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A randomized study (acronym: MC-FludT.14/L Trial II) demonstrated that fludarabine plus treosulfan (30 g/m²) was an effective and well tolerated conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT) in older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). To further evaluate this regimen, all 252 study patients aged 50 to 70 years were compared with similar patients, who underwent allo-HCT after fludarabine/melphalan (140 mg/m²) (FluMel) or busulfan (12.8 mg/kg)/cyclophosphamide (120 mg/kg) (BuCy) regimens and whose data was provided by the European Society for Blood and Marrow Transplantation registry. In 1:1 propensity-score matched-paired analysis (PSA) of AML patients, there was no difference in 2-year-relapse-incidence after FluTreo compared with either FluMel (n = 110, p = 0.28) or BuCy (n = 78, p = 0.98). However, 2-year-non-relapse-mortality (NRM) was lower compared with FluMel (p = 0.019) and BuCy (p < 0.001). Consequently, 2-year-overall-survival (OS) after FluTreo was higher compared with FluMel (p = 0.04) and BuCy (p < 0.001). For MDS patients, no endpoint differences between FluTreo and FluMel (n = 30) were evident, whereas 2-year-OS after FluTreo was higher compared with BuCy (n = 25, p = 0.01) due to lower 2-year-NRM. Multivariate sensitivity analysis confirmed all significant results of PSA. Consequently, FluTreo (30 g/m²) seems to retain efficacy compared with FluMel and BuCy, but is better tolerated by older patients.

Most cancer patients diagnosed with late-stage head and neck squamous cell carcinoma are treated with chemoradiotherapy, which can lead to toxicity. One potential alternative is tumor-limited conversion of a prodrug into its cytotoxic form. We reason this could be achieved by transient and tumor-specific expression of purine nucleoside phosphorylase (PNP), an Escherichia coli enzyme that converts fludarabine into 2-fluoroadenine, a potent cytotoxic drug. To efficiently express bacterial PNP in tumors, we evaluate 44 chemically distinct lipid nanoparticles (LNPs) using species-agnostic DNA barcoding in tumor-bearing mice. Our lead LNP, designated LNP intratumoral (LNP IT ), delivers mRNA that leads to PNP expression in vivo. Additionally, in tumor cells transfected with LNP IT , we observe upregulated pathways related to RNA and protein metabolism, providing insight into the tumor cell response to LNPs in vivo. When mice are treated with LNP IT -PNP, then subsequently given fludarabine phosphate, we observe anti-tumor responses. These data are consistent with an approach in which LNP-mRNA expression of a bacterial enzyme activates a prodrug in solid tumors. Lipid nanoparticles (LNPs) delivering mRNA after intratumoral administration could be a promising cancer treatment strategy. Here this group reports the intratumoral delivery of mRNA with LNPs inducing the expression of purine nucleoside phosphorylase and inhibiting the progression of head and neck squamous cell carcinoma in vivo.

In this study, the potential effects of bacteria on the efficacy of frequently used chemotherapies was examined. Bacteria and cancer cell lines were examined in vitro and in vivo for changes in the efficacy of cancer cell killing mediated by chemotherapeutic agents. Of 30 drugs examined in vitro , the efficacy of 10 was found to be significantly inhibited by certain bacteria, while the same bacteria improved the efficacy of six others. HPLC and mass spectrometry analyses of sample drugs (gemcitabine, fludarabine, cladribine, CB1954) demonstrated modification of drug chemical structure. The chemoresistance or increased cytotoxicity observed in vitro with sample drugs (gemcitabine and CB1954) was replicated in in vivo murine subcutaneous tumour models. These findings suggest that bacterial presence in the body due to systemic or local infection may influence tumour responses or off-target toxicity during chemotherapy.

Type I interferon responses are considered the primary means by which viral infections are controlled in mammals. Despite this view, several pathogens activate antiviral responses in the absence of type I interferons. The mechanisms controlling type I interferon-independent responses are undefined. We found that RIG-I like receptors (RLRs) induce type III interferon expression in a variety of human cell types, and identified factors that differentially regulate expression of type I and type III interferons. We identified peroxisomes as a primary site of initiation of type III interferon expression, and revealed that the process of intestinal epithelial cell differentiation upregulates peroxisome biogenesis and promotes robust type III interferon responses in human cells. These findings highlight the importance of different intracellular organelles in specific innate immune responses.

