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The anticancer agent indisulam inhibits cell proliferation by causing degradation of RBM39, an essential mRNA splicing factor. Indisulam promotes an interaction between RBM39 and the DCAF15 E3 ligase substrate receptor, leading to RBM39 ubiquitination and proteasome-mediated degradation. To delineate the precise mechanism by which indisulam mediates the DCAF15–RBM39 interaction, we solved the DCAF15–DDB1–DDA1–indisulam–RBM39(RRM2) complex structure to a resolution of 2.3 Å. DCAF15 has a distinct topology that embraces the RBM39(RRM2) domain largely via non-polar interactions, and indisulam binds between DCAF15 and RBM39(RRM2), coordinating additional interactions between the two proteins. Studies with RBM39 point mutants and indisulam analogs validated the structural model and defined the RBM39 α-helical degron motif. The degron is found only in RBM23 and RBM39, and only these proteins were detectably downregulated in indisulam-treated HCT116 cells. This work further explains how indisulam induces RBM39 degradation and defines the challenge of harnessing DCAF15 to degrade additional targets. The crystal and cryo-electron microscopy structure analysis of the DCAF15–DDB1–DDA1–indisulam–RBM39 complex revealed the detailed mechanism of action of indisulam-induced RBM39 degradation and defined an α-helical degron motif in RBM39.

The post-genomic era has seen many advances inBaryza and G. Rice for helpful our understanding of cancer pathways, yet resistance and tumor heterogeneity necessitate multiple approaches to target even monogenic tumors. Here, we combine phenotypic screening with chemical genetics to identify pre-messenger RNA endonuclease cleavage and polyadenylation specificity factor 3 (CPSF3) as the target of JTE-607, a small molecule with previously unknown target. We show that CPSF3 represents a synthetic lethal node in a subset of acute myeloid leukemia (AML) and Ewing’s sarcoma cancer cell lines. Inhibition of CPSF3 by JTE-607 alters expression of known downstream effectors in AML and Ewing’s sarcoma lines, upregulates apoptosis and causes tumor-selective stasis in mouse xenografts. Mechanistically, it prevents the release of newly synthesized pre-mRNAs, resulting in read-through transcription and the formation of DNA-RNA hybrid R-loop structures. This study implicates pre-mRNA processing, and specifically CPSF3, as a druggable target providing an avenue to therapeutic intervention in cancer. The RNA endonuclease CPSF3 was identified as the cellular efficacy target of the small molecule JTE-607, revealing pre-mRNA processing as a vulnerability in cancers such as Ewing’s sarcoma that are characterized by aberrant transcription.

Background Diabetic foot ulcers (DFUs) are a common and debilitating complication of diabetes mellitus, often leading to hospitalization, amputation, and reduced quality of life. Monitoring biomarkers that reflect inflammatory processes can be crucial for assessing DFU severity and guiding treatment. This study explores the relationship between plasma fibrinogen levels and DFU severity, along with its association with various clinical and inflammatory biomarkers. Objective To assess the relationship between plasma fibrinogen levels and DFU severity, vascular health, infection risk, and other biomarkers in diabetic patients, with the aim of improving the prediction and management of DFU outcomes. Methods A cross-sectional, observational study was conducted at Mardan Medical Complex from June 2024 to January 2025, involving 93 diabetic patients with active DFUs. The severity of DFUs was classified using the Wagner system, and vascular health was assessed using the Ankle-Brachial Index (ABI) and Doppler ultrasound. Plasma fibrinogen levels, along with other biomarkers such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and fasting blood glucose, were measured through fasting blood samples. Data analysis included statistical tests such as Kruskal-Wallis, Mann-Whitney, ANOVA, Decision Trees, Box Plots, Violin Plot, Histograms, and Regression models to explore the associations between fibrinogen levels and DFU severity, vascular impairment, and inflammatory markers. Significance was set at p < 0.05. Results The study examined 93 diabetic patients (mean age: 59.02 ± 7.86 years), comprising 49 males (52.68%) and 44 females (46.32%). Among the participants, 28 (30.11%) presented with severe ulcers (Wagner Grade 5), and 53 (56.99%) exhibited critical ischemia. Bacterial infections were identified in 71 (76.34%) of the patients. The mean plasma fibrinogen level was significantly elevated at 681 ± 160 mg/dL, surpassing the normal range. Plasma fibrinogen levels increased with ulcer severity, with medians of 503.51 mg/dL for Wagner Grade 2, 623.45 mg/dL for grade 3, 627.32 mg/dL for grade 4, and 720.77 mg/dL for grade 5 ulcers. Higher fibrinogen levels were also associated with greater ulcer depth (p = 0.046). Additionally, vascular impairment was significantly correlated with fibrinogen levels, with non-palpable pedal pulses and severe peripheral arterial disease showing associations with elevated fibrinogen levels (p = 0.0083 and p = 0.0478, respectively). Furthermore, fibrinogen levels were positively correlated with CRP (r = 0.50) and with comorbidities such as hypertension in 66 (70.97%) patients and chronic kidney disease in 20 (21.51%) patients. Conclusion Plasma fibrinogen levels are strongly associated with DFU severity and could serve as an effective biomarker for predicting disease progression. Monitoring fibrinogen, along with other biomarkers, may help clinicians stratify patients based on their risk of complications and guide more targeted treatment strategies.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The stability of the Wnt pathway transcription factor β-catenin is tightly regulated by the multi-subunit destruction complex. Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. However, the development of targeted Wnt pathway inhibitors has been hampered by the limited number of pathway components that are amenable to small molecule inhibition. Here, we used a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits β-catenin-mediated transcription. XAV939 stimulates β-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. Thus, our study provides new mechanistic insights into the regulation of axin protein homeostasis and presents new avenues for targeted Wnt pathway therapies. Target for Wnt inhibitors Deregulation of the Wnt pathway, a signalling system involved in embryogenesis and in many other processes in living cells, has been implicated in many cancers, making it an attractive target for anticancer therapies. But while inhibitors of Notch and Hedgehog pathways have reached the clinical trial stage, 'drugable' targets for Wnt inhibitors have proved elusive. Now, using a chemical genetics approach, a small molecule inhibitor of the Wnt pathway has been identified and its direct target and mechanism of action characterized. XAV939 inhibits Wnt signalling with high specificity via the stabilization of axin, a concentration-limiting factor of the β-catenin degradation complex. As well as suggesting new drug targets, this work provides insights into how the Wnt pathway is physiologically regulated. Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. Here, a small molecule inhibitor of the Wnt pathway is identified and its direct target and mechanism of action are characterized, providing new insights into the physiological regulation of the Wnt pathway and new possibilities for targeted Wnt pathway therapeutics.

