Drug Ther Bull. 2024 Dec 22:dtb-2024-000068. doi: 10.1136/dtb.2024.000068. Online ahead of print.

NO ABSTRACT

PMID:39797680 | DOI:10.1136/dtb.2024.000068

Cancers (Basel). 2024 Dec 29;17(1):76. doi: 10.3390/cancers17010076.

ABSTRACT

Cancer immunotherapy, particularly immune checkpoint inhibitors, has positively impacted oncological treatments. Despite its effectiveness, immunotherapy is associated with immune-related adverse events (irAEs) that can affect any organ, including the liver. Hepatotoxicity primarily manifests as immune-related hepatitis and, less frequently, cholangitis. Several risk factors, such as pre-existing autoimmune and liver diseases, the type of immunotherapy, and combination regimens, play a role in immune-related hepatotoxicity (irH), although reliable predictive markers or models are still lacking. The severity of irH ranges from mild to severe cases, up to, in rare instances, acute liver failure. Management strategies require regular monitoring for early diagnosis and interventions, encompassing strict monitoring for mild cases to the permanent suspension of immunotherapy for severe forms. Corticosteroids are the backbone of treatment in moderate and high-grade damage, alone or in combination with additional immunosuppressive drugs for resistant or refractory cases. Given the relatively low number of events and the lack of dedicated prospective studies, much uncertainty remains about the optimal management of irH, especially in the most severe cases. This review presents the main features of irH, focusing on injury patterns and mechanisms, and provides an overview of the management landscape, from standard care to the latest evidence.

PMID:39796705 | DOI:10.3390/cancers17010076

Funding Opportunity RFA-HL-26-007 from the NIH Guide for Grants and Contracts. The B2B Pediatric Cardiac Genomics Consortium (PCGC) (http://www.benchtobassinet.com/) will evolve to the B2B CHANGE Cohort (Congenital Heart disease Advancing New understanding in GEnomics). The B2B CHANGE Cohorts mission will be to conduct long-term clinical follow up on participants from the original PCGC Cohort, to perform deeper cohort phenotyping and to support investigators in applying for funding to conduct multi-center, collaborative ancillary studies to further understand how genetic variants relate to clinical outcomes. The Administrative Coordinating Center (ACC) will serve to lead and advance data and resource management and sharing, and coordinate critical data collection and participant outreach efforts at the clinical research sites. The ACC will work in a collaborative fashion with site PIs, as well as the broader congenital heart disease (CHD) research community.

Funding Opportunity RFA-MH-26-105 from the NIH Guide for Grants and Contracts. This initiative will leverage cutting edge generative AI technology to augment existing narrow AI/ML approaches used in clinical care that will expand our capacity to address the dynamic, complex, and evolving HIV epidemic.

Funding Opportunity PAR-25-358 from the NIH Guide for Grants and Contracts. The NEI supports large-scale clinical vision research projects, including randomized clinical trials and epidemiologic studies on eye/vision conditions. At the time of submission, applications requesting support for these activities are expected to provide detailed information regarding the study rationale, design, analytic methods, protocols and procedures, facilities and environment, organizational structure, and collaborative arrangements. This information is best conveyed in a study protocol and Manual of Procedures (MOP), the development of which represents a costly and time-consuming activity. This clinical research planning grant funding opportunity supports applicants in their planning efforts to conduct collaborative clinical research. The grant may be used to support the development of a study protocol and MOP, as well as to conduct preliminary studies to refine study procedures or document recruitment potential. The grant must not be used to generate data on the effects of a proposed intervention. This NEI NOFO is applicable to both epidemiologic and clinical trial research studies.

Notice NOT-CA-25-032 from the NIH Guide for Grants and Contracts

Notice NOT-AG-24-090 from the NIH Guide for Grants and Contracts

Funding Opportunity PAR-25-091 from the NIH Guide for Grants and Contracts. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) announces a program that provides NIDDK-supported K01, K08, K23, and K25 recipients the opportunity to apply for Small Grant (R03) support at some point during the latter years of their award period of their K award. Through the use of this mechanism, the NIDDK is seeking to enhance the capability of its K01, K08, K23, and K25 award recipients to conduct research as they complete their transition to fully independent investigator status. The R03 grant mechanism supports different types of projects, including pilot and feasibility studies; secondary analysis of existing data; small, self-contained research projects; development of research methodology; and development of new research technology. The R03 is, therefore, intended to support research projects that can be carried out in a short period of time with limited resources and that may provide preliminary data to support a subsequent R01, or equivalent, application.

Notice NOT-AG-24-091 from the NIH Guide for Grants and Contracts

Notice NOT-AI-25-019 from the NIH Guide for Grants and Contracts

Notice NOT-CA-25-031 from the NIH Guide for Grants and Contracts

Notice NOT-AG-24-033 from the NIH Guide for Grants and Contracts

Notice NOT-OD-25-061 from the NIH Guide for Grants and Contracts

Notice NOT-OD-25-054 from the NIH Guide for Grants and Contracts

Notice NOT-OD-25-062 from the NIH Guide for Grants and Contracts

Notice NOT-OD-25-060 from the NIH Guide for Grants and Contracts

Notice NOT-CA-25-028 from the NIH Guide for Grants and Contracts

Neurotherapeutics. 2025 Jan 9:e00522. doi: 10.1016/j.neurot.2024.e00522. Online ahead of print.

