To describe the development and implementation of a standardized, pharmacy-led assessment of risk (AOR) process for investigational products (IPs) in compliance with United States Pharmacopeia (USP) chapter <800> across a large academic health network. USP <800> mandates institutions to maintain a hazardous drug list but offers limited guidance for investigational agents. The US National Institute for Occupational Safety and Health (NIOSH) has a published list of hazardous drugs that institutions should reference. However, the list only includes agents approved through December 2015, leaving a large gap in hazardous drug standardization for marketed products, providing less precedent for those working with investigational agents. In response, a multidisciplinary workgroup led by pharmacy services developed a system-wide IP AOR process. Two distinct tools incorporating toxicological and biosafety criteria were created to assess small-molecule and biopharmaceutical agents. A centralized database and oversight committee were established to ensure consistency, transparency, and regulatory compliance. As of July 2025, 255 IPs were assessed: 8 high-risk hazardous, 126 low-risk hazardous, and 121 nonhazardous agents. The process has enabled appropriate labeling, safe handling, and efficient review workflows across research pharmacies. The IP AOR process demonstrates the essential role of pharmacists in operationalizing USP <800> requirements for investigational drugs. This model supports occupational safety, regulatory compliance, and scalable implementation across health systems engaged in clinical research. The process outlined in this manuscript is applicable to both investigational agents and any newly marketed drugs being brought into an institution that haven't been reviewed by NIOSH for inclusion on their list.

Recent advances in structural biology, functional genomics, and artificial intelligence (AI) have expanded understanding of the solute carrier (SLC) transporter superfamily. Emerging evidence indicates that SLC transporters play central roles in the multi-hit pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD). In this review, we build upon the classical "two-hit" hypothesis to summarize how CRISPR-based screening, cryo-electron microscopy (cryo-EM), and AI-driven platforms such as AlphaFold and RosettaVS have advanced the study of SLC transporters. These approaches have enabled the identification of SLCs implicated in MAFLD pathogenesis, including SLC13A5 (NaCT) and SLC25A47, as well as the determination of high-resolution structures that support rational drug design for targets such as sodium-glucose cotransporter 2 (SLC5A2) and monocarboxylate transporter 10 (SLC16A10). In addition, ultra-large virtual screening strategies have accelerated the discovery of small-molecule inhibitors targeting SLC transporters. We synthesize current evidence defining the mechanistic roles of SLC transporters in lipid and glucose metabolism, mitochondrial dysfunction, and gut-liver axis dysregulation. Finally, we discuss therapeutic implications, ranging from clinically repurposed SGLT2 inhibitors to investigational agents such as the SLC13A5 inhibitor ETG5773, and outline future directions for technology-driven precision medicine treating MAFLD.

Background/Objectives: Metformin, a widely used antidiabetic drug, has recently gained attention in dermatology due to its pleiotropic effects. Given the high prevalence, chronicity, and therapeutic challenges of several dermatological conditions, there is growing interest in repurposing metformin as a topical agent with anti-inflammatory, antioxidant, metabolic, and regenerative properties. This narrative review aimed to synthesize and critically analyze the available preclinical and clinical evidence regarding the mechanisms of action, efficacy, safety, and therapeutic potential of topical metformin across different skin disorders. Methods: A literature search was conducted in PubMed and complementary databases for studies published between 2015 and 2025 addressing topical metformin in dermatology, including experimental, observational, interventional, and review articles. Results: The findings indicate that topical metformin has been associated with beneficial biological effects in conditions such as melasma, photoaging, wound healing, psoriasis, acne, skin cancer, and hair disorders, largely through AMPK activation, modulation of inflammation and oxidative stress, inhibition of melanogenesis, enhancement of tissue regeneration, and regulation of immune and metabolic pathways, although evidence remains predominantly preclinical and methodologically heterogeneous. Conclusions: Topical metformin represents a promising investigational multifunctional dermatological agent; however, its clinical translation depends on well-designed randomized controlled trials with standardized formulations, adequate sample sizes, and long-term follow-up to establish its efficacy, safety, and optimal therapeutic protocols.

