OBJECTIVE:Five-year overall survival (OS) remains < 50% for patients with resectable, locally advanced (LA) primary oral squamous cell carcinoma (OSCC) and soft palate, receiving current standard of care (SOC). The aim of our study was to examine neoadjuvant Leukocyte Interleukin Injection (LI) with CIZ (intravenous low dose cyclophosphamide, indomethacin and zinc multivitamins) effect on OS, in low-risk (LR) OSCC patients. PATIENTS AND METHODS:In a randomized, controlled Phase 3 trial, treatment-naïve locally advanced patients, with stage III/IVa OSCC and soft-palate cancer, had surgical tumor samples assessed for pre-defined thresholds of PD-L1 tumor proportion score (TPS). OS was analyzed using proportional hazard models for LI + CIZ + SOC vs SOC, in the intention-to-treat (ITT) population. RESULTS:OS was superior in low risk (LR) patients receiving LI + CIZ + SOC compared to SOC; OS advantage hazard ratio (HR) 0.64, p = 0.0569 (without selecting for N0, PD-L1 TPS < 10%), and the Kaplan-Meier (K-M) lifetable achieved significance (log rank p = 0.0340) favoring LI + CIZ + SOC vs SOC. Applying the selection criteria (cN0 and TPS < 10%) to ITT, OS reached HR 0.34p = 0.0012, Kaplan-Meier log rank p = 0.0015. The ITT LR cohort (cN0 and TPS < 10%) achieved a HR 0.26 (p = 0.0023), Kaplan-Meier log rank p = 0.0013, supported by progression free survival (PFS) HR 0.43, p = 0.0178, Kaplan-Meier log rank p = 0.0431, with 32% absolute survival advantage over control at 60 months. CONCLUSIONS:Significant OS prolongation was observed in ITT population for LI + CIZ + SOC vs SOC, in LR and in ITT LR cN0, PD-L1TPS < 10% cohort having locally advanced squamous cell carcinoma tumors in oral cavity/soft-palate. TRIAL REGISTRATION:Clinicaltrials.gov Identifier: NCT01265849; EudraCT (Identifier: 2010-019952-35).

MRTX1133 is a first-in-class KRAS G12D inhibitor being in phase I/II clinical trials. KRAS is the most frequently mutated oncogene in pancreatic ductal adenocarcinoma (PDAC), with a predominance of the G12D variant. PDAC is a highly lethal cancer type with an extremely low 5-year survival rate. Although PDAC metastasis most frequently targets the liver, the influence of MRTX1133 treatment on hepatic metastases has not yet been investigated thoroughly. Thus, we aimed to analyze the effect of MRTX1133 treatment on local tumor growth and liver metastasis development. Cell proliferation and migration were investigated in vitro using clonogenic, scratch, Boyden chamber, and immunoblot assay in three KRAS G12D mutated PDAC cell lines (ASPC1, SW1990, PANC1). Moreover, PANC1 was examined in vivo in a spleen-to-liver metastatic xenograft model using NXG female mice. The MRTX1133 treatment decreased clonogenic proliferation and migratory activity; furthermore, it inhibited both local tumor growth in the spleen and liver colonization. MRTX1133 induced alterations associated with mesenchymal-to-epithelial transition; furthermore, lower levels of activated Erk, altered FAK expression, and activation were observed. In addition to the antiproliferative effects of MRTX1133, our in vitro and in vivo results indicate the importance of MRTX1133 as a potential antimetastatic drug in PDAC therapy.

Abstract Background Prenylation (geranylgeranylation or farnesylation) plays an important role in the regulation of RAS proteins. This observation led to development of farnesyltransferase inhibitors (FTI) which were extensively tested in clinical studies of various cancer types. Unfortunately, these studies failed and the development of these drugs stalled. Main body The renaissance of FTIs started with the approval of lonafarnib in children’s progeria syndromes and continued with the approval of tipifarnib in HRAS-mutant head and neck cancers. Although there are several trials running on various viral infections (HDV, RSV, SARS), their future in oncology is based on the novel preclinical findings that FTIs can potentiate the efficacy of novel KRAS inhibitors or other target therapies such as EGFR- or multikinase inhibitors. Conclusions The „second chance” for FTIs is here but the successful clinical implementation of FTIs can only be achieved if the design of the new clinical trials do not repeat mistakes of the past: application of these drugs without predictive markers.