ABSTRACT

Paclitaxel (PCX) based treatments, commonly used to treat breast, ovarian and lung cancers, have the highest incidence of chemotherapy-induced neuropathic pain, affecting from 38 to 94 ​% of patients. Unfortunately, analgesic treatments are not always effective for PCX-induced neuropathic pain (PINP). This study aimed to evaluate the antinociceptive effect of clavulanic acid (CLAV), a clinically used β-lactam molecule, in both therapeutic and preventive contexts in mice with PINP. A single dose of CLAV administered after the onset of PINP significantly reduced mechanical hyperalgesia. Interestingly, preventive administration of CLAV prevented PINP development. The effect of preventive CLAV on PINP was associated with increased levels of IL-10 and IFN-β in serum, and decreased levels of IL-1β and TNF-α in both the serum and CNS. Immunostaining experiments revelated that CLAV increased the levels of glutamate transporter type 1 (GLT-1) and toll-like receptor type 4 (TLR4) in the spinal cord, while reducing levels of the astrocytic marker the glial fibrillary acidic protein (GFAP). Notably, co-incubation with CLAV and PCX in triple-negative breast cancer cells did not interfere with PCX-induced cytotoxic effects. Hence, these findings suggest that CLAV could be employed as a clinical treatment aimed at preventing PINP without compromission the cytotoxic efficacy of PCX.

PMID:39794241 | DOI:10.1016/j.neurot.2024.e00522

Mol Cell Proteomics. 2025 Jan 8:100905. doi: 10.1016/j.mcpro.2025.100905. Online ahead of print.

ABSTRACT

Protein phosphorylation plays a crucial role in regulating diverse biological processes. Perturbations in protein phosphorylation are closely associated with downstream pathway dysfunctions, while alterations in protein expression could serve as sensitive indicators of pathological status. However, there are currently few methods that can accurately identify the regulatory links between protein phosphorylation and expression, given issues like reverse causation and confounders. Here, we present Phoslink, a causal inference model to infer causal effects between protein phosphorylation and expression, integrating prior evidence and multi-omics data. We demonstrated the feasibility and advantages of our method under various simulation scenarios. Phoslink exhibited more robust estimates and lower FDR than commonly used Pearson and Spearman correlations, with better performance than canonical IV selection methods for Mendelian randomization. Applying this approach, we identified 345 causal links involving 109 phosphosites and 310 proteins in 79 lung adenocarcinoma (LUAD) samples. Based on these links, we constructed a causal regulatory network and identified 26 key regulatory phosphosites as regulators strongly associated with LUAD. Notably, 16 of these regulators were exclusively identified through phosphosite-protein causal regulatory relationships, highlighting the significance of causal inference. We explored potentially druggable phosphoproteins and provided critical clues for drug repurposing in LUAD. We also identified significant mediation between protein phosphorylation and LUAD through protein expression. In summary, our study introduces a new approach for causal inference in phosphoproteomics studies. Phoslink demonstrates its utility in potential drug target identification thereby accelerating the clinical translation of cancer proteomics and phosphoproteomic data.

PMID:39793886 | DOI:10.1016/j.mcpro.2025.100905

Eur J Med Chem. 2025 Jan 4;285:117245. doi: 10.1016/j.ejmech.2025.117245. Online ahead of print.

ABSTRACT

Breast cancer, a leading cause of cancer-related mortality in women, is characterized by genomic instability and aberrant gene expression, often influenced by noncanonical nucleic acid structures such as G-quadruplexes (G4s). These structures, commonly found in the promoter regions and 5'-untranslated RNA sequences of several oncogenes, play crucial roles in regulating transcription and translation. Stabilizing these G4 structures offers a promising therapeutic strategy for targeting key oncogenic pathways. In this study, we employed a drug repurposing approach to identify FDA-approved drugs capable of binding and stabilizing G4s in breast cancer-related genes. Using ligand-based virtual screening and biophysical methods, we identified several promising compounds, such as azelastine, belotecan, and irinotecan, as effective G4 binders, with significant antiproliferative effects in breast cancer cell lines. Notably, belotecan and irinotecan exhibited a synergistic mechanism, combining G4 stabilization with their established topoisomerase I inhibition activity to enhance cytotoxicity in cancer cells. Our findings support the therapeutic potential of G4 stabilization in breast cancer, validate drug repurposing as an efficient strategy to identify G4-targeting drugs, and highlight how combining G4 stabilization with other established drug activities may improve anticancer efficacy.

PMID:39793440 | DOI:10.1016/j.ejmech.2025.117245