Safety and efficacy of fordadistrogene movaparvovec in ambulatory participants with Duchenne muscular dystrophy (CIFFREO): a phase 3, double-blind, randomised, placebo-controlled study.

Phase III placebo-controlled oncology trials in the last decade: evolution, methodological foundations, and clinical impact.

Advancements in radionuclide imaging and therapy techniques have created a groundswell of enthusiasm in the recently designated field of theranostics. This has increased the need for facilities that are able to participate in clinical trials for investigational theranostic agents. Theranostics clinical trials present several unique challenges that will tax the resources and staff of most medical centers. Our purpose is to describe the unique logistical and administrative challenges associated with theranostics clinical trials, propose strategies for addressing them, and make recommendations regarding trial conduct to the community at large. The authors' experiences reviewing, implementing, and managing theranostics trials at their institution were used to identify common activities and challenges. Several key categories of requirements and challenges were identified. Multidisciplinary teams consisting of nuclear medicine, oncology, nursing, clinical research, and administrative staff are necessary to adequately perform all trial-related activities. Strategies are proposed to address these challenges and activities at the institutional and industry levels. The unique challenges inherent to theranostics clinical trials require a focused investment of time, effort, and resources from all stakeholders. Institutions that wish to participate in these trials must develop the infrastructure necessary to fully support the breadth of activities they require. Implementation of the strategies and recommendations presented here will ensure the successful conduct of these trials and will improve efficiency across the community.

Background: Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic conditions that affect the gastrointestinal tract. Since the initial approval of infliximab (IFX), a monoclonal antibody targeting TNF-α, numerous novel therapeutic targets have been identified, and many new therapies have been approved for the treatment of IBD. Methods: We conducted a narrative review of the literature using major biomedical databases, including EMBASE, Scopus, PubMed, CENTRAL, and ClinicalTrials.gov (last search date: 10 December 2025). Results: This review summarizes the current evidence on therapies approved for IBD (both CD and UC) and provides an overview of investigational agents currently being evaluated in ongoing phase II and III clinical trials. Conclusions: Moderate optimism arises from the expanding array of therapeutic targets under investigation and from emerging treatment strategies. However, only through a deeper understanding of the pathophysiological mechanisms underlying IBD will substantial improvements in treatment outcomes be achieved for conditions that continue to impose a significant burden on patients’ quality of life.

Acute lymphoblastic leukemia (ALL) remains the most common pediatric malignancy worldwide. Standard protocols such as BFM and GBTLI rely on long-established cytotoxic agents, yet novel targeted compounds have recently entered phase I/II trials. Despite these advances, no prior study has systematically compared the pharmacokinetic, ADMET, and quantum descriptor profiles of protocol-based drugs versus emerging clinical-phase agents. This study addresses that gap by integrating pharmacoinformatic and quantum-chemical approaches to highlight differences with potential clinical implications. We retrieved all small-molecule drugs from the BFM/GBTLI 2009 protocols and a representative set of phase I/II investigational compounds for pediatric ALL. In silico tools were used to assess physicochemical properties, ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles, and quantum chemical descriptors. We evaluated physicochemical and pharmacokinetic properties, including solubility, permeability, metabolic liabilities, and toxicity risks. Quantum chemical descriptors were calculated with density functional theory (DFT) to assess molecular reactivity (HOMO, LUMO, gap, dipole moment, electrophilicity). Multivariate analyses were applied to compare and cluster drug profiles. The comparative analysis revealed significant variability between guideline and clinical-phase compounds. Clinical-phase compounds generally exhibited higher molecular weight and lipophilicity, together with greater variability in permeability and solubility-related descriptors, indicating potential formulation and bioavailability challenges. Several investigational agents were identified as P-gp substrates and hERG inhibitors, suggesting increased risk of efflux-mediated resistance and cardiotoxicity. Quantum chemical analysis revealed that phase I/II compounds (e.g., Pelabresib, Molibresib) displayed smaller HOMO-LUMO gaps and higher electrophilicity, consistent with higher theoretical reactivity, whereas guideline drugs (e.g., Vincristine, Methotrexate) showed more stable electronic profiles. Cluster analysis confirmed distinct grouping between guideline and clinical-phase compounds. This in silico comparison integrates pharmacoinformatic and quantum descriptor analyses of established and emerging ALL therapeutics. By revealing key differences in drug-likeness, ADMET, and electronic reactivity, the study provides a comparative framework that may support the prioritization, optimization, and clinical translation of next-generation therapies for pediatric ALL.

