Publications by authors named "Alberto Toso"

18 Publications

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

Early Hum Dev 2019 03 18;130:44-50. Epub 2019 Jan 18.

Departamento de Neonatología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile.

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.
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http://dx.doi.org/10.1016/j.earlhumdev.2019.01.008DOI Listing
March 2019

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

Nat Commun 2016 12 12;7:13719. Epub 2016 Dec 12.

Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona CH 6500, Switzerland.

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.
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http://dx.doi.org/10.1038/ncomms13719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5159884PMC
December 2016

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

Oncoimmunology 2015 Sep 3;4(9):e988473. Epub 2015 Jun 3.

Institute of Oncology Research (IOR); Oncology Institute of Southern Switzerland ; Bellinzona, Switzerland.

The present study supports a model in which loss-induced senescence is hindered in prostate tumor cells by non cell-autonomous mechanisms. Indeed, paracrine signaling by tumor-infiltrating CD11bGr-1 myeloid cells triggers senescence evasion in prostate lesions of -null mice, eventually promoting tumor progression.
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http://dx.doi.org/10.4161/2162402X.2014.988473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570142PMC
September 2015

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

Nat Commun 2015 Jun 18;6:7227. Epub 2015 Jun 18.

1] Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), CH 6500 Bellinzona, Switzerland [2] Faculty of Biology and Medicine, University of Lausanne (UNIL), CH-1011 Lausanne, Switzerland.

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.
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http://dx.doi.org/10.1038/ncomms8227DOI Listing
June 2015

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

Clin Cancer Res 2015 Jul 12;21(14):3108-12. Epub 2015 May 12.

Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. Faculty of Biology and Medicine, University of Lausanne UNIL, Lausanne, Switzerland.

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.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-2261DOI Listing
July 2015

Enhancing chemotherapy efficacy by reprogramming the senescence-associated secretory phenotype of prostate tumors: A way to reactivate the antitumor immunity.

Oncoimmunology 2015 Mar 22;4(3):e994380. Epub 2015 Jan 22.

Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI) ; Bellinzona, Switzerland ; Faculty of Biology and Medicine; University of Lausanne ; Lausanne, Switzerland.

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http://dx.doi.org/10.4161/2162402X.2014.994380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404842PMC
March 2015

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

Cell Rep 2014 Oct 25;9(1):75-89. Epub 2014 Sep 25.

Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland; Faculty of Biology and Medicine, University of Lausanne, UNIL, Rue du Bugnon 21, Lausanne 1011, Switzerland. Electronic address:

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.
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http://dx.doi.org/10.1016/j.celrep.2014.08.044DOI Listing
October 2014

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

Nature 2014 Nov 24;515(7525):134-7. Epub 2014 Aug 24.

1] Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona CH6500, Switzerland [2] Faculty of Biology and Medicine, University of Lausanne UNIL, Lausanne CH1011, Switzerland.

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.
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http://dx.doi.org/10.1038/nature13638DOI Listing
November 2014

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

J Cell Biol 2014 Mar 24;204(7):1099-109. Epub 2014 Mar 24.

Institute of Biochemistry, Department of Biology, and 2 Light Microscopy Center, Swiss Federal Institute of Technology Zurich, CH-8093 Zurich, Switzerland.

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.
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http://dx.doi.org/10.1083/jcb.201310116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971743PMC
March 2014

[Interests and perspectives of first and last year medical students].

Rev Med Chil 2012 May;140(5):609-15

Escuela de Medicina, Facultad de Medicina, Universidad de Chile, Santiago, Chile.

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.
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http://dx.doi.org/10.4067/S0034-98872012000500008DOI Listing
May 2012

CLASPs prevent irreversible multipolarity by ensuring spindle-pole resistance to traction forces during chromosome alignment.

Nat Cell Biol 2012 Feb 5;14(3):295-303. Epub 2012 Feb 5.

Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal.