The worldwide standard guideline for treating heart failure (HF) is inhibition of the patients’ chronically enhanced sympathetic nervous system activity. However, despite gains in the treatment of HF with angiotensin and β-adrenergic receptor (β-AR) blockers, some patients do not tolerate β-AR blocking therapy to inhibit cardiac function and contract the respiratory tract. One approach to address this would be adenylyl cyclase (AC) isoform-specific therapy. Indeed, we have demonstrated that vidarabine’s selective AC-inhibitory effect in the heart can inhibit the development of HF and arrhythmia without suppressing cardiac function in mice. However, the potential usefulness of vidarabine is limited by its poor solubility, which requires continuous infusion in a large volume of intravenous fluid over a prolonged period. Here, in order to overcome this problem, we aimed to develop vidarabine derivatives with increased solubility and maintained activity. We synthesized derivatives substituted with a (dimethylamino)acetyl group at the 2’-, 3’- or 5’- position of the arabinose ring (V2E, V3E and V5E, respectively) and evaluated their activity in vitro and in vivo . V2E, V3E and V5E all possess greater water solubility than vidarabine and their inhibitory effect on cardiac AC activity is comparable to that of vidarabine. Furthermore, V2E, V3E and V5E ameliorated the development of HF and reduced the susceptibility to atrial fibrillation in a mouse model.

Tissue stromal cells interact with leukaemia cells and profoundly affect their viability and drug sensitivity. Here we show a biochemical mechanism by which bone marrow stromal cells modulate the redox status of chronic lymphocytic leukaemia (CLL) cells and promote cellular survival and drug resistance. Primary CLL cells from patients exhibit a limited ability to transport cystine for glutathione (GSH) synthesis owing to a low expression level of Xc-transporter. In contrast, bone marrow stromal cells effectively import cystine and convert it to cysteine, which is then released into the microenvironment for uptake by CLL cells to promote GSH synthesis. The elevated level of GSH enhances leukaemia cell survival and protects them from drug-induced cytotoxicity. Furthermore, disabling this protective mechanism significantly sensitizes CLL cells to drug treatment in the stromal environment. This stromal–leukaemia interaction is critical for CLL cell survival and represents a key biochemical pathway for effectively targeting leukaemia cells to overcome drug resistance in vivo . Chronic lymphocytic leukaemia cells depend on glutathione to counteract their high reactive oxygen species (ROS) levels. However, their ability to synthesize this antioxidant is compromised by inefficient cystine uptake. Huang and colleagues now show that bone marrow stromal cells promote leukaemia cell survival by metabolizing cystine to cysteine and releasing it into the microenvironment to be taken up by leukaemia cells.

Background High UGT2B17 is associated with poor prognosis in untreated chronic lymphocytic leukaemia (CLL) patients and its expression is induced in non-responders to fludarabine-containing regimens. We examined whether UGT2B17, the predominant lymphoid glucuronosyltransferase, affects leukaemic drug response and is involved in the metabolic inactivation of anti-leukaemic agents. Methods Functional enzymatic assays and patients’ plasma samples were analysed by mass-spectrometry to evaluate drug inactivation by UGT2B17. Cytotoxicity assays and RNA sequencing were used to assess drug response and transcriptome changes associated with high UGT2B17 levels. Results High UGT2B17 in B-cell models led to reduced sensitivity to fludarabine, ibrutinib and idelalisib. UGT2B17 expression in leukaemic cells involved a non-canonical promoter and was induced by short-term treatment with these anti-leukaemics. Glucuronides of both fludarabine and ibrutinib were detected in CLL patients on respective treatment, however UGT2B17 conjugated fludarabine but not ibrutinib. AMP-activated protein kinase emerges as a pathway associated with high UGT2B17 in fludarabine-treated patients and drug-treated cell models. The expression changes linked to UGT2B17 exposed nuclear factor kappa B as a key regulatory hub. Conclusions Data imply that UGT2B17 represents a mechanism altering drug response in CLL through direct inactivation but would also involve additional mechanisms for drugs not inactivated by UGT2B17.