Abstract While CDK4/6 inhibitors (CDK4/6i) have changed the therapeutic landscape of hormone receptor-positive (HR+) breast cancer, resistance to these therapies is a major challenge limiting their clinical benefit. Recent studies have shown that CDK2 activity is a key mechanism of resistance to CDK4/6i. Adaptation to CDK4 inhibition can arise from the overexpression or amplification of cyclin E1 or E2, leading to increased CDK2 activity that phosphorylates Rb and bypasses CDK4/6i-induced G1 arrest. Additional alterations, such as p53 loss of function, can activate CDK2. It has been proposed that targeting CDK2, in addition to CDK4, can lead to more durable cell cycle arrest in HR+ cancer cells. In this study, we evaluated the preclinical activity of GDC-4198, a next-generation CDK4/2 inhibitor currently being tested in clinical trials, and its potential to address CDK2-driven resistance to CDK4 inhibition. In biochemical kinase activity assays, GDC-4198 has sub-nanomolar potency against CDK4 and is a more potent inhibitor of CDK2 than CDK6/CycD3, unlike approved CDK4/6i. Immunofluorescence data from HR+ breast cancer cells revealed that the shift in cell cycle distribution induced by GDC-4198 was differentiated from the effects of CDK4/6i and can most closely be reproduced by a combination of atirmociclib (a CDK4 inhibitor) and tagtociclib (a CDK2 inhibitor). This observation was most pronounced in cell line models that have developed resistance to CDK4/6i. RNA-seq data collected after 96 hours of treatment confirmed that the effects of GDC-4198 on gene expression are differentiated from CDK4 inhibition alone. In cell viability assays, GDC-4198 induced growth inhibition and sustained cell cycle arrest in a diverse panel of HR+ breast cancer cell lines. Notably, time-course assays demonstrated that parental T-47D cells can reenter the cell cycle within two days after initial arrest under treatment with CDK4/6i, whereas GDC-4198 led to sustained growth inhibition over five days. Across CDK4/6i resistant HR+ cells, engineered via either long-term exposure to palbociclib or CCNE1/2 overexpression, GDC-4198 was substantially more effective at inhibiting growth than approved CDK4/6i or atirmociclib. Notably, the activity of GDC-4198 was comparable to the combination of CDK4 and CDK2 inhibitors. Additional studies in patient-derived cell lines obtained in the setting of metastatic HR+ breast cancer following progression on letrozole/ribociclib, as well as in patient-derived cell lines with acquired in vitro resistance to palbociclib, confirmed the enhanced antitumor activity of GDC-4198 compared to current CDK4/6i or atirmociclib. In xenograft studies of HR+ breast cancer, GDC-4198 demonstrated dose-dependent tumor growth inhibition. Pharmacokinetic and pharmacodynamic analyses indicated favorable drug exposure and pharmacodynamic modulation in tumor tissues consistent with the effects observed in in vitro experiments. Taken together, these preclinical findings demonstrate that GDC-4198 can induce more durable cell cycle arrest than approved CDK4/6i by overcoming CDK2-driven adaptive and intrinsic resistance to CDK4 inhibition. These results suggest that GDC-4198 is a promising investigational agent with the potential to provide benefit to those who have progressed on approved CDK4/6i while prolonging benefit in earlier disease settings. Citation Format: M. Hafner, S. Vartanian, G. Luca, N. Kosaisawe, M. Hwang, E. Lin, L. Wang, J. Oeh, J. Vijay, K. N. Islam, A. Zheng, K. Samy, U. Segal, J. Moffat, D. Zingg, A. Collier, I. Sanidas, J. Xie, S. A. Wander. Gdc-4198, a next-generation CDK4/2 inhibitor, induces durable cell cycle arrest and overcomes CDK2-driven adaptation to CDK4 inhibition [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-11-28.

