The authors wish to add the following sentence into the ‘Competing interests’ section of this Article: “P.W.K. has investment interest in Context Therapeutics LLC, DRGT, Placon, Seer Biosciences and Tarveda Therapeutics, is a company board member for Context Therapeutics LLC, is a consultant and scientific advisory board member for BIND Biosciences, Inc., BN Immunotherapeutics, DRGT, GE Healthcare, Janssen, Metamark, New England Research Institutes, Inc., OncoCellMDX, Progenity, Sanofi, Seer Biosciences, Tarveda Therapeutics and Thermo Fisher, and serves on data safety monitoring boards for Genentech/Roche and Merck.” This has now been included.

Multiple myeloma (MM) remains an incurable hematologic malignancy, and immunomodulatory imide drugs (IMiDs) have been used as an effective treatment option. A significant challenge with IMiDs such as pomalidomide, as with other treatment options, is the development of drug resistance. This has become a substantial impediment to extending patients' lives. Currently, no effective strategy exists for overcoming IMiD resistance in MM patients. Exploring alternative approaches that could improve the efficacy of pomalidomide might help myeloma patients live longer. Genetic alterations in cereblon (CRBN) contribute to more than one-third of clinical cases of pomalidomide resistance. This study aims to restore sensitivity to pomalidomide-resistant cells through mRNA-based wildtype CRBN restoration. First, we repeatedly exposed multiple myeloma cell lines (MM1.S) to pomalidomide at increasing doses, starting from 2 nM to 10 μM. Following six months of pomalidomide exposure, we generated MM1.S cells that are resistant to pomalidomide and confirmed the absence of CRBN with RNA sequencing and western blotting. Through in vitro transcription, we synthesized CRBN mRNA and electroporated it to the resistant cells. We found restoration of wildtype cereblon and subsequent pomalidomide sensitivity compared to cells without CRBN mRNA treatment. As electroporation is impractical beyond laboratory studies, we are designing a polymer-lipid hybrid nanoparticle to efficiently deliver the mRNA to the cells. Additionally, to ensure targeted delivery of the nanoparticle-coated CRBN mRNA to plasma cells, we applied phage display peptide library screens and identified a cyclic peptide with a high affinity for B-cell maturation antigen (BCMA), a protein known to be almost exclusively expressed by plasma and myeloma cells. This peptide is being validated for BCMA binding, and will be conjugated with the nanoparticle-coated CRBN mRNA for targeted delivery to the malignant plasma cells. Findings from this work will advance mRNA-based therapeutics for overcoming drug resistance caused by genetic alterations in target proteins. Joseph U. Ogbede, Michael S. Rogers, Robert J. D'Amato, Bruce R. Zetter. mRNA-based restoration of pomalidomide sensitivity in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4432.

Supplementary figures and table

PDF file - 184K, Characterization of pancreatic immune infiltrate in iKras*;IL6-/- mice.

PDF file - 302K, IL6 deficiency facilitates tissue repair following Kras* inactivation.

PDF file - 253K, IHC staining of IL6, p-Stat3, p-Akt and SMA in iKras* and iKras*;IL6-/- pancreata.

PDF file - 139K, Includes tables of antibodies and PCR primers and detailed methods for common procedures.

Supplementary Tables 1-4 from Collagen XXIII: A Potential Biomarker for the Detection of Primary and Recurrent Non–Small Cell Lung Cancer

PDF file - 221K, IL6 is up-regulated in pancreatic cancer and required for PanIN formation.

PDF file - 223K, Acinar cell proliferation contributes to faster recovery following Kras* inactivation in IL6 deficient mice.

PDF file - 227K, IL6 regulates ROS accumulation and survival of PanIN cells.

Supplementary Data from Cystatin B As a Tissue and Urinary Biomarker of Bladder Cancer Recurrence and Disease Progression

Abstract We have synthesized an oxetane derivative of the benzimidazole compound mebendazole (OBD9) with enhanced solubility and strong anticancer activity in multiple types of cancer cells, especially colorectal cancer. In this report, we provide evidence that OBD9 suppresses colorectal cancer growth by interfering with the Wnt signaling pathway, a main driver of cell growth in colorectal cancer. Specifically, we find that OBD9 induces autophagic degradation of TNIK (traf2 and Nck-interacting kinase), which promotes T-cell factor-4 (TCF4)/beta-catenin–mediated gene expression. Thus, OBD9 as a TNIK inhibitor blocks Wnt/beta-catenin signaling at the final step of transcriptional activation. We suggest that OBD9 provides a potential novel autophagy-mediated, Wnt-damping therapeutic strategy for the treatment of colorectal cancer.