A BRCA1/2-mutációk kiemelt klinikai jelentőséggel bírnak a metasztatikus, kasztrációrezisztens prosztatarákban (mCRPC), mivel előfordulási arányuk magas (10–15%), és jelenlétük összefüggést mutat a rosszabb prognózissal, valamint a célzott PARP-gátló terápiákra adott kedvezőbb válasszal. Vizsgálatunk célja a Semmelweis Egyetem Urológiai Klinikája által 2019 és 2024 között indított BRCA1/2-génszekvenálások klinikai, technikai és terápiás tapasztalatainak összegzése volt. Összesen 143 PC-beteg esetében történt vizsgálatkérés, amely csoportból 124 esetben készült sikeres vizsgálat, 17%-os BRCA1/2-pozitivitási arány mellett. A vizsgálatokat az esetek 92%-ában metasztatikus stádiumban indították, és leggyakrabban tűbiopsziás, illetve radikális vagy transurethralis műtétből származó szövetmintából, vagy pedig vérből történtek. A tűbiopszia esetében volt a legmagasabb a sikertelen vizsgálatok aránya (13%; p=0,016). A minták kora nem befolyásolta szignifikánsan a szekvenálás sikerességét. A BRCA1/2-pozitív betegek általánosságban több vonalbeli kezelést kaptak, és 38%-uk részesült PARP-gátló vagy platinaalapú terápiában. Eredményeink megerősítik, hogy a BRCA1/2-szekvenálás rutinszerű alkalmazása a prosztatarák diagnosztikájában és terápiatervezésében hatékony, és hozzájárul a személyre szabott onkológiai ellátás hazai elterjedéséhez.

Using several melanoma proteomics data sets we created a single analysis platform that enables the discovery, knowledge build, and validation of diagnostic, predictive, and prognostic biomarkers at the protein level. Quantitative mass-spectrometry-based proteomic data was obtained from five independent cohorts, including 489 tissue samples from 394 patients with accompanying clinical metadata. We established an interactive R-based web platform that enables the comparison of protein levels across diverse cohorts, and supports correlation analysis between proteins and clinical metadata including survival outcomes. By comparing differential protein levels between metastatic, primary tumor, and nonmalignant samples in two of the cohorts, we identified 274 proteins showing significant differences among the sample types. Further analysis of these 274 proteins in lymph node metastatic samples from a third cohort revealed that 45 proteins exhibited a significant effect on patient survival. The three most significant proteins were HP (HR = 4.67, p = 2.8e-06), LGALS7 (HR = 3.83, p = 2.9e-05), and UBQLN1 (HR = 3.2, p = 4.8e-05). The user-friendly interactive web platform, accessible at https://www.tnmplot.com/melanoma, provides an interactive interface for the analysis of proteomic and clinical data. The MEL-PLOT platform, through its interactive capabilities, streamlines the creation of a comprehensive knowledge base, empowering hypothesis formulation and diligent monitoring of the most recent advancements in the domains of biomedical research and drug development.

The molecular landscape of cutaneous melanoma is complex and heterogeneous, and a deeper understanding of the genesis and progression of the tumor driven by genetic alterations is essential for the development of effective diagnostic and therapeutic strategies. Molecular diagnostics and the use of biomarkers are increasingly playing a role in treatment decisions. However, further research is urgently needed to elucidate the relationships between complex genetic alterations and the effectiveness of target therapies (although BRAF mutation is still the only targeted genetic alteration). Further research is required to exploit other targetable genetic alterations such as NRAS, KIT or rare mutations. Treatment guidelines for cutaneous melanoma are continually evolving based on data from recent and ongoing clinical trials. These advancements reflect changes mainly in the optimal timing of systemic therapy and the choice of combination therapies increasingly tailored to molecular profiles of individual tumors. Mono- or combination immunotherapies demonstrated unprecedented success of melanoma treatment; still, there is room for improvement: though several factors of primary or acquired resistance are known, they are not part of patient management as biomarkers. The novel developments of cancer vaccines to treat melanoma (melanoma-marker-based or personalized neoantigen-based) are encouraging; introduction of them into clinical practice without proper biomarkers would be the same mistake made in the case of first-generation immunotherapies.