Tumor necrosis factor-alpha (TNF-α), a crucial proinflammatory cytokine, is involved in immune regulation and in the pathogenesis of a variety of chronic inflammatory and autoimmune diseases. TNF-α signaling dysregulation is linked to chronic inflammatory diseases, multiorgan dysfunction, and tissue destruction through activation of TNF receptor 1 (TNFR1)-mediated inflammatory, apoptotic, and necroptotic pathways, while TNF receptor 2 (TNFR2) stimulation promotes immune regulation and tissue repair. Understanding these divergent signaling mechanisms is crucial for augmenting therapeutic interventions. The present review summarizes the molecular structure of TNF-α, compares TNFR1 and TNFR2 signaling cascades, and describes the cytokine’s role in diseases such as rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, multiple sclerosis, diabetes mellitus, atherosclerosis, heart failure, systemic lupus erythematosus, and cancer. We further evaluate clinically approved TNF inhibitors and emergent investigational agents, prominent advances in receptor-selective modulation, and small-molecule TNF suppression. Overall, this review emphasizes the therapeutic potential of selectively targeting TNF-α signaling while preserving essential immunoregulatory functions, offering insights that may support next-generation drug development.

Ulcerative colitis is a chronic inflammatory bowel disease with rising global prevalence. Despite therapeutic advances including biologic agents targeting tumor necrosis factor-alpha, integrins, and interleukin pathways, alongside Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators, substantial unmet needs persist in moderate to severe disease. Current advanced therapies achieve clinical response rates of only 30-60% in trials, with approximately 20% of patients requiring hospitalization and 7% undergoing colectomy within five years of diagnosis. The therapeutic pipeline for moderate to severe ulcerative colitis currently encompasses over 100 investigational agents in Phase II and III clinical development. Emerging mechanisms include next-generation Janus kinase and tyrosine kinase 2 inhibitors with enhanced selectivity, novel cell trafficking modulators, advanced tumor necrosis factor-alpha inhibition strategies, and selective interleukin-23 pathway antagonists. Tumor necrosis factor-like ligand 1A pathway inhibitors demonstrate particularly robust efficacy in early trials, with clinical remission rates exceeding 25% compared to less than 2% for placebo. Additional promising approaches target immune checkpoint pathways, receptor-interacting protein kinase 1, and intracellular signaling cascades. innovative combination therapy approaches demonstrated to achieve superior response rates compared to monotherapy. The convergence of novel therapeutic targets, gut-selective compounds minimizing systemic immunosuppression, and biomarker-guided therapy selection represents a paradigm shift toward precision medicine. These advances hold genuine promise for transforming moderate to severe ulcerative colitis management.

Background:Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been shown to reduce major adverse cardiovascular events (MACEs) in patients with type 2 diabetes mellitus (T2DM) and high cardiovascular risk. However, the efficacy of GLP-1 RAs on the outcomes of MACEs across different racial and sex groups among patients with and without T2DM remains underexplored. Thus, this study aimed to evaluate the association between GLP-1 RAs and MACEs in patients with and without T2DM based on race and sex.Methods:We conducted a systematic literature search on the PubMed and Scopus databases, as well as ClinicalTrials.gov, for relevant randomized controlled trials (RCTs) from inception to July 5, 2025. Trials were eligible for inclusion if the included adults (≥18 years) had been randomized to a GLP-1 RA versus placebo group, and MACEs were reported as an outcome. Trials combining GLP-1 RAs with other investigational glucose-lowering agents were excluded. Risk ratios (RRs) and 95% confidence intervals (CIs) were pooled using a random-effect model, and a p-value of <0.05 was considered statistically significant.Results:Nine RCTs involving 81,266 patients were included in the analysis. The mean age of patients was 65 years. Compared with the placebo, GLP-1 RAs significantly reduced the risk of MACEs in males (RR, 0.82; 95% CI: 0.77–0.86; p < 0.001) and females (RR, 0.81; 95% CI: 0.75–0.88; p < 0.001). Meanwhile, across racial groups, GLP-1 RAs significantly reduced the risk of MACEs in Caucasian patients (RR, 0.87; 95% CI: 0.79–0.96; p < 0.001) compared with placebo. However, no significant difference was observed for the risk of MACEs in Black patients (RR, 1.05; 95% CI: 0.72–1.53; p = 0.80) when comparing GLP-1 RAs with placebo.Conclusion:This meta-analysis demonstrates that GLP-1 RAs significantly reduce the risk of MACEs in both males and females, as well as across various racial groups in patients with or without T2DM. However, the lack of significant benefit in Black patients suggests potential racial disparities in the enrollment and efficacy of GLP-1 RAs for cardiovascular outcomes.

