Structural Complexity and Seismogenesis: The Role of the Transpressive Structures in the 1976 Friuli Earthquakes (Eastern Southern Alps, NE Italy)

We reconstructed the seismotectonic setting of the area comprising the northeastern Friuli Plain and the Julian pre-Alpine border (NE Italy) by integrating geological and seismological data. The study area represents the junction between the SSE-verging polyphase thrust-front of the southAlpine Chain and the NW–SE-trending strike-slip faults of the eastern Friuli–western Slovenia domain. Following a multidisciplinary approach, the 3D geometry of the Susans–Tricesimo thrust system was reconstructed through the elaboration of four geological cross sections derived from the interpretation of ENI industrial seismic lines. In a second step, the seismogenic volume of the central-eastern Friuli area was investigated through hypocentral distribution analysis: the seismic events of the latest 50 years (1976–1977 and 1978–2019 time intervals) were plotted on four NE-SWoriented seriated sections together with the fault plane’s geometry. Through this procedure, we were able to investigate the relationship between the NW-SE-striking high-angle faults, which characterize the northern Julian pre-Alps, and the WSW-verging medium-angle reverse fronts located at the piedmont of the Friuli plain, which experienced NW-SE-to NNW-SSE-oriented compression starting at least from the Pliocene. In detail, we examined the involvement of these structures during the seismic sequences of May and September 1976, in terms of activation and/or interaction. The resulting seismotectonic model highlights the interplay between transpressive/strike-slip and reverse planes. In particular, this study suggests that Predjama and Maniaglia transpressive faults strongly control the stress release and likely played a fundamental role both during the 6 May (Mw 6.5) and 15 September (Mw 6.0) Friuli earthquakes

The Leukemic Stem Cell Niche: Adaptation to “Hypoxia” versus Oncogene Addiction

Previous studies based on low oxygen concentrations in the incubation atmosphere revealed that metabolic factors govern the maintenance of normal hematopoietic or leukemic stem cells (HSC and LSC). The physiological oxygen concentration in tissues ranges between 0.1 and 5.0%. Stem cell niches (SCN) are placed in tissue areas at the lower end of this range (“hypoxic” SCN), to which stem cells are metabolically adapted and where they are selectively hosted. The data reported here indicated that driver oncogenic proteins of several leukemias are suppressed following cell incubation at oxygen concentration compatible with SCN physiology. This suppression is likely to represent a key positive regulator of LSC survival and maintenance (self-renewal) within the SCN. On the other hand, LSC committed to differentiation, unable to stand suppression because of addiction to oncogenic signalling, would be unfit to home in SCN. The loss of oncogene addiction in SCN-adapted LSC has a consequence of crucial practical relevance: the refractoriness to inhibitors of the biological activity of oncogenic protein due to the lack of their molecular target. Thus, LSC hosted in SCN are suited to sustain the long-term maintenance of therapy-resistant minimal residual disease

The metabolically-modulated stem cell niche: a dynamic scenario regulating cancer cell phenotype and resistance to therapy.

This Perspective addresses the interactions of cancer stem cells (CSC) with environment which result in the modulation of CSC metabolism, and thereby of CSC phenotype and resistance to therapy. We considered first as a model disease chronic myeloid leukemia (CML), which is triggered by a well-identified oncogenetic protein (BCR/Abl) and brilliantly treated with tyrosine kinase inhibitors (TKi). However, TKi are extremely effective in inducing remission of disease, but unable, in most cases, to prevent relapse. We demonstrated that the interference with cell metabolism (oxygen/glucose shortage) enriches cells exhibiting the leukemia stem cell (LSC) phenotype and, at the same time, suppresses BCR/Abl protein expression. These LSC are therefore refractory to the TKi Imatinib-mesylate, pointing to cell metabolism as an important factor controlling the onset of TKi-resistant minimal residual disease (MRD) of CML and the related relapse. Studies of solid neoplasias brought another player into the control of MRD, low tissue pH, which often parallels cancer growth and progression. Thus, a 3-party scenario emerged for the regulation of CSC/LSC maintenance, MRD induction and disease relapse: the “hypoxic” versus the “ischemic” vs. the “acidic” environment. As these environments are unlikely constrained within rigid borders, we named this model the “metabolically-modulated stem cell niche.