BACKGROUND:Melanoma, the deadliest form of skin cancer, exhibits resistance to conventional therapies, particularly in advanced and metastatic stages. Mitochondrial pathways, including oxidative phosphorylation and mitochondrial translation, have emerged as critical drivers of melanoma progression and therapy resistance. This study investigates the mitochondrial proteome in melanoma to uncover novel therapeutic vulnerabilities. METHODS:Quantitative proteomics was performed on 151 melanoma-related samples from a prospective cohort and postmortem tissues. Differential expression analysis identified mitochondrial proteins linked to disease aggression and treatment resistance. Functional enrichment analyses and in vitro validation using mitochondrial inhibitors were conducted to evaluate therapeutic potential. RESULTS:Mitochondrial translation and oxidative phosphorylation (OXPHOS) were significantly upregulated in aggressive melanomas, particularly in BRAF-mutant and metastatic tumors. Inhibition of mitochondrial pathways using antibiotics (doxycycline, tigecycline, and azithromycin) and OXPHOS inhibitors (VLX600, IACS-010759, and BAY 87-2243) demonstrated dose-dependent antiproliferative effects in melanoma cell lines, sparing noncancerous melanocytes. These treatments disrupted mitochondrial function, suppressed key metabolic pathways, and induced apoptosis, highlighting the clinical relevance of targeting these pathways. CONCLUSIONS:This study reveals mitochondrial pathways as critical drivers of melanoma progression and resistance, providing a rationale for targeting mitochondrial translation and OXPHOS in advanced melanoma. Combining mitochondrial inhibitors with existing therapies could overcome treatment resistance and improve patient outcomes.

BACKGROUND/AIM:The prognostic significance of proliferating cell nuclear antigen (PCNA) has not yet been defined in either colorectal adenoma or carcinoma. This study aimed to compare the differences in PCNA expression between pathologically altered tissue (polyp, adenoma, carcinoma) and the surrounding tissue (termed PCNA expression difference, PCNA-ED) as a potential prognostic marker in colorectal tumor progression. PATIENTS AND METHODS:Tissue specimens used for this study were obtained from 63 non-neoplastic epithelial polyps, 211 colorectal adenomas, and 156 colorectal adenocarcinomas, as well as adjacent normal mucosa. RESULTS:PCNA-ED was absent in non-neoplastic polyps, present in 13.7% of adenomas, and significantly more frequent in adenocarcinomas (33.3%). Higher PCNA-ED correlated with increasing adenoma size, grade of dysplasia, depth of invasion, and Dukes staging. High PCNA-ED was significantly associated with early recurrence, lymphovascular invasion, liver metastases, and reduced survival. Among patients with Astler-Coller B2 tumors, high PCNA-ED suggested a need for adjuvant chemotherapy. CONCLUSION:PCNA-ED is strongly associated with malignant transformation, recurrence, and adverse prognosis in colorectal neoplasms. Its measurement may offer valuable prognostic insight and inform postoperative management strategies.

The randomized controlled pivotal phase 3 study evaluated efficacy and safety of neoadjuvant complex biologic, Leukocyte Interleukin Injection (LI), administered for 3 consecutive weeks pre-surgery, in treatment naïve resectable locally advanced primary squamous cell carcinoma of oral cavity and soft palate. Randomization 3:1:3 to LI+/-CIZ (cyclophosphamide, indomethacin, and zinc)+SOC, or SOC (standard of care) alone. LI-treated patients received 400 IU (as interleukin-2 equivalent; 200 IU peritumorally, 200 IU perilymphatically) sequentially, daily 5 days/week for 3 weeks before surgery. All subjects were to receive SOC. Post-surgery, patients with low risk for recurrence were to receive radiotherapy, while those with high risk received concurrent chemoradiotherapy. Median follow-up was 56 months. There were 923 ITT (Intent-to-Treat) subjects (380 ITT low-risk and 467 ITT high-risk). Pre-surgery objective early response (45 objective early responders; 5 complete responses [CRs], 40 partial responses [PRs], confirmed by pathology at surgery. LI (+/− CIZ) had 8.5% objective early responders (45/529 ITT) and 16% objective early responders (34/212 ITT low-risk) vs. no reported SOC objective early responders (0/394 ITT). Objective early responders significantly lowered death rate to 22.2% (ITT LI-treated), 12.5% (ITT low-risk LI + CIZ + SOC), while the ITT low-risk SOC death rate was 48.7%. Thus, objective early response impacted overall survival (OS); proportional hazard ratios were 0.348 (95% CI: 0.152–0.801) for ITT low-risk LI-treated, 0.246 (95% CI: 0.077–0.787) for ITT low-risk LI + CIZ + SOC. ITT low-risk LI + CIZ + SOC demonstrated significant OS advantage vs. ITT low-risk SOC (unstratified log-rank p = 0.048; Cox hazard ratio = 0.68; 95% CI: 0.48–0.95, Wald p = 0.024 [controlling for tumor stage, tumor location, and geographic region]). Absolute OS advantage increased over time for ITT low-risk (LI + CIZ + SOC)-treated vs. ITT low-risk SOC: reaching 14.1% (62.7% vs. 48.6%) at 60 months, with 46.5 months median OS advantage (101.7 months vs. 55.2 months), respectively. Quality of life benefit for complete responders sustained for >3 years post LI treatment. Percent treatment-emergent adverse events were comparable among all treated groups. No excess safety issues were reported for LI over SOC alone post-surgery. NCT01265849, EUDRA:2010-019952-35.