Haemophilia, an X-linked disorder, is linked to reduced bone mineral density (BMD). Emicizumab, a factor VIII (FVIII) mimetic, provides a model to study the role of FVIII in bone health. To evaluate BMD in adults with severe haemophilia under different prophylactic regimens, focusing on whether emicizumab maintains bone health comparable to FVIII prophylaxis. Forty male adults with severe haemophilia A or B were prospectively enrolled at a single centre (2019-2024) and assigned to five prophylactic groups: emicizumab (with/without inhibitors), FVIII, factor IX (FIX) or investigational agents. Annual assessments included dual-energy X-ray absorptiometry, joint status, mobility and bone turnover markers. Of the 40 patients, 18 received FVIII, 10 FIX, 4 haemophilia A with inhibitors on emicizumab, 4 haemophilia A without inhibitors on emicizumab and 4 investigational therapies. At baseline, spine BMD z-scores were comparable to age-matched norms, whereas hip BMD was significantly lower (median -0.8; p < 0.001). After 1 year, spine and hip BMD changes did not differ significantly across treatment groups (p = 0.9010 and p = 0.8073, respectively). Lower annual bleeding rate, middle age and BMI extremes were associated with BMD improvement. Emicizumab-treated patients, with or without inhibitors, showed non-inferior BMD outcomes compared to those receiving FVIII, with all 95% confidence intervals within the predefined margin (±0.5). BMD outcomes did not differ across regimens. Emicizumab was comparable to FVIII, suggesting bleed control, not factor replacement, is key to bone health in haemophilia. People with haemophilia often have problems with joint bleeding, which can limit movement and reduce bone strength. Different treatments are now available to prevent bleeding, including factor replacement and newer medicines such as emicizumab. It is not clear whether these treatments affect bone health differently. In this study, we followed 40 adults with haemophilia and measured their bone health for 1 year. We found that bone outcomes were similar across all treatment groups. Emicizumab worked just as well as factor VIII in maintaining bone strength. This means that good bleeding control may be the key to keeping bones healthy in haemophilia, regardless of the treatment type.

Intratumoral T regulatory cells (Tregs) promote an immunosuppressive tumor microenvironment and are frequently associated with a lack of response to immunotherapy. Selective targeting of intratumoral Tregs while sparing broader Tregs and effector T cell populations is an attractive strategy to enhance antitumor immune responses. CCR8 is a G protein-coupled receptor (GPCR) that is predominantly upregulated on tumor resident Tregs in a range of human solid tumors making it a promising target for their selective depletion. In preclinical studies using the mouse tumor models, anti-mouse CCR8 antibody treatment resulted in depletion of CCR8+ intratumoral Tregs, significant antitumor activity and enhanced survival in combination with anti-PD-1. CHS-114 is a highly selective, afucosylated human anti-CCR8 monoclonal antibody that is being developed as a cancer immunotherapy. CHS-114 selectively binds human CCR8 and potently kills CCR8 expressing cells by inducing antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). Ex vivo studies evaluating human dissociated tumor cells (DTCs) demonstrated the selectivity of CHS-114 in depleting intratumoral Tregs while sparing CCR8 negative Tregs and effector T cells. Treatment of tumor bearing human CCR8 knock-in (huCCR8KI) mice with CHS-114 resulted in significant tumor growth inhibition (62.6%) accompanied by remodeling of the tumor immune microenvironment and enhanced differentiation of a subset of cytotoxic CD8+ T cells. Based on the promising preclinical data, we are evaluating CHS-114 in clinical trials as an investigational agent for the treatment of solid tumors with and without the anti-PD-1 antibody toripalimab (NCT05635643, NCT06657144).