Loss of spindle-pole integrity during mitosis leads to multipolarity independent of centrosome amplification. Multipolar-spindle conformation favours incorrect kinetochore-microtubule attachments, compromising faithful chromosome segregation and daughter-cell viability. Spindle-pole organization influences and is influenced by kinetochore activity, but the molecular nature behind this critical force balance is unknown. CLASPs are microtubule-, kinetochore- and centrosome-associated proteins whose functional perturbation leads to three main spindle abnormalities: monopolarity, short spindles and multipolarity. The first two reflect a role at the kinetochore-microtubule interface through interaction with specific kinetochore partners, but how CLASPs prevent spindle multipolarity remains unclear. Here we found that human CLASPs ensure spindle-pole integrity after bipolarization in response to CENP-E- and Kid-mediated forces from misaligned chromosomes. This function is independent of end-on kinetochore-microtubule attachments and involves the recruitment of ninein to residual pericentriolar satellites. Distinctively, multipolarity arising through this mechanism often persists through anaphase. We propose that CLASPs and ninein confer spindle-pole resistance to traction forces exerted during chromosome congression, thereby preventing irreversible spindle multipolarity and aneuploidy.
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http://dx.doi.org/10.1038/ncb2423DOI Listing
February 2012

Mechanisms of aneuploidy and its suppression by tumour suppressor proteins.

Swiss Med Wkly 2011 8;141:w13170. Epub 2011 Mar 8.

Institute of Cell Biology, ETH Zurich, Switzerland.

Aneuploidy, as a result of numerical changes in chromosome number, was observed in tumours almost a century ago. The molecular mechanisms underlying this phenomenon and their impact on tumour development are still poorly understood. A series of recent observations provide direct linkages between the normal function of tumour suppressor proteins and the suppression of aneuploidy. The prospects that these findings offer for understanding the role of aneuploidy in cancer are discussed in this review.
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http://dx.doi.org/10.4414/smw.2011.13170DOI Listing
May 2011

Kinetochore alignment within the metaphase plate is regulated by centromere stiffness and microtubule depolymerases.

J Cell Biol 2010 Mar;188(5):665-79

Marine Biological Laboratory, Woods Hole, MA 02543, USA.

During mitosis in most eukaryotic cells, chromosomes align and form a metaphase plate halfway between the spindle poles, about which they exhibit oscillatory movement. These movements are accompanied by changes in the distance between sister kinetochores, commonly referred to as breathing. We developed a live cell imaging assay combined with computational image analysis to quantify the properties and dynamics of sister kinetochores in three dimensions. We show that baseline oscillation and breathing speeds in late prometaphase and metaphase are set by microtubule depolymerases, whereas oscillation and breathing periods depend on the stiffness of the mechanical linkage between sisters. Metaphase plates become thinner as cells progress toward anaphase as a result of reduced oscillation speed at a relatively constant oscillation period. The progressive slowdown of oscillation speed and its coupling to plate thickness depend nonlinearly on the stiffness of the mechanical linkage between sisters. We propose that metaphase plate formation and thinning require tight control of the state of the mechanical linkage between sisters mediated by centromeric chromatin and cohesion.
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http://dx.doi.org/10.1083/jcb.200909005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835940PMC
March 2010

VHL loss causes spindle misorientation and chromosome instability.

Nat Cell Biol 2009 Aug 20;11(8):994-1001. Epub 2009 Jul 20.

Institute of Cell Biology, ETH Zurich, 8093 Zurich, Switzerland.

Error-free mitosis depends on fidelity-monitoring checkpoint systems that ensure correct temporal and spatial coordination of chromosome segregation by the microtubule spindle apparatus. Defects in these checkpoint systems can lead to genomic instability, an important aspect of tumorigenesis. Here we show that the von Hippel-Lindau (VHL) tumour suppressor protein, pVHL, which is inactivated in hereditary and sporadic forms of renal cell carcinoma, localizes to the mitotic spindle in mammalian cells and its functional inactivation provokes spindle misorientation, spindle checkpoint weakening and chromosomal instability. Spindle misorientation is linked to unstable astral microtubules and is supressed by the restoration of wild-type pVHL in pVHL-deficient cells, but not in naturally-occurring VHL disease mutants that are defective in microtubule stabilization. Impaired spindle checkpoint function and chromosomal instability are the result of reduced Mad2 (mitotic arrest deficient 2) levels actuated by pVHL-inactivation and are rescued by re-expression of either Mad2 or pVHL in VHL-defective cells. An association between VHL inactivation, reduced Mad2 levels and increased aneuploidy was also found in human renal cancer, implying that the newly identified functions of pVHL in promoting proper spindle orientation and chromosomal stability probably contribute to tumour suppression.
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http://dx.doi.org/10.1038/ncb1912DOI Listing
August 2009

Analysing kinetochore function in human cells: spindle checkpoint and chromosome congression.

