MTOR cross-talk in cancer and potential for combination therapy

The mammalian Target of Rapamycin (mTOR) pathway plays an essential role in sensing and integrating a variety of exogenous cues to regulate cellular growth and metabolism, in both physiological and pathological conditions. mTOR functions through two functionally and structurally distinct multi-component complexes, mTORC1 and mTORC2, which interact with each other and with several elements of other signaling pathways. In the past few years, many new insights into mTOR function and regulation have been gained and extensive genetic and pharmacological studies in mice have enhanced our understanding of how mTOR dysfunction contributes to several diseases, including cancer. Single-agent mTOR targeting, mostly using rapalogs, has so far met limited clinical success; however, due to the extensive cross-talk between mTOR and other pathways, combined approaches are the most promising avenues to improve clinical efficacy of available therapeutics and overcome drug resistance. This review provides a brief and up-to-date narrative on the regulation of mTOR function, the relative contributions of mTORC1 and mTORC2 complexes to cancer development and progression, and prospects for mTOR inhibition as a therapeutic strategy

Role of mTOR signaling in tumor microenvironment. An overview

The mammalian target of rapamycin (mTOR) pathway regulates major processes by integrating a variety of exogenous cues, including diverse environmental inputs in the tumor microenvironment (TME). In recent years, it has been well recognized that cancer cells co-exist and co-evolve with their TME, which is often involved in drug resistance. The mTOR pathway modulates the interactions between the stroma and the tumor, thereby affecting both the tumor immunity and angiogenesis. The activation of mTOR signaling is associated with these pro-oncogenic cellular processes, making mTOR a promising target for new combination therapies. This review highlights the role of mTOR signaling in the characterization and the activity of the TME’s elements and their implications in cancer immunotherapy

Dielectric characterization of Plasmodium falciparum infected red blood cells using microfluidic impedance cytometry

Although malaria is the world’s most life-threatening parasitic disease, there is no clear understanding of how certain biophysical properties of infected cells change during the malaria infection cycle. In this article, we use microfluidic impedance cytometry to measure the dielectric properties of Plasmodium falciparum-infected red blood cells (i-RBCs) at specific time-points during the infection cycle. Individual parasites were identified within i-RBCs using Green Fluorescent Protein (GFP) emission. The dielectric properties of cell sub-populations were determined using the multi-shell model. Analysis showed that the membrane capacitance and cytoplasmic conductivity of i-RBCs increased along the infection time-course, due to membrane alterations caused by parasite infection. The volume ratio occupied by the parasite was estimated to vary from <10% at earlier stages, to ~90% at later stages. This knowledge could be used to develop new label-free cell sorting techniques for sample pre-enrichment, improving diagnosis

Current therapeutic strategies for advanced pancreatic cancer: A review for clinicians

Pancreatic cancer (PC) would become the second leading cause of cancer death in the near future, despite representing only 3% of new cancer diagnosis. Survival improvement will come from a better knowledge of risk factors, earlier diagnosis, better integration of locoregional and systemic therapies, as well as the development of more efficacious drugs rising from a deeper understanding of disease biology. For patients with unresectable, non-metastatic disease, combined strategies encompassing primary chemotherapy and radiation seems to be promising. In fit patients, new polychemotherapy regimens can lead to better outcomes in terms of slight but significant survival improvement associated with a positive impact on quality of life. The upfront use of these regimes can also increase the rate of radical resections in borderline resectable and locally advanced PC. Second line treatments showed to positively affect both overall survival and quality of life in fit patients affected by metastatic disease. At present, oxaliplatin-based regimens are the most extensively studied. Nonetheless, other promising drugs are currently under evaluation. Presently, in addition to surgery and conventional radiation therapy, new locoregional treatment techniques are emerging as alternative options in the multimodal approach to patients or diseases not suitable for radical surgery. As of today, in contrast with other types of cancer, targeted therapies failed to show relevant activity either alone or in combination with chemotherapy and, thus, current clinical practice does not include them. Up to now, despite the fact of extremely promising results in different tumors, also immunotherapy is not in the actual therapeutic armamentarium for PC. In the present paper, we provide a comprehensive review of the current state of the art of clinical practice and research in PC aiming to offer a guide for clinicians on the most relevant topics in the management of this disease

AN INFORMATIVE CONTENT 3D MODEL FOR THE HALL HOLDING THE RESURRECTION OF CHRIST BY PIERO DELLA FRANCESCA MURAL PAINTING AT SANSEPOLCRO, ITALY

