Explore the vast range of titles available.

In the tumour microenvironment, IL-1α promotes neoangiogenesis, matrix remodelling, tumour proliferation, chemoresistance, and metastases. Highly expressed in human colorectal cancers, IL-1α is associated with poor prognosis. XB2001, a fully human monoclonal antibody neutralizing IL-1α, was evaluated for safety and preliminary efficacy with trifluridine/tipiracil (FTD/TPI) and bevacizumab in metastatic colorectal cancer patients previously treated with oxaliplatin- and irinotecan-based chemotherapies. This single institution, phase 1 study used a 3 + 3 design to assess XB2001 at doses of 250 mg, 500 mg and 1000 mg every 14 days, associated with FTD/TPI 35 mg/m² (days 1–5 and 8-12, every 28 days) (NCT05201352). The Maximum Tolerated Dose of XB2001 + FTD/TPI was then associated in combination with bevacizumab (5 mg/kg, days 1 and 15). Safety, efficacy, pharmacokinetics and pharmacodynamics were assessed. Seventeen patients (median age: 67.4 years) were enroled. No patient exhibited dose-limiting toxicity at any dose. The most common treatment-related adverse events (TRAE) of any grade (G) were diarrhoea (35.3%), nausea (47.1%) and anaemia (35.3%). G3-4 TRAE were neutropenia (17.6%) hypertension and infection (5.9% each). The RP2D (recommended phase 2 dose) of XB2001 was 1000 mg. The disease control rate was 76%, with 23% of patients achieving an objective response, including one complete response. Response and longer progression-free survival were associated with a decrease in serum IL-6 levels during therapy. High intratumoral IL-1α expression at baseline and CD8/PD-L1 infiltration are associated with a better progression-free survival. The combination of XB2001 with FTD/TPI and bevacizumab is feasible and safe, and showed encouraging clinical activity in chemotherapy-resistant mCRC.

FTO demethylates internal N⁶-methyladenosine (m⁶A) and N⁶,2′-O-dimethyladenosine (m⁶Am; at the cap +1 position) in mRNA, m⁶A and m⁶Am in snRNA, and N¹-methyladenosine (m¹A) in tRNA in vivo, and in vitro evidence supports that it can also demethylate N⁶-methyldeoxyadenosine (6mA), 3-methylthymine (3mT), and 3-methyluracil (m³U). However, it remains unclear how FTO variously recognizes and catalyzes these diverse substrates. Here we demonstrate—in vitro and in vivo—that FTO has extensive demethylation enzymatic activity on both internal m⁶A and cap m⁶Am. Considering that 6mA, m⁶A, and m⁶Am all share the same nucleobase, we present a crystal structure of human FTO bound to 6mA-modified ssDNA, revealing the molecular basis of the catalytic demethylation of FTO toward multiple RNA substrates. We discovered that (i) N⁶-methyladenine is the most favorable nucleobase substrate of FTO, (ii) FTO displays the same demethylation activity toward internal m⁶A and m⁶Am in the same RNA sequence, suggesting that the substrate specificity of FTO primarily results from the interaction of residues in the catalytic pocket with the nucleobase (rather than the ribose ring), and (iii) the sequence and the tertiary structure of RNA can affect the catalytic activity of FTO. Our findings provide a structural basis for understanding the catalytic mechanism through which FTO demethylates its multiple substrates and pave the way forward for the structure-guided design of selective chemicals for functional studies and potential therapeutic applications.

Abstract Background Trifluridine/tipiracil (FTD/TPI), an oral fluoropyrimidine (FP) from the class of antimetabolites, approved for refractory metastatic colorectal cancer, is thought, to have no cardiac toxicity. The aim of this observational, prospective, multicenter study was to identify the incidence of cardiotoxicity of FTD/TPI; secondary objectives were to evaluate whether patients with previous heart diseases or cardiovascular risk factors, who were treated with FTD/TPI, were more susceptible to cardiotoxicity. Materials and Methods Patients received FTD/TPI according to clinical practice and provided informed consent to participate in this prospective study. Any symptoms that occurred during the treatment were reported by patients using a daily questionnaire (patient-reported outcome). In the case of symptoms suspected of cardiotoxicity patients were investigated with an ECG, enzymes, and a cardiology examination. Quality of life (QoL) was analyzed using a GF7 item of the FACT-G questionnaire. Univariate and multivariate logistic regression models were used to test associations between covariates and cardiotoxicity. Changes in QoL were evaluated during treatment. Results Four out of seventy-seven patients had cardiotoxicity ≥ G3 according to the common terminology criteria for adverse events during FTD/TPI treatment. There was: chest pain in 3 cases, and heart failure in one case. The overall incidence of cardiotoxicity was 5.19%. By univariate analysis, obesity, and anemia were demonstrated to be risk factors of cardiotoxicity, while with multivariate analysis, only hemoglobin levels were statistically associated with cardiotoxicity. Average QoL after treatment was not significantly decreased as compared to average basal QoL. Conclusions The risk of developing cardiotoxicity with FTD/TPI is lower than with other FP but it is not negligible. Previous heart diseases or cardiovascular risk factors do not represent an increased risk of cardiotoxicity of FTD/TPI. Further studies are needed to investigate this topic.