PDF file - 160K, IL6 regulates the fibro-inflammatory environment and survival of pancreatic cancer.

The rapid emergence of immune-evading viral variants of SARS-CoV-2 calls into question the practicality of a vaccine-only public-health strategy for managing the ongoing COVID-19 pandemic. It has been suggested that widespread vaccination is necessary to prevent the emergence of future immune-evading mutants. Here, we examined that proposition using stochastic computational models of viral transmission and mutation. Specifically, we looked at the likelihood of emergence of immune escape variants requiring multiple mutations and the impact of vaccination on this process. Our results suggest that the transmission rate of intermediate SARS-CoV-2 mutants will impact the rate at which novel immune-evading variants appear. While vaccination can lower the rate at which new variants appear, other interventions that reduce transmission can also have the same effect. Crucially, relying solely on widespread and repeated vaccination (vaccinating the entire population multiple times a year) is not sufficient to prevent the emergence of novel immune-evading strains, if transmission rates remain high within the population. Thus, vaccines alone are incapable of slowing the pace of evolution of immune evasion, and vaccinal protection against severe and fatal outcomes for COVID-19 patients is therefore not assured.

PDF file - 184K, MAPK and IL6 signaling pathways activity following Kras* inactivation.

Supplementary Figure S1 and Legend

The transcript encoding Antizyme Inhibitor 1 (AZIN1) is frequently edited in various cancers, and this editing is associated with enhanced tumor aggressiveness. After comparison of wild-type AZIN1 (wtAZIN1) and edited AZIN1 (edAZIN1, which contains a Ser367Gly substitution), we report differential binding of edAZIN1 to a small set of proteins; specifically, edAZIN1 binds to alpha-smooth muscle actin (ACTA2), gamma actin 1 (ACTG1), and myosin9, whereas wtAZIN1 does not. This binding enables nuclear translocation of edAZIN1. In contrast to overexpression of edAZIN1 and, to a lesser extent, (editable) wtAZIN1, overexpression of an uneditable AZIN1 allele does not promote a cellular phenotype associated with increased tumorigenicity. In patients, both editing and nuclear localization of AZIN1 are common and are associated with tumor aggressiveness, i.e., a higher Gleason score, higher genomic instability, and a shorter progression-free survival time. In conclusion, the data indicate that binding of edAZIN1 to the actin/myosin9 complex supports its nuclear translocation, leading to enhanced cellular aggressiveness, and is associated with worse prostate cancer outcomes.

We have entered a new phase of the ongoing COVID-19 pandemic, as the strategy of relying solely on the current SARS-CoV-2 vaccines to bring the pandemic to an end has become infeasible. In response, public-health authorities in many countries have advocated for a strategy of using the vaccines to limit morbidity and mortality while permitting unchecked SARS-CoV-2 spread (“learning to live with the disease”). The feasibility of this strategy is critically dependent on the infection fatality rate (IFR) of COVID-19. An expectation exists, both in the lay public and in the scientific community, that future waves of the virus will exhibit decreased IFR, either due to viral attenuation or the progressive buildup of immunity. In this work, we examine the basis for that expectation, assessing the impact of virulence on transmission. Our findings suggest that large increases in virulence for SARS-CoV-2 would result in minimal loss of transmission, implying that the IFR may be free to increase or decrease under neutral evolutionary drift. We further examine the effect of changes in the IFR on the steady-state death toll under conditions of endemic COVID-19. Our modeling suggests that endemic SARS-CoV-2 implies vast transmission resulting in yearly US COVID-19 death tolls numbering in the hundreds of thousands under many plausible scenarios, with even modest increases in the IFR leading to an unsustainable mortality burden. Our findings thus highlight the critical importance of enacting a concerted strategy (involving for example global access to vaccines, therapeutics, prophylactics and nonpharmaceutical interventions) to suppress SARS-CoV-2 transmission, thereby reducing the risk of catastrophic outcomes. Our findings also highlight the importance of continued investment in novel biomedical interventions to prevent viral transmission. ### Competing Interest Statement M.S. and A.C. are employees of Fractal Therapeutics, Inc. ### Funding Statement A.N. acknowledges funding from the National Science Foundation Graduate Research Fellowship Program under Grant No. DGE-1762114. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. M.S. received funding from Fractal Therapeutics during the execution of this study. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the author. Relevant code is available at