The Resurrection of Christ by Piero della Francesca (about 1460) at Sansepolcro (Italy) is a masterpiece in the development of painting. The painting is located in a hall of the city government building, which today holds the Civic Museum of Sansepolcro. This mural painting was realized on a brick wall (15&thinsp;cm thick) located in a different place as it is today. Shortly later, the painting was moved by means of a transport to solid-wall and placed against a pre-existing wall (60&thinsp;cm thick), where it is today, erecting against this wall a counter wall (15&thinsp;cm thick) where the mural painting wall-panel (225&thinsp;&times;&thinsp;200&thinsp;cm) had been inserted.Within the studies aimed at restoration and conservation of the painting, the type and characteristics of the walls of the museum hall and of the wall where the painting is located have been defined through different types of diagnostic surveys. Geometric, physical, mechanical and material data from surveys are knowledge that must be archived and made accessible for future maintenance operations. Building Information Modeling (BIM) is a valid methodology that allows to build a three-dimensional database in which to collect information about diagnostics and conservation of the historical building. The aim of this paper is digitalization through the HBIM methodology of the hall of Resurrection, in order to create a “3D informative model” that describes the geometry with objects linking them the information related to knowledge of cultural heritage and it can represent a technical and organizational support for future conservation operations.</p

mTOR Cross-Talk in Cancer and Potential for Combination Therapy.

The mammalian Target of Rapamycin (mTOR) pathway plays an essential role in sensing and integrating a variety of exogenous cues to regulate cellular growth and metabolism, in both physiological and pathological conditions. mTOR functions through two functionally and structurally distinct multi-component complexes, mTORC1 and mTORC2, which interact with each other and with several elements of other signaling pathways. In the past few years, many new insights into mTOR function and regulation have been gained and extensive genetic and pharmacological studies in mice have enhanced our understanding of how mTOR dysfunction contributes to several diseases, including cancer. Single-agent mTOR targeting, mostly using rapalogs, has so far met limited clinical success; however, due to the extensive cross-talk between mTOR and other pathways, combined approaches are the most promising avenues to improve clinical efficacy of available therapeutics and overcome drug resistance. This review provides a brief and up-to-date narrative on the regulation of mTOR function, the relative contributions of mTORC1 and mTORC2 complexes to cancer development and progression, and prospects for mTOR inhibition as a therapeutic strategy

PTEN as a Prognostic/Predictive Biomarker in Cancer: An Unfulfilled Promise?

Abstract Identifying putative biomarkers of clinical outcomes in cancer is crucial for successful enrichment, and for the selection of patients who are the most likely to benefit from a specific therapeutic approach. Indeed, current research in personalized cancer therapy focuses on the possibility of identifying biomarkers that predict prognosis, sensitivity or resistance to therapies. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene that regulates several crucial cell functions such as proliferation, survival, genomic stability and cell motility through both enzymatic and non-enzymatic activities and phosphatidylinositol 3-kinase (PI3K)-dependent and -independent mechanisms. Despite its undisputed role as a tumor suppressor, assessment of PTEN status in sporadic human tumors has yet to provide clinically robust prognostic, predictive or therapeutic information. This is possibly due to the exceptionally complex regulation of PTEN function, which involves genetic, transcriptional, post-transcriptional and post-translational events. This review shows a brief summary of the regulation and function of PTEN and discusses its controversial aspects as a prognostic/predictive biomarker

Viability, Sublethal Injury, and Release of Cellular Components From Alicyclobacillus acidoterrestris Spores and Cells After the Application of Physical Treatments, Natural Extracts, or Their Components

Alicyclobacillus acidoterrestris is a spoiling microorganism regarded as one of the most important causes of spoilage of fruit juices and acidic products. In this paper, four strains of A. acidoterrestris (type strain-DSM 3922; two wild strains isolated from soil-C8 and C24; wild strain isolated from a spoiled pear juice CB1) were treated through natural extracts/active compounds from essential oils (EOs), and physical treatments were used to assess their susceptibility and the presence of sublethal injury. The characterization of damage was also performed. The results suggest that it is possible to control A. acidoterrestris through alternative approaches, although the effect relied upon the age of spores. In addition to the mere antimicrobial effect, some treatments could cause a sublethal injury on spores. Lemon extract was the most effective treatment for both the antimicrobial effect and the sublethal injury, as evidenced by the release of proteins, and calcium dipicolinate [dipicolinic acid (DPA)] by fresh spores and only DPA (with an exception for C8) by old spores. A sublethal injury with protein release was also found for physical treatments [US (ultrasound) or heating]. For the first time, this paper reports on the existence of a sublethal injury for A. acidoterrestris, and this evidence could also be a challenge, because injured microorganisms could restore their metabolism, or an opportunity to design new preserving treatments