BACKGROUND:Metastatic melanoma is a highly aggressive disease with poor survival rates despite recent therapeutic advancements with immunotherapy. The proteomic landscape of advanced melanoma remains poorly understood, especially regarding proteomic heterogeneity across metastases within patients. METHODS:We collected 83 melanoma metastases from 19 different metastatic sites in 24 patients with advanced metastatic melanoma almost exclusively from the pre-immunotherapy era, using semi-rapid autopsies. The metastases were subjected to histopathological evaluation, RNA-sequencing and mass spectrometry-based proteomics for protein quantitation and non-reference peptide (NRP) sequence detection using a proteogenomic data integration approach. RESULTS:NRPs associated with mutations frequently occurred in proteins related to focal adhesion, vesicle-mediated transport, MAPK signalling and immune response pathways across the cohort. Intrapatient heterogeneity was negligible when considering morphology and driver gene mutation status but was substantial at the proteogenomic level. This heterogeneity was not driven by metastasis location, albeit liver metastases exhibited distinct proteogenomic patterns, including upregulation of metabolic pathways. Cluster analysis outlined four proteomic clusters (C1-4) of the metastases, characterised by the upregulation of cell cycle and RNA-splicing (C1), mitochondrial processes (C3), extracellular matrix (ECM) and immune pathways (C2) and ECM and vesicle-mediated transport pathways (C4). Around two-thirds of patients had metastases that had strongly distinct phenotypes. Patients in our cohort whose metastases were primarily assigned to clusters C1 and C3 exhibited shorter overall survival than patients whose metastases were categorised mainly into the C2 and C4 clusters. CONCLUSION:Our unique multi-metastasis cohort captured the proteogenomic heterogeneity of immunotherapy-naïve melanoma distant metastases, establishing a foundation for future studies aimed at identifying novel therapeutic targets to complement current immunotherapies. KEY POINTS:Comprehensive proteogenomic profiling of post-mortem melanoma metastases, collected primarily before the immunotherapy era. Description of 1177 protein sequence variants predicted by RNA-Seq and validated via mass spectrometry-based proteomics. Empirical evidence of prominent intrapatient heterogeneity, driven by heterogeneous protein expression related to cell cycle- and mitochondrial processes, immune system and extracellular matrix organization.

KRAS mutant lung cancer is the most prevalent molecular subclass of adenocarcinoma (LUAD), which is a heterogenous group depending on the mutation-type which affects not only the function of the oncogene but affects the biological behavior of the cancer as well. Furthermore, KRAS mutation affects radiation sensitivity but leads also to bevacizumab and bisphosphonate resistance as well. It was highly significant that allele specific irreversible inhibitors have been developed for the smoking associated G12C mutant KRAS (sotorasib and adagrasib). Based on trial data both sotorasib and adagrasib obtained conditional approval by FDA for the treatment of previously treated advanced LUAD. Similar to other target therapies, clinical administration of KRASG12C inhibitors (sotorasib and adagrasib) resulted in acquired resistance due to various genetic changes not only in KRAS but in other oncogenes as well. Recent clinical studies are aiming to increase the efficacy of G12C inhibitors by novel combination strategies.

Mismatch repair deficiency (dMMR) with microsatellite instability (MSI) is frequent in cancer, particularly in gastrointestinal and endometrial malignancies. The increased tumor mutational burden renders dMMR/MSI tumors suitable targets for immune checkpoint inhibitors—provided the regulatory genetic defect can be detected. dMMR and MSI are considered equally effective predictors of the efficacy of ICIs; however, while dMMR testing is based on detection of missing MMR proteins in immunohistochemistry (IHC), MSI polymerase chain reaction (PCR) testing focuses on the consequences of dMMR at the genomic level. A retrospective analysis was carried out in a large cancer cohort (n = 1306). dMMR was tested by four IHC reactions (MLH1, PMS2, MSH2, MSH6), and MSI was assessed by pentaplex PCR (BAT-25, BAT-26, MONO-27, NR-21, NR-24) in 703 cases. In 64 cases (5

