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Cells subjected to treatment with anti-cancer therapies can evade apoptosis through cellular senescence. Persistent senescent tumor cells remain metabolically active, possess a secretory phenotype, and can promote tumor proliferation and metastatic dissemination. Removal of senescent tumor cells (senolytic therapy) has therefore emerged as a promising therapeutic strategy. Here, using single-cell RNA-sequencing, we find that senescent tumor cells rely on the anti-apoptotic gene Mcl-1 for their survival. Mcl-1 is upregulated in senescent tumor cells, including cells expressing low levels of Bcl-2, an established target for senolytic therapy. While treatment with the Bcl-2 inhibitor Navitoclax results in the reduction of metastases in tumor bearing mice, treatment with the Mcl-1 inhibitor S63845 leads to complete elimination of senescent tumor cells and metastases. These findings provide insights on the mechanism by which senescent tumor cells survive and reveal a vulnerability that can be exploited for cancer therapy. Cell senescence remains a barrier to tumor elimination in many cancers. Here, the authors use single cell RNA-seq to identify a role for Mcl-1 in senescent cell survival, and show that Mcl-1 inhibition may be an effective therapeutic strategy.

The circular economy (i.e., reuse and recycling of waste materials) is gaining attention for the goal of achieving net-zero waste. In this regard, the use of waterproofing membrane waste in bituminous materials can be a valid option, as every year, a lot of bituminous membrane wastes are generated both as production scraps or end-of-life wastes. Given this background, the recycling feasibility of end-of-life bituminous membrane waste (MW) in asphalt mixtures was assessed in this research study. To this aim, MW shreds (≤20 mm) were added to dense-graded bituminous mixtures using the dry-mixing method. The shreds were dosed at 0.5% by the mix weight (mix coded as SH−) or at 2% by mix weight (mix coded as SH+). A corresponding reference mix without MW was also tested for comparison purposes. The mixtures’ workability, strength and stiffness as well as permanent deformation, moisture and fatigue resistance were evaluated. Overall, the laboratory experimental findings showed that MW-modified bituminous mixtures with a higher dosage of membrane waste (SH+) have relatively higher moisture resistance, fatigue resistance, stiffness and high-temperature performance with respect to the corresponding reference mix. Moreover, both the reference and MW-modified mixtures showed similar workability regardless of the MW content.

The mechanisms by which mitochondrial metabolism supports cancer anabolism remain unclear. Here, we found that genetic and pharmacological inactivation of pyruvate dehydrogenase A1 (PDHA1), a subunit of the pyruvate dehydrogenase complex (PDC), inhibits prostate cancer development in mouse and human xenograft tumor models by affecting lipid biosynthesis. Mechanistically, we show that in prostate cancer, PDC localizes in both the mitochondria and the nucleus. Whereas nuclear PDC controls the expression of sterol regulatory element-binding transcription factor (SREBF)-target genes by mediating histone acetylation, mitochondrial PDC provides cytosolic citrate for lipid synthesis in a coordinated manner, thereby sustaining anabolism. Additionally, we found that PDHA1 and the PDC activator pyruvate dehydrogenase phosphatase 1 (PDP1) are frequently amplified and overexpressed at both the gene and protein levels in prostate tumors. Together, these findings demonstrate that both mitochondrial and nuclear PDC sustain prostate tumorigenesis by controlling lipid biosynthesis, thus suggesting this complex as a potential target for cancer therapy. Inactivation of pyruvate dehydrogenase A1 (PDHA1), a subunit of the pyruvate dehydrogenase complex (PDC) regulating mitochondrial metabolism, inhibits lipid biosynthesis and prostate cancer development in mouse and human xenograft tumor models.

In North America and Europe, asphalt shingle waste created during the installation of roofing membranes and tear-off shingles retrieved at the end of the membrane’s life cycle are two major sources of municipal solid waste. Since almost 15–35% of recycled asphalt shingles (RAS) consist of an asphalt binder, the effective recycling of RAS into asphalt mixtures could also allow a reduction in the consumption of non-renewable resources such as asphalt binders. In this context, several studies investigating the use of RAS in asphalt mixtures can be found in the literature, although they exhibit widespread and sometimes conflicting information about the investigated materials, the mix preparation and testing methodologies and the experimental findings. Given this background, this review paper aims at summarizing the existing information and research gaps, providing a synthetic and rational picture of the current literature, where similar attempts cannot be found. In particular, different research studies show that the use of RAS in asphalt mixtures is an economical as well as an eco-friendly option. RAS with up to 20% by weight of binder or 5% by weight of aggregate/mixtures (eventually in combination with 15% reclaimed asphalt pavement aggregate) were found to be relatively suitable to improve the performance properties of asphalt mixtures, both in the laboratory and in the field. Adding RAS to asphalt mixtures could enhance their stiffness, strength and rutting resistance (i.e., high-temperature properties), while negatively affecting the mixtures’ fatigue and thermal cracking resistance. However, the addition of specific biomaterials (e.g., bio-binders, bio-oils) or additives to asphalt mixtures can mitigate such issues, resulting in lower brittleness and shear susceptibilities and thus improving the anti-cracking performance. On the other hand, the literature review revealed that several aspects still need to be studied in detail. As an example, RAS-modified porous asphalt mixtures (fatigue, rutting, moisture susceptibility and thermal cracking) need specific research, and there are no comprehensive research studies on the effects of the RAS mixing time, size and mixing temperature in asphalt mixtures. Moreover, the addition of waste cooking/engine oils (biomaterials) as asphalt binder rejuvenators in combination with RAS represents an attractive aspect to be studied in detail.