Combination therapies offer promise for improving cancer treatment efficacy and preventing recurrence. Preclinical screening strategies can prioritize synergistic drug combinations. However, identifying optimal drug combinations tailored to specific cancer subtypes and individual patients is extremely challenging due to the vast number of possible combinations and tumor heterogeneity. To address this gap, we combined deep learning with transfer learning to incorporate prior scientific knowledge and predicted drug synergy based on tumor-specific transcriptome profiles. PAIRWISE explicitly modeled synergistic effects of drug combinations in cancer cell lines or individual tumor samples based on drug chemical structures, drug targets, and transcriptomes of inferred samples. Of note, PAIRWISE outperformed competing models with an AUROC (the area under the receiver operating characteristic curve) of 0.847 on held-out cancer cell lines. Moreover, when applied to an independent dataset of combinations with Bruton Tyrosine Kinase inhibitors (BTKi) in Diffuse Large B Cell Lymphoma (DLBCL) cell lines, PAIRWISE accurately predicted synergistic drug combinations with an AUROC of 0.720. To further confirm the robustness of PAIRWISE predictions, we selected 30 approved or investigational agents for DLBCL treatment and validated their synergy with BTKi across eight non-Hodgkin lymphoma cell lines. The synergistic predictions of PAIRWISE showed strong concordance with in vitro screening results. These findings highlight PAIRWISE’s potential as a powerful in silico tool to prioritize candidate personalized drug combinations for further experimental validation.

The Ethics of Right to Try Investigational Agents in Oncology—Balancing Hope With Evidence

Adolescents with neurodevelopmental disorders (NDDs) often display challenging behaviors such as hypersexuality, severe irritability, and aggression. This review emphasizes current management strategies, focusing on the evaluation of problematic behaviors and considering both pharmacological and nonpharmacological options, as well as their level of evidence in the current literature. Hypersexuality in adolescents with NDDs may result from conditions such as precocious puberty, polycystic ovary syndrome, neurologic disorders, trauma, or medication effects. Management should be etiology-based; limited evidence suggests selective serotonin reuptake inhibitors (SSRIs) and opioid antagonists may help in compulsive sexual behavior, though data in youth remain scarce. Irritability is most consistently improved with atypical antipsychotics, particularly risperidone and aripiprazole. Adjunctive options include NMDA modulators, stimulants, alpha-2 agonists, and anti-inflammatory or nutraceutical agents. Aggression management relies on antipsychotics, with clozapine considered for refractory cases; benzodiazepines, guanfacine, sertraline, and investigational agents such as vafidemstat show early promise. Psychotherapeutic and family-based interventions remain essential. Effective care requires holistic evaluation, elimination of iatrogenic contributors, and individualized treatment. Combining behavioral therapies with judicious medication use can improve functioning and safety. Emerging pharmacologic and biologic strategies warrant further investigation in this vulnerable population.