Background: Metastasis accounts for the most lethal reason for the death of ovarian cancer patients, but remains largely untreated. Epithelial–mesenchymal transition (EMT) is critical for the conversion of early-stage ovarian tumours into metastatic malignancies. Thus the exploration of the signalling pathways promoting EMT would open potential opportunities for the treatment of metastatic ovarian cancer. Herein, the putative role of MDM2 in regulating EMT and metastasis of ovarian cancer SKOV3 cells was investigated. Methods: The regulatory effects by MDM2 on cell motility was emulated by wound-healing and transwell assays. The effects on EMT transition and Smad pathway were studied by depicting the expression levels of epithelial marker E-cadherin as well as key components of Smad pathway. To evaluate the clinical relevance of our findings, the correlation of MDM2 expression levels with the stages of 104 ovarian cancer patients was investigated by immunohistochemistry assay. Results: We demonstrate that MDM2 functions as a key factor to drive EMT and motility of ovarian SKOV3 cells, by facilitating the activation of TGF- β -Smad pathway, which results in the increased transcription of snail/slug and the subsequent loss of E-cadherin levels. Such induction of EMT is sustained in either E3 ligase-depleted MDM2 or E3 ligase inhibitor HLI-373-treated cells, while being impaired by the N-terminal deletion of MDM2, which is also reflected by the inhibitory effects against EMT by Nutlin-3a, the N-terminal targeting agent. The expression levels of MDM2 is highly correlated with the stages of the ovarian cancer patients, and the higher expression of MDM2 together with TGFB are closely correlated with poor prognosis and predict a high risk of ovarian cancer patients. Conclusions: This study suggests that MDM2 activates Smad pathway to promote EMT in ovarian cancer metastasis, and targeting the N-terminal of MDM2 can reprogram EMT and impede the mobility of cancer cells.

Variants in the FTO (fat mass and obesity associated) gene are associated with increased body mass index in humans. Here, we show by bioinformatics analysis that FTO shares sequence motifs with Fe(II)- and 2-oxoglutarate-dependent oxygenases. We find that recombinant murine Fto catalyzes the Fe(II)- and 2OG-dependent demethylation of 3-methylthymine in single-stranded DNA, with concomitant production of succinate, formaldehyde, and carbon dioxide. Consistent with a potential role in nucleic acid demethylation, Fto localizes to the nucleus in transfected cells. Studies of wild-type mice indicate that Fto messenger RNA (mRNA) is most abundant in the brain, particularly in hypothalamic nuclei governing energy balance, and that Fto mRNA levels in the arcuate nucleus are regulated by feeding and fasting. Studies can now be directed toward determining the physiologically relevant FTO substrate and how nucleic acid methylation status is linked to increased fat mass.

GluK3-kainate receptors are atypical members of the iGluR family that reside at both the pre- and postsynapse and play a vital role in the regulation of synaptic transmission. For a better understanding of structural changes that underlie receptor functions, GluK3 receptors were trapped in desensitized and resting/closed states and structures analyzed using single particle cryo-electron microscopy. While the desensitized GluK3 has domain organization as seen earlier for another kainate receptor-GluK2, antagonist bound GluK3 trapped a resting state with only two LBD domains in dimeric arrangement necessary for receptor activation. Using structures as a guide, we show that the N-linked glycans at the interface of GluK3 ATD and LBD likely mediate inter-domain interactions and attune receptor-gating properties. The mutational analysis also identified putative N-glycan interacting residues. Our results provide a molecular framework for understanding gating properties unique to GluK3 and exploring the role of N-linked glycosylation in their modulation.

Background Metastatic colorectal cancer (mCRC) remains an incurable disease with a poor prognosis. Recently, the global phase 3 SUNLIGHT study demonstrated that adding bevacizumab to trifluridine/tipiracil (FTD/TPI) in refractory disease significantly improves overall survival (OS). As a result, this combination is set to become the new standard of care for refractory mCRC. Immune checkpoint inhibitors (ICIs), including Pembrolizumab, have shown excellent results in mCRC patients with mismatch-repair deficiency (dMMR) or high microsatellite instability (MSI-H) mCRC. Additionally, recent trials evaluating both concomitant and sequential chemoimmunotherapy in mismatch-repair-proficient (pMMR) and microsatellite-stable (MSS) mCRC have yielded promising outcomes. Dendritic cell (DC) vaccines, though historically limited in effectiveness, show potential when combined with ICIs. Preliminary studies suggest they enhance chemotherapy response while maintaining favorable safety profiles. These evidences support the exploration of immunotherapy and FTD/TPI plus Bevacizumab in pMMR/MSS mCRC patients. Methods This is a single-arm, open-label, multicenter, phase 2 clinical trial evaluating the clinical and immunological activity of an innovative approach combining induction immunotherapy (Pembrolizumab plus DC vaccine) followed by maintenance chemotherapy (FTD/TPI plus Bevacizumab) in patients with refractory MSS/pMMR mCRC. The primary endpoint is the objective response rate (ORR). Secondary endpoints include progression-free survival (PFS), safety, and overall survival (OS). Discussion This study explores a novel sequential immunochemotherapy approach combining a DC-based vaccine with anti-PD-1 immunotherapy and standard chemotherapy in patients with refractory pMMR/MSS mCRC. By integrating cellular immunotherapy without omitting the current standard of care (FTD/TPI plus bevacizumab), the trial aims to enhance treatment efficacy in a setting traditionally resistant to immunological strategies. To the best of our knowledge, this is the only ongoing trial investigating this therapeutic combination in this specific patient population. Trial registration This study, acronym CombiCoR-Vax, has been registered on clinicaltrials.gov registry with identifier NCT06522919, on July 9, 2024.