Methods Mol Biol 2009 ;545:205-20

Institute of Biochemistry, ETH Zurich, Zurich, Switzerland.

During cell division microtubules of the mitotic spindle segregate the duplicated chromosomes into the two daughter cells. Chromosome-microtubule attachment is mediated by kinetochores, multiprotein complexes assembled on specialized regions of the DNA. Kinetochores modulate microtubule dynamics to generate the forces necessary to power chromosome movement and regulate the spindle checkpoint. Errors in kinetochore function can cause aneuploidy, a hallmark of 80% of solid tumors in humans, suggesting a fundamental link to tumorigenesis. Human kinetochores are complex protein machines with over 100 different proteins. Here we present fixed- and live-cell-based assays used to functionally categorize kinetochore proteins with regard to spindle checkpoint activity and kinetochore-microtubule attachment.
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http://dx.doi.org/10.1007/978-1-60327-993-2_12DOI Listing
November 2009

Kinetochore-generated pushing forces separate centrosomes during bipolar spindle assembly.

J Cell Biol 2009 Feb;184(3):365-72

Institute of Biochemistry, ETH Zurich, CH-8093 Zurich, Switzerland.

In animal somatic cells, bipolar spindle formation requires separation of the centrosome-based spindle poles. Centrosome separation relies on multiple pathways, including cortical forces and antiparallel microtubule (MT) sliding, which are two activities controlled by the protein kinase aurora A. We previously found that depletion of the human kinetochore protein Mcm21R(CENP-O) results in monopolar spindles, raising the question as to whether kinetochores contribute to centrosome separation. In this study, we demonstrate that kinetochores promote centrosome separation after nuclear envelope breakdown by exerting a pushing force on the kinetochore fibers (k-fibers), which are bundles of MTs that connect kinetochores to centrosomes. This force is based on poleward MT flux, which incorporates new tubulin subunits at the plus ends of k-fibers and requires stable k-fibers to drive centrosomes apart. This kinetochore-dependent force becomes essential for centrosome separation if aurora A is inhibited. We conclude that two mechanisms control centrosome separation during prometaphase: an aurora A-dependent pathway and a kinetochore-dependent pathway that relies on k-fiber-generated pushing forces.
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http://dx.doi.org/10.1083/jcb.200809055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646558PMC
February 2009

The human kinetochore proteins Nnf1R and Mcm21R are required for accurate chromosome segregation.

EMBO J 2006 Sep 24;25(17):4033-49. Epub 2006 Aug 24.

Department of Biology, MIT, Cambridge, MA, USA.

Kinetochores (KTs) assemble on centromeric DNA, bi-orient paired sister chromatids on spindle microtubules (MTs) and control cell-cycle progression via the spindle assembly checkpoint. Genetic and biochemical studies in budding yeast have established that three 'linker' complexes, MIND, COMA and NDC80, play essential but distinct roles in KT assembly and chromosome segregation. To determine whether similar linker activities are present at human KTs, we have compared the functions of Nnf1R and Mcm21R, recently identified MIND and COMA subunits, and Nuf2R, a well-characterized NDC80 subunit. We find that the three proteins bind to KTs independent of each other and with distinct cell-cycle profiles. MT-KT attachment is aberrant in Nnf1R- and Mcm21R-depleted cells, whereas it is lost in the absence of Nuf2R. Defective attachments in Nnf1R-depleted cells prevent chromosome congression, whereas those in Mcm21R-depleted cells interfere with spindle assembly. All three human KT proteins are necessary for correct binding of spindle checkpoint proteins to KTs. The differing functions and KT-binding properties of Nnf1R, Mcm21R and Nuf2R suggest that, like their yeast counterparts, the proteins act independent of each other in KT assembly, but that their combined activities are required for checkpoint signaling.
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http://dx.doi.org/10.1038/sj.emboj.7601293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1560365PMC
September 2006