Currently, the most applied 89Zr-immuno-PET platform is the [89Zr]Zr-deferoxamine (DFO)-monoclonal antibody (mAb) constructs, where the investigational agent is obtained through combining [89Zr]Zr-oxalate with mAbs conjugated to the bifunctional chelator p-SCN-Bn-DFO. This approach struggles with several limitations, including the inability of DFO to incorporate lanthanide-based radiometals such as 177Lu or 161Tb and the instability of the [89Zr]Zr-DFO complex in ascorbate-containing formulations. Conversely, whereas pentetic acid (DTPA)-based bifunctional chelators have been extensively applied to generate clinical β-therapeutic mAb constructs, the previous efforts to create stable [89Zr]Zr-DTPA-mAb complexes using [89Zr]Zr-oxalate have been unsuccessful. However, [89Zr]ZrCl4, which exists as [Zr4(OH)8(OH2)16]8+ in aqueous solutions, is chemically more accessible than its commercially available oxalate form, enabling the direct labeling of p-SCN-Bn-CHX-A″-DTPA. The methodology described here allows for the generation of [89Zr]Zr-DTPA-mAb and [177Lu]Lu/[161Tb]Tb-DTPA-mAb radiotheranostic pairs, where the targeting vector in the diagnostic and the therapeutic analogs is identical. Methods: Pertuzumab was selected for proof-of-concept studies and was conjugated to p-SCN-Bn-CHX-A″-DTPA. Radiolabeling of DTPA-pertuzumab with [89Zr]ZrCl4 involved a 10-min incubation in acetate buffer (pH 4.5), followed by PD-10 desalting gel column purification. The in-formulation radiochemical purity and pooled human serum stability were assessed using size-exclusion high-performance liquid chromatography, and radioimmunoreactivity was evaluated using the stationary antigen magnetic bead-based method. Biodistribution of [89Zr]Zr-DTPA-pertuzumab was assessed in BT-474 tumor mouse models and compared with biodistribution of [89Zr]Zr-DFO-pertuzumab and [161Tb]Tb-DTPA-pertuzumab. Results: Conjugated batches consistently produced DTPA-pertuzumab with acceptable chelate-to-mAb ratios and chemical purity. DTPA-pertuzumab was radiolabeled with up to 3.4 GBq (92 mCi) of 89Zr. In formulation, DTPA-pertuzumab exhibited greater chemical stability, and the radioaggregate formation was lower in [89Zr]Zr-DTPA-pertuzumab than in [89Zr]Zr-DFO-pertuzumab. [89Zr]Zr-DTPA-pertuzumab was also stable in ascorbate-containing formulations. In human serum, the drop in radiomonomer content for [89Zr]Zr-DTPA-pertuzumab was smaller than for [89Zr]Zr-DFO-pertuzumab. Compared with [89Zr]Zr-DFO-pertuzumab, [89Zr]Zr-DTPA-pertuzumab biodistribution exhibited lower liver and higher blood and tumor uptake and was more consistent with the biodistribution of [161Tb]Tb-DTPA-pertuzumab. Conclusion: The ability to radiolabel CHX-A″-DTPA-mAbs with 89Zr has been demonstrated, allowing for the generation of 89Zr/177Lu/161Tb-based true radiotheranostic pairs. On the basis of our biodistribution data, [89Zr]Zr-DTPA-mAbs may be better suited as a companion diagnostic to radiotherapeutic DTPA-mAb analogs than is [89Zr]Zr-DFO-mAbs.

A review on pathological implications and therapeutic interventions of sepsis-associated encephalopathy.

Most patients with advanced BRAF or NRAS-driven melanoma receive front-line immunotherapy. However, if immunotherapy fails, BRAF-mutated patients have effective second-line therapies, whereas NRAS-mutated patients lack pathway-targeted options. Recently, RAS(ON) multi-selective inhibitors like RMC-7977, and the investigational agent daraxonrasib, were described that, in partnership with cyclophilin-A (CYPA), inhibit RAS[GTP] signaling. Both compounds demonstrate potent anti-proliferative activity against NRAS-mutated melanoma cell lines and robust anti-tumor activity against preclinical melanoma models. However, in preclinical models, resistance to RMC-7977 monotherapy arose through mutations in Ppia (encoding CYPA) or Map2k1 (encoding MEK1). Moreover, two clinical case studies in patients with NRAS-mutated melanoma treated with daraxonrasib demonstrated clear anti-tumor activity in one patient, but progressive disease in another with co-occurring NRAS and MAP2K1 mutations at baseline. These findings support the potential for daraxonrasib in treatment of patients with NRAS-mutated melanoma, and reveal candidate mechanisms of monotherapy resistance, underscoring the need for combination therapies to improve outcomes.