Activating mutations of NOTCH1 (a well-known oncogene in T-cell acute lymphoblastic leukemia) are present in ∼4–13% of chronic lymphocytic leukemia (CLL) cases, where they are associated with disease ...progression and chemorefractoriness. However, the specific role of NOTCH1 in leukemogenesis remains to be established. Here, we report that the active intracellular portion of NOTCH1 (ICN1) is detectable in ∼50% of peripheral blood CLL cases lacking gene mutations. We identify a “NOTCH1 gene-expression signature” in CLL cells, and show that this signature is significantly enriched in primary CLL cases expressing ICN1, independent of NOTCH1 mutation. NOTCH1 target genes include key regulators of B-cell proliferation, survival, and signal transduction. In particular, we show that NOTCH1 transactivates MYC via binding to B-cell–specific regulatory elements, thus implicating this oncogene in CLL development. These results significantly extend the role of NOTCH1 in CLL pathogenesis, and have direct implications for specific therapeutic targeting.
Folate metabolism enables cell growth by providing one-carbon (1C) units for nucleotide biosynthesis. The 1C units are carried by tetrahydrofolate, whose production by the enzyme dihydrofolate ...reductase is targeted by the important anticancer drug methotrexate. 1C units come largely from serine catabolism by the enzyme serine hydroxymethyltransferase (SHMT), whose mitochondrial isoform is strongly upregulated in cancer. Here we report the SHMT inhibitor SHIN2 and demonstrate its in vivo target engagement with
C-serine tracing. As methotrexate is standard treatment for T-cell acute lymphoblastic leukemia (T-ALL), we explored the utility of SHIN2 in this disease. SHIN2 increases survival in NOTCH1-driven mouse primary T-ALL in vivo. Low dose methotrexate sensitizes Molt4 human T-ALL cells to SHIN2, and cells rendered methotrexate resistant in vitro show enhanced sensitivity to SHIN2. Finally, SHIN2 and methotrexate synergize in mouse primary T-ALL and in a human patient-derived xenograft in vivo, increasing survival. Thus, SHMT inhibition offers a complementary strategy in the treatment of T-ALL.
Activating mutations in NOTCH1 are common in T cell acute lymphoblastic leukemia (T-ALL). Here we identify glutaminolysis as a critical pathway for leukemia cell growth downstream of NOTCH1 and a key ...determinant of the response to anti-NOTCH1 therapies in vivo. Mechanistically, inhibition of NOTCH1 signaling in T-ALL induces a metabolic shutdown, with prominent inhibition of glutaminolysis and triggers autophagy as a salvage pathway supporting leukemia cell metabolism. Consequently, inhibition of glutaminolysis and inhibition of autophagy strongly and synergistically enhance the antileukemic effects of anti-NOTCH1 therapy in mice harboring T-ALL. Moreover, we demonstrate that Pten loss upregulates glycolysis and consequently rescues leukemic cell metabolism, thereby abrogating the antileukemic effects of NOTCH1 inhibition. Overall, these results identify glutaminolysis as a major node in cancer metabolism controlled by NOTCH1 and as therapeutic target for the treatment of T-ALL.
This paper reports on the pee power urinal field trials, which are using microbial fuel cells for internal lighting. The first trial was conducted on Frenchay Campus (UWE, Bristol) from February–May ...2015 and demonstrated the feasibility of modular MFCs for lighting, with University staff and students as the users; the next phase of this trial is ongoing. The second trial was carried out during the Glastonbury Music Festival at Worthy Farm, Pilton in June 2015, and demonstrated the capability of the MFCs to reliably generate power for internal lighting, from a large festival audience (∼1000 users per day). The power output recorded for individual MFCs is 1–2 mW, and the power output of one 36-MFC-module, was commensurate of this level of power. Similarly, the real-time electrical output of both the pee power urinals was proportional to the number of MFCs used, subject to temperature and flow rate: the campus urinal consisted of 288 MFCs, generating 75 mW (mean), 160 mW (max) with 400 mW when the lights were connected directly (no supercapacitors); the Glastonbury urinal consisted of 432 MFCs, generating 300 mW (mean), 400 mW (max) with 800 mW when the lights were connected directly (no supercapacitors). The COD removal was >95% for the campus urinal and on average 30% for the Glastonbury urinal. The variance in both power and urine treatment was due to environmental conditions such as temperature and number of users. This is the first time that urinal field trials have demonstrated the feasibility of MFCs for both electricity generation and direct urine treatment. In the context of sanitation and public health, an independent power source utilising waste is essential in terms of both developing and developed world.
The Notch1 gene is a major oncogenic driver and therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL). However, inhibition of NOTCH signaling with γ-secretase inhibitors (GSIs) has shown ...limited antileukemic activity in clinical trials. Here we performed an expression-based virtual screening to identify highly active antileukemic drugs that synergize with NOTCH1 inhibition in T-ALL. Among these, withaferin A demonstrated the strongest cytotoxic and GSI-synergistic antileukemic effects in vitro and in vivo. Mechanistically, network perturbation analyses showed eIF2A-phosphorylation–mediated inhibition of protein translation as a critical mediator of the antileukemic effects of withaferin A and its interaction with NOTCH1 inhibition. Overall, these results support a role for anti-NOTCH1 therapies and protein translation inhibitor combinations in the treatment of T-ALL.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy. Despite recent advances in treatments with intensified chemotherapy regimens, relapse rates and associated ...morbidities remain high. In this context, metabolic dependencies have emerged as a druggable opportunity for the treatment of leukemia. Here, we tested the antileukemic effects of MB1-47, a newly developed mitochondrial uncoupling compound. MB1-47 treatment in T-ALL cells robustly inhibited cell proliferation via both cytostatic and cytotoxic effects as a result of compromised mitochondrial energy and metabolite depletion, which severely impaired nucleotide biosynthesis. Mechanistically, acute treatment with MB1-47 in primary leukemias promoted adenosine monophosphate-activated serine/threonine protein kinase (AMPK) activation and downregulation of mammalian target of rapamycin (mTOR) signaling, stalling anabolic pathways that support leukemic cell survival. Indeed, MB1-47 treatment in mice harboring either murine NOTCH1-induced primary leukemias or human T-ALL patient-derived xenografts (PDXs) led to potent antileukemic effects with a significant extension in survival without overlapping toxicities. Overall, our findings demonstrate a critical role for mitochondrial oxidative phosphorylation in T-ALL and uncover MB1-47-driven mitochondrial uncoupling as a novel therapeutic strategy for the treatment of this disease.
Alignment strategy for IFMIF-DONES facility Arranz, Fernando; Becerril, Santiago; Bernardi, Davide ...
Fusion engineering and design,
March 2024, 2024-03-00, Letnik:
200
Journal Article
Recenzirano
Odprti dostop
This article addresses the challenges associated with the alignment of the equipment within the IFMIF DONES installation and presents the strategy devised to achieve acceptable levels of uncertainty. ...The primary obstacles stem from the need to align equipment located in different rooms, some of which are inaccessible for manual operations. Additionally, the elevated radiation levels in certain areas impose restrictions on the fiducials that can be employed.
The article details the outcomes of implementing the proposed alignment procedure, including the specific equipment used and the achieved levels of uncertainty.
PDF
