. Se incluyeron un total de 11.753 RNMBPN con una mortalidad global del 25,6 %. Las causas de muerte predominantes en SP fueron malformaciones congénitas (43,3 %), enfermedades respiratorias (14,3 %) y prematuridad (11,4 %). Las causas de muerte predominantes en UCIN fueron las respiratorias (24,2 %) e infecciosas (24,1 %). La edad promedio de muerte fue de 10,2 días y mediana de 4 días. El 10,2 % de las muertes ocurrieron en SP; el 21,5 %, durante el primer día; el 52 % ocurrió en los primeros 4 días y el 63,8 %, durante la primera semana de vida. Conclusiones. Se encuentran importantes diferencias en las causas de muerte de RNMBPN según ocurra en SP o en UCIN. Las infecciosas y respiratorias son las más relevantes luego del ingreso a la unidad de cuidados intensivos.

Introduction. Mortality in very low birth weight infants (VLBWIs) has remained at ~26% in the past 16 years in the NEOCOSUR Neonatal Network. Objective. To determine the cause of death of VLBWIs and its temporality in the 2007-2016 period in the NEOCOSUR Neonatal Network. Population and methods. Observational, multicenter cohort study; retrospective analysis of data collected prospectively. Newborn infants born between 24 and 31+6 weeks of gestation age with a birth weight between 500 and 1500 g in the 26 sites of the NEOCOSUR Neonatal Network were included. The causes of death were analyzed depending on whether they occurred in the delivery room (DR) or in the neonatal intensive care unit (NICU). The postnatal age at time of death was determined using the KaplanMeier test. Results. A total of 11 753 VLBWIs were included; overall mortality was 25.6%. The prevailing causes of death in the DR were congenital malformations (43.3%), respiratory diseases (14.3%), and prematurity (11.4%). The prevailing causes of death in the NICU were respiratory diseases (24.2%) and infections (24.1%). The average and median age at death were 10.2 and 4 days, respectively. Also, 10.2% of deaths occurred in the DR; 21.5% on day 1, 52% in the first 4 days, and 63.8% in the first week of life. Conclusions. Important differences were observed in the causes of death of VLBWIs depending on their occurrence in the DR or the NICU. Infectious and respiratory conditions were the most relevant factors following admission to the NICU.

JAK and mTOR inhibitors prevent cytokine release while retaining T cell bispecific antibody in vivo efficacy.

BACKGROUND: T cell engaging therapies, like chimeric antigen receptor T cells and T cell bispecific antibodies (TCBs), efficiently redirect T cells towards tumor cells, facilitating the formation of a cytotoxic synapse and resulting in subsequent tumor cell killing, a process that is accompanied by the release of cytokines. Despite their promising efficacy in the clinic, treatment with TCBs is associated with a risk of cytokine release syndrome (CRS). The aim of this study was to identify small molecules able to mitigate cytokine release while retaining T cell-mediated tumor killing. METHODS: By screening a library of 52 Food and Drug Administration approved kinase inhibitors for their impact on T cell proliferation and cytokine release after CD3 stimulation, we identified mTOR, JAK and Src kinases inhibitors as potential candidates to modulate TCB-mediated cytokine release at pharmacologically active doses. Using an in vitro model of target cell killing by human peripheral blood mononuclear cells, we assessed the effects of mTOR, JAK and Src kinase inhibitors combined with 2+1 T cell bispecific antibodies (TCBs) including CEA-TCB and CD19-TCB on T cell activation, proliferation and target cell killing measured by flow cytometry and cytokine release measured by Luminex. The combination of mTOR, JAK and Src kinase inhibitors together with CD19-TCB was evaluated in vivo in non-tumor bearing stem cell humanized NSG mice in terms of B cell depletion and in a lymphoma patient-derived xenograft (PDX) model in humanized NSG mice in terms of antitumor efficacy. RESULTS: The effect of Src inhibitors differed from those of mTOR and JAK inhibitors with the suppression of CD19-TCB-induced tumor cell lysis in vitro, whereas mTOR and JAK inhibitors primarily affected TCB-mediated cytokine release. Importantly, we confirmed in vivo that Src, JAK and mTOR inhibitors strongly reduced CD19-TCB-induced cytokine release. In humanized NSG mice, continuous treatment with a Src inhibitor prevented CD19-TCB-mediated B cell depletion in contrast to mTOR and JAK inhibitors, which retained CD19-TCB efficacy. Ultimately, transient treatment with Src, mTOR and JAK inhibitors minimally interfered with antitumor efficacy in a lymphoma PDX model. CONCLUSIONS: Taken together, these data support further evaluation of the use of Src, JAK and mTOR inhibitors as prophylactic treatment to prevent occurrence of CRS.

Neonatal outcomes of antenatal corticosteroids in preterm multiple pregnancies compared to singletons.