Patients with AML and measurable residual disease (MRD) undergoing allogeneic hematopoietic cell transplantation (HCT) may benefit from myeloablative conditioning (MAC) when feasible to reduce relapse risk. Fludarabine-Melphalan (FluMel) is a common reduced intensity conditioning (RIC) regimen; however, data in MRD+ patients is sparse. We performed a retrospective review of AML patients who underwent their first HCT (2016–2021) without morphologic disease at City of Hope who had pre-transplant marrow evaluated for MRD using multicolor flow cytometry (MFC) and received radiation-based MAC or FluMel conditioning. We identified 312 patients; 44 with MRD+ disease pre-HCT. The 24-month overall survival (OS), leukemia-free survival (LFS) and cumulative incidence of relapse (CIR) were 47.7%, 40.9%, and 38.6% in MRD+, and 78.0%, 73.9%, and 14.6% in MRD− patients. Radiation-based MAC was given to 136 (43.5%) patients ( n  = 20 with MRD+) and FluMel was given to 174 (55.8%) patients ( n  = 24 with MRD+). In patients with MRD+, there was no statistically significant difference between those who received MAC vs. FluMel in 24-month OS (60% vs. 38%, p  = 0.21), or CIR (35% vs. 42%, p  = 0.59), respectively. Our data substantiates the adverse impact of MRD in patients with AML undergoing HCT; FluMel is a reasonable option for MRD+ patients unfit for MAC.

Drug discovery and development is a challenging and time-consuming process. Laboratory experiments conducted on Vidarabine showed IC 50 6.97 µg∕mL, 25.78 µg∕mL, and ˃ 100 µg∕mL against non-small Lung cancer (A-549), Human Melanoma (A-375), and Human epidermoid Skin carcinoma (skin/epidermis) (A-431) respectively. To address these challenges, this paper presents an Artificial Intelligence (AI) model that combines the capabilities of Deep Learning (DL) to identify potential new drug candidates, Fuzzy Rough Set (FRS) theory to determine the most important chemical compound features, Explainable Artificial Intelligence (XAI) to explain the features’ importance in the last layer, and medicinal chemistry to rediscover anticancer drugs based on natural products like Vidarabine. The proposed model aims to identify potential new drug candidates. By analyzing the results from laboratory experiments on Vidarabine, the model identifies Sulfur and magnesium oxide (MgO) as new potential anticancer agents. The proposed model selected Sulfur and MgO based on Interpreting their promising features, and further laboratory experiments were conducted to validate the model’s predictions. The results demonstrated that, while Vidarabine was inactive against the A-431 cell line (IC 50 ˃ 100 µg∕mL), Sulfur and MgO exhibited significant anticancer activity (IC 50 4.55 and 17.29 µg/ml respectively). Sulfur displayed strong activity against A-549 and A-375 cell lines (IC 50 3.06 and 1.86 µg/ml respectively) better than Vidarabine (IC 50 6.97 and 25.78 µg/ml respectively). However, MgO showed weaker activity against these two cell lines. This paper emphasizes the importance of uncovering hidden chemical features that may not be discernible without the assistance of AI. This highlights the ability of AI to discover novel compounds with therapeutic potential, which can significantly impact the field of drug discovery. The promising anticancer activity exhibited by Sulfur and MgO warrants further preclinical studies.

Since genomics, epigenomics and transcriptomics have provided only a partial explanation of chronic lymphocytic leukaemia (CLL) heterogeneity, and since concordance between mRNA and protein expression is incomplete, we related the CLL proteome to clinical outcome. CLL samples from patients who received fludarabine-containing chemoimmunotherapy were analysed by mass spectrometry (SWATH-MS). One dataset compared pre-treatment samples associated with an optimal versus suboptimal response, while another compared paired samples collected before treatment and at disease progression. eIF2 signalling (pivotal to the unfolded protein response (UPR)), was identified as the most enriched pathway in both datasets (respective z-scores: − 6.245 and 3.317; p  < 0.0001), as well as in a fludarabine-resistant CLL cell line established from HG3 cells (z-score: − 2.121; p  < 0.0001). Western blotting revealed that fludarabine-resistant HG3 cells expressed higher levels of PERK, which phosphorylates the regulatory eIF2α subunit, and lower levels of BiP, an HSP70 molecular chaperone that inactivates PERK but preferentially binds to misfolded proteins during ER stress. The PERK inhibitor, GSK2606414, sensitised resistant, but not sensitive, HG-3 cells to fludarabine without affecting background cell viability or cytotoxicity induced by the BCL-2 inhibitor venetoclax. These findings identify the UPR as a novel determinant of therapy outcome and disease progression in CLL.