Background. Farnesyltransferase inhibitors (FTI) failed as monotherapies for various cancer types until the discovery of their potency in HRAS mutant human head and neck and bladder cancers. On the other hand, RAS mutant cancers have been a great challenge for cancer research until the discoveries and approvals of several KRAS-G12C allele specific inhibitors. However, G12C inhibitors were effective mainly in lung cancer and de novo and acquired resistance prompted the development of various combinational modalities including immunotherapy as well as SOS- and SHP2-inhibitors. Based on in-silico analysis of drug sensitivities of KRAS mutant cancer cell lines treated with various drugs including FTIs, we have explored the possibility of the combination of FTIs with KRAS inhibitors.Methods. Clinically approved farnesyl-transferase inhibitors (tipifarnib and lonafarnib) were combined with, novel KRAS G12C inhibitors (sotorasib and adagrasib) using human lung-, pancreatic and colorectal- adenocarcinoma cells in vitro and in vivo. Antitumoral effects were evaluated for cell proliferation, apoptosis and migratory activity. Mechanisms of action were investigated by immunoblot analyzes of various farnesylated proteins, RAS activation and signaling, videomicroscopy and also by histopathology of xenograft tumors. Results. Synergistic anticancer effects were observed upon the combination of FTIs with G12C inhibitors in KRAS G12C mutant human cancer cell lines in vitro. We found that the combination interfered with the compensatory re-activation of HRAS, farnesylation of RHEB in the PI3K/mTOR pathway and lamin. Furthermore, we observed enhanced efficacy of sotorasib upon combination with tipifarnib in the xenograft models of lung adenocarcinoma affecting mitotic- and apoptotic rates and inducing necrosis.Discussion. Our findings suggest the potential clinical applicability of the combination of KRAS-G12C inhibitors and farnesyl-transferase inhibitors. Furthermore, our preliminary data suggest that the synergistic effect of FTIs on KRAS-G12C inhibitors can be projected to G12D inhibitors as well. Citation Format: Jozsef Timar, Marcell Baranyi, Eszter Molnar, Ivan Randelovic, Mihaly Cserepes, Jozsef Tovari, Balazs Hegedus. Farnesyltransferase inhibitors show synergistic anticancer effects in combination with novel KRAS G12C inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB220.

Mutated genes may lead to cancer development in numerous tissues. While more than 600 cancer-causing genes are known today, some of the most widespread mutations are connected to the RAS gene; RAS mutations are found in approximately 25% of all human tumors. Specifically, KRAS mutations are involved in the three most lethal cancers in the U.S., namely pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, and lung adenocarcinoma. These cancers are among the most difficult to treat, and they are frequently excluded from chemotherapeutic attacks as hopeless cases. The mutated KRAS proteins have specific three-dimensional conformations, which perturb functional interaction with the GAP protein on the GAP-RAS complex surface, leading to a signaling cascade and uncontrolled cell growth. Here, we describe a gluing docking method for finding small molecules that bind to both the GAP and the mutated KRAS molecules. These small molecules glue together the GAP and the mutated KRAS molecules and may serve as new cancer drugs for the most lethal, most difficult-to-treat, carcinomas. As a proof of concept, we identify two new, drug-like small molecules with the new method; these compounds specifically inhibit the growth of the PANC-1 cell line with KRAS mutation G12D in vitro and in vivo. Importantly, the two new compounds show significantly lower IC50 and higher specificity against the G12D KRAS mutant human pancreatic cancer cell line PANC-1, as compared to the recently described selective G12D KRAS inhibitor MRTX-1133.