BACKGROUND: Antenatal corticosteroids (ACS) during preterm labour reduce neonatal mortality and morbidity. Evidence on preterm multiple pregnancies is limited and contradictory. OBJECTIVE: Compare the effect of ACS on very low birth weight infant's (VLBW) mortality and morbidity among singleton and multiple pregnancies. STUDY DESIGN: Retrospective cohort study, employing prospectively collected data, of infants 23 to 34 weeks' gestation and 500 to 1500 g born at the Neocosur Neonatal Network centers during 2007-2016. Neonatal outcomes were compared among singleton and multiple pregnancies exposed to at least one dose of ACS to those not exposed using logistic regression analyses controlled for birthweight, gestational age, sex, small for gestational age (SGA) and mode of delivery. RESULTS: A total of 13,864 infants were studied; 2948 multiple (21.3%) and 10,904 singleton pregnancies (78.7%). Overall, 11,218 (81.4%) received at least one dose of ACS with a significant reduction in the risk of death, RDS and grade III or IV IVH compared to those not exposed. Both singleton and multiple pregnancies exposed to ACS showed similar reduced risk of death (aRR 0.41 [95% CI, 0.36-0.47] vs. aRR 0.46 [95% CI, 0.34-0.64]). However, ACS were not associated with reduced odds of RDS (aRR 0.89 [95% CI, 0.66-1.23]) or grade III or IV IVH (aRR 0.99 [95% CI, 0.67-1.48]) in multiple pregnancies. CONCLUSION: The benefit of administration of at least one dose of ACS in VLBW multiple and singleton pregnancies is comparable in terms of death. However, ACS showed no relevant impact in short-term morbidity in multiple pregnancies.

Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence.

Activation of NOTCH signalling is associated with advanced prostate cancer and treatment resistance in prostate cancer patients. However, the mechanism that drives NOTCH activation in prostate cancer remains still elusive. Moreover, preclinical evidence of the therapeutic efficacy of NOTCH inhibitors in prostate cancer is lacking. Here, we provide evidence that PTEN loss in prostate tumours upregulates the expression of ADAM17, thereby activating NOTCH signalling. Using prostate conditional inactivation of both Pten and Notch1 along with preclinical trials carried out in Pten-null prostate conditional mouse models, we demonstrate that Pten-deficient prostate tumours are addicted to the NOTCH signalling. Importantly, we find that pharmacological inhibition of γ-secretase promotes growth arrest in both Pten-null and Pten/Trp53-null prostate tumours by triggering cellular senescence. Altogether, our findings describe a novel pro-tumorigenic network that links PTEN loss to ADAM17 and NOTCH signalling, thus providing the rational for the use of γ-secretase inhibitors in advanced prostate cancer patients.

Tumor-infiltrating myeloid cells drive senescence evasion and chemoresistance in tumors.

The present study supports a model in which Pten loss-induced senescence is hindered in prostate tumor cells by non cell-autonomous mechanisms. Indeed, paracrine signaling by tumor-infiltrating CD11b+Gr-1+ myeloid cells triggers senescence evasion in prostate lesions of Pten-null mice, eventually promoting tumor progression.

A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours.

Enhancement of cellular senescence in tumours triggers a stable cell growth arrest and activation of an antitumour immune response that can be exploited for cancer therapy. Currently, there are only a limited number of targeted therapies that act by increasing senescence in cancers, but the majority of them are not selective and also target healthy cells. Here we developed a chemogenomic screening to identify compounds that enhance senescence in PTEN-deficient cells without affecting normal cells. By using this approach, we identified casein kinase 2 (CK2) as a pro-senescent target. Mechanistically, we show that Pten loss increases CK2 levels by activating STAT3. CK2 upregulation in Pten null tumours affects the stability of Pml, an essential regulator of senescence. However, CK2 inhibition stabilizes Pml levels enhancing senescence in Pten null tumours. Taken together, our screening strategy has identified a novel STAT3-CK2-PML network that can be targeted for pro-senescence therapy for cancer.

Molecular Pathways: Targeting Tumor-Infiltrating Myeloid-Derived Suppressor Cells for Cancer Therapy.

Tumor-infiltrating myeloid-derived suppressor cells (MDSC) are a heterogeneous and immunosuppressive cell subset that blocks the proliferation and the activity of both T and natural killer (NK) cells and promotes tumor vasculogenesis and progression. Recent evidences demonstrate that the recruitment of MDSCs in tumors also blocks senescence induced by chemotherapy promoting chemoresistance. Hence, the need of novel therapeutic approaches that can efficiently target MDSC recruitment and function in cancer. Among them, novel combinatorial treatments of chemotherapy and immunotherapy or treatments that induce depletion of MDSCs in peripheral sites should be taken in consideration.

Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity.

Prosenescence therapy has recently emerged as a novel therapeutic approach for treating cancer. However, this concept is challenged by conflicting evidence showing that the senescence-associated secretory phenotype (SASP) of senescent tumor cells can have pro- as well as antitumorigenic effects. Herein, we report that, in Pten-null senescent tumors, activation of the Jak2/Stat3 pathway establishes an immunosuppressive tumor microenvironment that contributes to tumor growth and chemoresistance. Activation of the Jak2/Stat3 pathway in Pten-null tumors is sustained by the downregulation of the protein tyrosine phosphatase PTPN11/SHP2, providing evidence for the existence of a novel PTEN/SHP2 axis. Importantly, treatment with docetaxel in combination with a JAK2 inhibitor reprograms the SASP and improves the efficacy of docetaxel-induced senescence by triggering a strong antitumor immune response in Pten-null tumors. Altogether, these data demonstrate that immune surveillance of senescent tumor cells can be suppressed in specific genetic backgrounds but also evoked by pharmacological treatments.

Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer.

Aberrant activation of oncogenes or loss of tumour suppressor genes opposes malignant transformation by triggering a stable arrest in cell growth, which is termed cellular senescence. This process is finely tuned by both cell-autonomous and non-cell-autonomous mechanisms that regulate the entry of tumour cells to senescence. Whether tumour-infiltrating immune cells can oppose senescence is unknown. Here we show that at the onset of senescence, PTEN null prostate tumours in mice are massively infiltrated by a population of CD11b(+)Gr-1(+) myeloid cells that protect a fraction of proliferating tumour cells from senescence, thus sustaining tumour growth. Mechanistically, we found that Gr-1(+) cells antagonize senescence in a paracrine manner by interfering with the senescence-associated secretory phenotype of the tumour through the secretion of interleukin-1 receptor antagonist (IL-1RA). Strikingly, Pten-loss-induced cellular senescence was enhanced in vivo when Il1ra knockout myeloid cells were adoptively transferred to PTEN null mice. Therapeutically, docetaxel-induced senescence and efficacy were higher in PTEN null tumours when the percentage of tumour-infiltrating CD11b(+)Gr-1(+) myeloid cells was reduced using an antagonist of CXC chemokine receptor 2 (CXCR2). Taken together, our findings identify a novel non-cell-autonomous network, established by innate immunity, that controls senescence evasion and chemoresistance. Targeting this network provides novel opportunities for cancer therapy.

SUN proteins facilitate the removal of membranes from chromatin during nuclear envelope breakdown.

SUN proteins reside in the inner nuclear membrane and form complexes with KASH proteins of the outer nuclear membrane that connect the nuclear envelope (NE) to the cytoskeleton. These complexes have well-established functions in nuclear anchorage and migration in interphase, but little is known about their involvement in mitotic processes. Our analysis demonstrates that simultaneous depletion of human SUN1 and SUN2 delayed removal of membranes from chromatin during NE breakdown (NEBD) and impaired the formation of prophase NE invaginations (PNEIs), similar to microtubule depolymerization or down-regulation of the dynein cofactors NudE/EL. In addition, overexpression of dominant-negative SUN and KASH constructs reduced the occurrence of PNEI, indicating a requirement for functional SUN-KASH complexes in NE remodeling. Codepletion of SUN1/2 slowed cell proliferation and resulted in an accumulation of morphologically defective and disoriented mitotic spindles. Quantification of mitotic timing revealed a delay between NEBD and chromatin separation, indicating a role of SUN proteins in bipolar spindle assembly and mitotic progression.

[Interests and perspectives of first and last year medical students]. / Intereses y perspectiva sobre la carrera de medicina: un contraste entre estudiantes de medicina de primero y séptimo año.

BACKGROUND: The interests that motivate medical students to study this career are diverse and they may change during the seven years of study. In Chile, 22 universities offer medicine and the number of graduated students has increased by more than 50% over the last 10 years. AIM: To determine the motivational profile of medical students at admission, and at the end of their career. SUBJECTS AND METHODS: A voluntary anonymous survey was applied to 275 first and 140 seventh year medical students from one traditional public and two private schools. RESULTS: The main reason for applying to medical school was social interest (68.7%), followed by interest in science and academia. Thirty six percent of students from seventh year would not study medicine again. In the seventh year, the interest in medical care persists in 88% of students, followed by academic interests in 64%. Only 24% had research interests. Fifty nine and 57% of students projected their medical work in private and public hospital settings, respectively. Only 11% projected themselves as doing research. Sixty nine percent of students would like to receive more information about post graduate education. CONCLUSIONS: There is a low interest in research and a high percentage of seventh year students that would not apply to medicine again. Medical schools should perform a systematic analysis of students' interests to improve faulty areas.