Rutting (i.e., depressions along the wheel path) is a distress exhibited by flexible asphalt pavements at high in-service temperatures negatively affecting ride comfort and safety. In this regard, the fine asphalt mortar (i.e., bitumen filler and fine sand) plays a key role in the rutting potential of the asphalt mixtures. Given this background, this manuscript presents a small-scale laboratory experimentation aimed at assessing the rutting-related performance of a plain bitumen combined with natural (limestone) or manufactured (steel slag) fine aggregates (size up to 0.18 mm) through advanced experimental and theoretical approaches. Specific rheological tests through dynamic shear were carried out to achieve this goal. The investigated asphalt blends came from a wider research project focused on the implementation of a pavement solar collector (a road system to harvest the solar energy irradiating the pavement). In particular, the present paper aimed at verifying the mechanical suitability of the produced asphalt mixes with respect to permanent deformation resistance. Such a small-scale investigation mainly showed that the previously selected constituent materials did not imply criticisms in terms of rutting response.

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. Notch signalling is involved in prostate cancer progression and therapeutic resistance. Here, the authors show that loss of PTEN in prostate cancer models results in increased Notch1 cleavage and activation through CUX1-mediated transactivation of ADAM17.

Androgen deprivation therapy (ADT) is a standard therapy for prostate cancer (PCa). Though disseminated disease is initially sensitive to ADT, an important fraction of the patients progresses to castration-resistant prostate cancer (CRPC). For this reason, the identification of novel effective therapies for treating CRPC is needed. Immunotherapeutic strategies focused on macrophages as antitumor effectors, directly enhancing their tumoricidal potential at the tumor microenvironment or their adoptive transfer after ex vivo activation, have arisen as promising therapies in several cancer types. Despite several approaches centered on the activation of tumor-associated macrophages (TAMs) in PCa are under investigation, to date there is no evidence of clinical benefit in patients. In addition, the evidence of the effectiveness of macrophage adoptive transfer on PCa is poor. Here we find that VSSP, an immunomodulator of the myeloid system, decreases TAMs and inhibits prostatic tumor growth when administered to castrated Pten-deficient prostate tumor-bearing mice. In mice bearing castration-resistant Pten pc−/− ; Trp53 pc−/− tumors, VSSP administration showed no effect. Nevertheless, adoptive transfer of macrophages activated ex vivo with VSSP inhibited Pten pc−/− ; Trp53 pc−/− tumor growth through reduction of angiogenesis and tumor cell proliferation and induction of senescence. Taken together, our results highlight the rationale of exploiting macrophage functional programming as a promising strategy for CRPC therapy, with particular emphasis on ex vivo-activated proinflammatory macrophage adoptive transfer. Graphical abstract 5rwXuKXp78386xwRRkt56h Video abstract

Current environmental awareness interests several aspects of civil engineering, including road construction. Indeed, new challenges related to environmental pollution and landscape preservation must be faced. In this sense, clear road pavement surfaces represent an effective technology aimed at guaranteeing environmental-friendly aesthetic pavements. The use of clear synthetic resin as a binder involves several benefits for the mitigation of in-service reached temperatures and the heat distribution within pavements (with appreciable effects on pavement mechanical performance too). The present paper illustrates an experimental study aimed at analysing the chromatic and mechanical properties of a clear synthetic resin and thus its suitability as a binder for road pavement mixes. Chromatic characteristics were assessed through digital image analysis at different aging conditions. A dynamic shear rheometer was used to evaluate the linear viscoelastic properties as well as fatigue and rutting potential of the binder in a wide range of temperatures and frequencies. A conventional 35/50 penetration grade bitumen was also investigated for comparison purposes. The clear resin exhibited limited changes in colour (darkening effects), mainly in the case of short-term aging. On the other hand, a low temperature-dependency of such a binder was observed up to 58°C. Slightly increased aptitude to rutting at the higher temperatures was detected, even if it is worth noting that clear in-service mixtures would achieve lower temperatures than traditional “black” materials at a given environmental condition (air temperature, solar radiation, etc.). The resin also exhibited a softer behaviour, along with an enhanced fatigue resistance. Overall, the studied innovative binder showed promising results in view of its effective use in road paving.

The high wear resistance and toughness of electric arc furnace slag (EAFS) means that this industrial by-product can successfully replace natural aggregate in hydraulic or bituminous concretes that withstand vehicle traffic. This article validates the use of concrete made with large amounts of EAFS for rigid pavements. Accordingly, three EAFS–concrete mixes made with metallic or synthetic fibers were designed. Their performance was studied through laboratory tests (compressive strength, modulus of elasticity, splitting tensile strength, and abrasion resistance) and field observations on full-scale slabs made with each of the studied mixes. All mechanical properties yielded adequate results for concrete for rigid pavements. The metallic fibers increased the strength and elastic stiffness by 7–10%, while the addition of synthetic fibers slowed the development of these properties over time. On the other hand, all the mixes allowed for a successful implementation of full-scale slabs, with none of them showing excessive deterioration after five years of exposure to the outdoor environment. Only minor cracking and some chips in the surface-treatment layer were detected. The strength development of the slabs and their slipperiness were adequate for use in high-speed pavements. The overall analysis of the results shows that concrete made with EAFS can be used in real rigid pavements.