Emission tomographic image reconstruction is an ill-posed problem due to limited and noisy data and various image-degrading effects affecting the data and leads to noisy reconstructions. Explicit regularization, through iterative reconstruction methods, is considered better to compensate for reconstruction-based noise. Local smoothing and edge-preserving regularization methods can reduce reconstruction-based noise. However, these methods produce overly smoothed images or blocky artefacts in the final image because they can only exploit local image properties. Recently, non-local regularization techniques have been introduced, to overcome these problems, by incorporating geometrical global continuity and connectivity present in the objective image. These techniques can overcome drawbacks of local regularization methods; however, they also have certain limitations, such as choice of the regularization function, neighbourhood size or calibration of several empirical parameters involved. This work compares different local and non-local regularization techniques used in emission tomographic imaging in general and emission computed tomography in specific for improved quality of the resultant images.

Multilayer of 2% Cu doped TiO 2 thin films have been grown by sol–gel spin coating on glass substrate in the form of three, five and seven layers. X-ray diffractrometer (XRD) confirms the doping of Cu into TiO 2 . Scanning electron microscopy (SEM) confirms the formation of nano particles with average size of 19, 25 and 35 nm for three, five and seven layers of thin films, respectively. The electrical resistivity of these multilayer films is found as 2.19 × 10 7 , 1.20 × 10 7 and 1.11 × 10 7 ohm-m respectively. UV–vis shows that the films have 80% transmittance in the visible region which is good for solar spectrum. The optical band gap energy decreases with an increase in the number of layers as 3.778, 3.768 and 3.736 eV respectively for 3, 5 and 7 layered thin films. This work provides an environment friendly and low cost use of an abundant material for optoelectronic devices.

The anti-cancer agent Indisulam inhibits cell proliferation by causing degradation of RBM39, an essential mRNA splicing factor. Indisulam promotes an interaction between RBM39 and the DCAF15 E3 ligase substrate receptor leading to RBM39 ubiquitination and proteasome-mediated degradation. To delineate the precise mechanism by which Indisulam mediates DCAF15-RBM39 interaction, we solved the DCAF15-DDB1-DDA1-Indisulam-RBM39(RRM2) complex structure to 2.3 Angstroms. DCAF15 has a novel topology which embraces the RBM39(RRM2) domain largely via nonpolar interactions, and Indisulam binds between DCAF15 and RBM39(RRM2) and coordinates additional interactions between the two proteins. Studies with RBM39 point mutants and Indisulam analogs validated the structural model and defined the RBM39 alpha-helical degron motif. The degron is found only in RBM23 and RBM39 and only these proteins were detectably downregulated in Indisulam-treated HCT116 cells. This work further explains how Indisulam induces RBM39 degradation and defines the challenge of harnessing DCAF15 to degrade novel targets.