Here, we rigorously test this model by simultaneously mapping the transcriptome and genome-wide DSBs induced by six replication stress induders with diverse mechanisms of action (hydroxyurea, methyl-methane sulfonate, camptothecin, actinomycin, doxorubicin and methotrexate). Our data provide support for a model where DSBs are driven by replication inhibitor-induced replication-transcription conflict. More importantly, they reveal active transcription histone markers as the impediments for replication fork progression, therefore a direct culprit for DSBs.

Although considerable research has been conducted and numerous results have been obtained, the available evidence remains predominantly of moderate quality. Consequently, current guidelines from CPIC and the DPWG do not recommend routine MTX dose adjustments based solely on single gene variants. It is, therefore, imperative to develop and validate multifactorial risk prediction tools that integrate a range of other clinical factors. Accordingly, the establishment of a comprehensive pharmacogenetics-guided dosing guideline for MTX remains an elusive goal.

We report the case of a 4-year-old girl initially diagnosed with oligoarticular JIA and treated with methotrexate followed by a tumor necrosis factor inhibitor, without significant clinical improvement and despite persistently normal inflammatory markers...This case highlights common diagnostic pitfalls in pediatric rheumatology and underscores the importance of considering genetic causes of chronic arthropathy when clinical and laboratory features are atypical for inflammatory disease. Early molecular diagnosis prevents unnecessary immunosuppressive therapy and enables appropriate multidisciplinary management.

Compared with the model group, both the EMO and methotrexate (MTX) treatment groups demonstrated attenuated synovial hyperplasia and cartilage destruction, along with significantly downregulated expression levels of key NF-κB pathway proteins, HIF-1α, and VEGF in joint tissues (p < 0.001)...This study demonstrates that EMO alleviates pathological damage in RA by inhibiting the activation of the NF-κB signaling pathway, which subsequently downregulates pathological angiogenesis and inflammatory responses mediated by the HIF-1α/VEGF axis. These findings provide a robust experimental basis for the potential application of EMO as a therapeutic agent for RA.

Herein, we propose a carrier-free, tumor microenvironment (TME)-responsive nanoplatform (FAM NPs-FA) constructed via coordination-driven self-assembly of Survivin antisense oligodeoxynucleotide (ASO), methotrexate (MTX), and Fe3+ ions...Meanwhile, the released Survivin ASO specifically silences Survivin mRNA, suppressing anti-apoptotic protein expression, and accelerating tumor cell apoptosis. Moreover, combined with the chemotherapeutic effects of MTX, this nanoplatform demonstrates exceptional synergistic therapeutic efficacy against tumors while minimizing adverse impacts on healthy tissues, thus opening a versatile and effective carrier-free platform for TME-responsive synergistic cancer therapy integrating gene regulation, reactive oxygen species generation, and chemotherapy.

P2, N=46, Not yet recruiting, Wake Forest University Health Sciences

This study evaluates the efficacy of liraglutide (LIRA), a glucagon-like peptide-1 receptor agonist, in RA management, particularly in conjunction with methotrexate (MTX), a standard RA therapy on complete Freund's adjuvant (CFA)-induced arthritis. Liraglutide presents opportunities for repurposing metabolic agents in the treatment of autoimmune illnesses. Liraglutide modulates metabolic dysfunction, normalizes autophagy markers, inflammatory pathways, and lower apoptotic signals in complete Freund's adjuvant-induced arthritis in rats.

These findings identify a novel immunomodulatory axis where TLR2 signaling differentially regulates P-gp function and effector capacity in NK cells depending on the specific heterodimer engaged and the cellular context. We propose that controlled TLR2/1 stimulation represents a potential dual-benefit strategy to protect NK cells from chemotherapy-induced suppression while boosting their anti-leukemic activity in ALL.

All of the aforementioned biochemical and histological abnormalities were greatly improved with ATOM. ATOM significantly improved MTX-induced pulmonary injury by suppressing TLR4/MYD88/NF-κB p65 and caspase-3-mediated apoptotic signaling pathways.

Treatment was started orally from day 8-28th (21 days) as normal and disease controls served with vehicle, standard group with methotrexate other 3 groups served with GA at doses of 20,40, and 60 mg/kg correspondingly whereas 7th group served with combination of GA (60 mg/kg) and MTX...Treatment with GA mainly in combination notably reinstated TNF-α, IL-6, NF-ĸβ, COX-2 and IL-4 expression as quantified by qRT-PCR in contrast to disease group. It can be concluded from data that the combination of GA with MTX showed noticeable anti-arthritic potential and can be used for treating after conducting safety and clinical studies.

Herein, we constructed pH-responsive methotrexate (MTX)-loaded bimetallic rare earth hydroxide nanoparticles (YMn(OH)x@MTX NPs)...This overcomes the challenges of tumor immune evasion and drug resistance, breaking the limitations of traditional single-mode therapy. This multi-pathway synergistic design offers a new paradigm for cancer treatment, allowing readers to intuitively appreciate the charm of interdisciplinary innovation between nanotechnology and tumor immunology and inspiring scientific research ideas.

Among patients with actively treated RA, eGFRcys is consistently lower than eGFRcr. Neither eGFRcys nor eGFRcr demonstrated a change following RA treatments, despite reductions in the disease activity biomarker TNF-RI. Further studies incorporating directly measured GFR are warranted.