Arachidonate 15-lipoxygenase is required for chronic myeloid leukemia stem cell survival

Cancer stem cells (CSCs) are responsible for the initiation and maintenance of some types of cancer, suggesting that inhibition of these cells may limit disease progression and relapse. Unfortunately, few CSC-specific genes have been identified. Here, we determined that the gene encoding arachidonate 15-lipoxygenase (Alox15/15-LO) is essential for the survival of leukemia stem cells (LSCs) in a murine model of BCR-ABL-induced chronic myeloid leukemia (CML). In the absence of Alox15, BCR-ABL was unable to induce CML in mice. Furthermore, Alox15 deletion impaired LSC function by affecting cell division and apoptosis, leading to an eventual depletion of LSCs. Moreover, chemical inhibition of 15-LO function impaired LSC function and attenuated CML in mice. The defective CML phenotype in Alox15-deficient animals was rescued by depleting the gene encoding P-selectin, which is upregulated in Alox15-deficient animals. Both deletion and overexpression of P-selectin affected the survival of LSCs. In human CML cell lines and CD34+ cells, knockdown of Alox15 or inhibition of 15-LO dramatically reduced survival. Loss of Alox15 altered expression of PTEN, PI3K/AKT, and the transcription factor ICSBP, which are known mediators of cancer pathogenesis. These results suggest that ALOX15 has potential as a therapeutic target for eradicating LSCs in CML

The Leukemic Stem Cell Niche: Adaptation to “Hypoxia” versus Oncogene Addiction

Previous studies based on low oxygen concentrations in the incubation atmosphere revealed that metabolic factors govern the maintenance of normal hematopoietic or leukemic stem cells (HSC and LSC). The physiological oxygen concentration in tissues ranges between 0.1 and 5.0%. Stem cell niches (SCN) are placed in tissue areas at the lower end of this range (“hypoxic” SCN), to which stem cells are metabolically adapted and where they are selectively hosted. The data reported here indicated that driver oncogenic proteins of several leukemias are suppressed following cell incubation at oxygen concentration compatible with SCN physiology. This suppression is likely to represent a key positive regulator of LSC survival and maintenance (self-renewal) within the SCN. On the other hand, LSC committed to differentiation, unable to stand suppression because of addiction to oncogenic signalling, would be unfit to home in SCN. The loss of oncogene addiction in SCN-adapted LSC has a consequence of crucial practical relevance: the refractoriness to inhibitors of the biological activity of oncogenic protein due to the lack of their molecular target. Thus, LSC hosted in SCN are suited to sustain the long-term maintenance of therapy-resistant minimal residual disease

Leukemia vaccine overcomes limitations of checkpoint blockade by evoking clonal T cell responses in a murine acute myeloid leukemia model

We have developed a personalized vaccine whereby patient derived leukemia cells are fused to autologous dendritic cells, evoking a polyclonal T cell response against shared and neo-antigens. We postulated that the dendritic cell (DC)/AML fusion vaccine would demonstrate synergy with checkpoint blockade by expanding tumor antigen specific lymphocytes that would provide a critical substrate for checkpoint blockade mediated activation. Using an immunocompetent murine leukemia model, we examined the immunologic response and therapeutic efficacy of vaccination in conjunction with checkpoint blockade with respect to leukemia engraftment, disease burden, survival and the induction of tumor specific immunity. Mice treated with checkpoint blockade alone had rapid leukemia progression and demonstrated only a modest extension of survival. Vaccination with DC/AML fusions resulted in the expansion of tumor specific lymphocytes and disease eradication in a subset of animals, while the combination of vaccination and checkpoint blockade induced a fully protective tumor specific immune response in all treated animals. Vaccination followed by checkpoint blockade resulted in upregulation of genes regulating activation and proliferation in memory and effector T cells. Long term survivors exhibited increased T cell clonal diversity and were resistant to subsequent tumor challenge. The combined DC/AML fusion vaccine and checkpoint blockade treatment offers unique synergy inducing the durable activation of leukemia specific immunity, protection from lethal tumor challenge and the selective expansion of tumor reactive clones

Toward a mechanistic understanding of the combined action of copper micropollutants and light irradiation on phytoplankton: an investigation across multiple levels of biological organization

In the aquatic environment, the effects of micropollutants to photosynthetic microorganisms are influenced by multiple biotic and abiotic factors. However, the combined effects of environmental stressors and specie-specie interaction on micropollutant effects are understudied. The present doctoral work aims to get an insight on the processes governing the combined action of light and copper micropollutants on phytoplankton. The research approach included studies with the green alga Chlamydomonas reinhardtii and cyanobacterium Synechocystis sp. at molecular, cellular and population level. The results revealed that the mechanisms of combined action of copper and light toward phytoplankton are complex, and might change depending on (i) light intensity and spectral composition, (ii) copper form (dissolved-nanoparticulate), (iii) exposure sequence and duration, (iv) phytoplankton species and their interaction. The outcomes of this work are expected to help reduce the uncertainties in lab-to-field extrapolation of toxicity data to perform multiple stressor risk assessment of micropollutants