Introduction Trifluridine-tipiracil (FTD/TPI) is approved as monotherapy and in combination with bevacizumab for the treatment of metastatic colorectal cancer (mCRC). This UK real-world retrospective analysis aimed to evaluate the use of granulocyte colony stimulating factor (G-CSF) to prevent FTD/TPI induced neutropenia in patients with mCRC. Methods Retrospective data were collected across five UK Healthcare sites. Consecutive patients with mCRC having received at least 2 cycles of FTD/TPI in addition to G-CSF administered as primary or secondary prophylaxis were included. The study assessed the timing and duration of G-CSF treatment, incidence of neutropenia, and subsequent dose delays/reductions. Time on FTD/TPI treatment, Progression free Survival (PFS), and Overall Survival (OS) were also calculated for this patient cohort. Results The data set included 55 mCRC patients in total; 25 receiving primary prophylaxis, and 30 receiving secondary prophylaxis. 68% of G-CSF prophylaxis commenced on day 15, with 99% initiated between days 14 and 22. Following G-CSF use, 25% of patients experienced a dose delay and 18% a dose reduction due to neutropenia. 14.5% of patients reported grade ≥3 neutropenia. In patients receiving primary prophylaxis a mean of 18.4 weeks of FTD/TPI were completed, whereas in those receiving secondary prophylaxis the mean was 28.8 weeks. Primary prophylaxis patients exhibited a median PFS of 3 months, and a median OS of 9.7 months. In secondary prophylaxis patients the median PFS was 7.2 months and the median OS 17.5 months. Conclusion G-CSF prophylaxis reduced the incidence of neutropenia, improved dose intensity, and extended PFS and OS in this real-world study of mCRC patients on FTD/TPI. G-CSF prophylaxis was commonly administered as a 5-day course of filgrastim starting on day 15.

NEIL1 (Nei-like 1) is a DNA repair glycosylase guarding the mammalian genome against oxidized DNA bases. As the first enzymes in the base-excision repair pathway, glycosylases must recognize the cognate substrates and catalyze their excision. Here we present crystal structures of human NEIL1 bound to a range of duplex DNA. Together with computational and biochemical analyses, our results suggest that NEIL1 promotes tautomerization of thymine glycol (Tg)—a preferred substrate—for optimal binding in its active site. Moreover, this tautomerization event also facilitates NEIL1-catalyzed Tg excision. To our knowledge, the present example represents the first documented case of enzyme-promoted tautomerization for efficient substrate recognition and catalysis in an enzyme-catalyzed reaction.

Purpose We aimed to identify the risk factors for severe neutropenia in the early phase of trifluridine-tipiracil (FTD/TPI) treatment, and their impact on overall survival (OS). Methods This single-center retrospective study included patients with unresectable metastatic colorectal cancer who were treated with FTD/TPI. The primary endpoint was OS, and the secondary endpoint was severe neutropenia during the first and second cycles of FTD/TPI. We assessed the association between outcomes and potential confounders using multivariate analysis. Results Of the 77 total patients, 33 developed severe neutropenia during the first and second treatment cycles. In Cox hazard analysis, the independent factors associated with OS were neutropenia ≥ grade 1 during cycles 1 and 2 (adjusted hazard ratio 0.43; 95% confidence interval (CI) 0.21–0.87), combined treatment with bevacizumab (0.47; 95% CI 0.27–0.83), number of metastatic organs ≥ 3 (2.15; 95% CI 1.22–3.82), and time since diagnosis of metastasis until commencement of FTD/TPI < 18 months (1.94; 95% CI 1.13–3.33). Severe neutropenia during cycles 1 and 2 was not associated with OS (0.75; 0.44–1.27). The risk of severe neutropenia adjusted for initial dose reduction was defined as renal impairment with creatinine clearance (Ccr) of < 60 ml/min (adjusted odds ratio, 4.67; 95% CI, 1.38–15.80) and absolute neutrophil count (per 1000/μl, 0.47; 0.27–0.81). Conclusion The neutropenia ≥ grade 1 during cycles 1 and 2 of FTD/TPI is a predictor of favorable outcomes; however, the effect of severe neutropenia on OS was not clear. Renal impairment was also associated with severe neutropenia.