Background Inhibition of mutant KRAS challenged cancer research for decades. Recently, allele-specific inhibitors were approved for the treatment of KRAS-G12C mutant lung cancer. However, de novo and acquired resistance limit their efficacy and several combinations are in clinical development. Our study shows the potential of combining G12C inhibitors with farnesyl-transferase inhibitors. Methods Combinations of clinically approved farnesyl-transferase inhibitors and KRAS G12C inhibitors are tested on human lung, colorectal and pancreatic adenocarcinoma cells in vitro in 2D, 3D and subcutaneous xenograft models of lung adenocarcinoma. Treatment effects on migration, proliferation, apoptosis, farnesylation and RAS signaling were measured by histopathological analyses, videomicroscopy, cell cycle analyses, immunoblot, immunofluorescence and RAS pulldown. Results Combination of tipifarnib with sotorasib shows synergistic inhibitory effects on lung adenocarcinoma cells in vitro in 2D and 3D. Mechanistically, we present antiproliferative effect of the combination and interference with compensatory HRAS activation and RHEB and lamin farnesylation. Enhanced efficacy of sotorasib in combination with tipifarnib is recapitulated in the subcutaneous xenograft model of lung adenocarcinoma. Finally, combination of additional KRAS G1C and farnesyl-transferase inhibitors also shows synergism in lung, colorectal and pancreatic adenocarcinoma cellular models. Discussion Our findings warrant the clinical exploration of KRAS-G12C inhibitors in combination with farnesyl-transferase inhibitors.

In recent years, the academic community has faced a growing threat from predatory journals. These are publications that prioritize profit over quality scholarship and compromise the integrity of scientific discourse. Predatory journals often bypass rigorous peer review processes, creating a platform for substandard and sometimes fraudulent research. The proliferation of such journals not only undermines trust in scientific publications but also poses serious challenges for researchers who are trying to responsibly share their findings. Recognizing these pressing issues, Semmelweis University held a symposium on 16 November 2023, titled 'Science Integrity in the Era of Predator Journals'. This event was a response to growing concerns about academic publishing. It brought together editors in chief (EiCs) from 14 top journals to discuss critical topics. These included using AI to detect publication fraud, the identification of AI-generated papers, combating paper mills, the necessity of robust submission and review processes and the importance of author identity and conflict of interest vetting. This editorial offers a thorough summary of the symposium's discussions. It highlights the collaborative efforts to improve publication standards and reinforce ethical practices in scientific research. Through shared insights and strategies, the participants tackled the complex challenges posed by predatory journals, setting a course for sustained integrity in the dissemination of scientific knowledge. Professor Péter Ferdinandy, the EiC of the British Journal of Pharmacology (BJP) and host of the event, presented how he plans to continue the long tradition of BJP excellence while improving overall publication quality as well as the experience of both authors and editors. In this regard, steps have been taken to simplify the BJP publication guidelines and improve turnaround times at every step of the review and publication process (Papapetropoulos et al., 2023). He also highlighted that BJP editors in partnership with the BJP publisher Wiley are taking aggressive steps to combat publication fraud. These steps have involved the development of an efficient pipeline to handle ethics investigations as well as the retention of a consulting editor dedicated to matters of research integrity. As a result, ethical concerns raised internally or by third parties are dealt with in a much timelier manner with corrective action being rapidly implemented where necessary. The EiC of the British Journal of Clinical Pharmacology (BJCP—a sister journal of BJP also published by Wiley), Professor Serge Cremers, delved into many issues surrounding the maintenance of publication integrity. As the BJCP deals with many clinical studies, a strong emphasis was placed on resolving the inherent conflicts of interest that arise between the economics of drug development and patient well-being that may bias the publication of clinical trial results. The BJCP requires all submissions to strongly adhere to good clinical practice (GCP) guidelines, have internal review board (IRB) approval and disclose the identity of the physician conducting the trial. The BJCP also utilizes AI-powered systems provided by Wiley for the detection of plagiarism, image manipulation and other forms of fraud. However, BJCP still heavily relies on its editors and reviewers to detect fraud and admits that despite all the safeguards in-place, intercepting all forms of deceit is not perfect. The EiC of Pharmacology Research & Perspectives (PR&P—a collaborative Open Access journal of the British Pharmacology Society [BPS], the American Society for Pharmacology and Experimental Therapeutics and Wiley), Michael Jarvis, highlighted ongoing strategic priorities of publishing pharmacological methods, research replication studies and negative research findings and providing a forum for early career researchers. While only in its 11th year, PR&P provides an important, geographically inclusive, venue for publication of scientifically rigorous papers that directly address issues of research reliability (Jarvis et al., 2023). Like BJP and BJCP, all papers and data submitted to PR&P are initially screened using Wiley's AL-powered manuscript integrity system. Professor Tomasz Guzik, the EiC of Cardiovascular Research, introduced the meeting attendees to the concepts of 'Open Science'. This is an initiative that strives to improve the trust and access to scientific knowledge by implementing 'open' processes at every step of the way from data generation and analysis through publication and dissemination. Pillars of this initiative are open data, open access publication, open source software, open evaluation and open educational resources. This model was also avidly supported by the EiC of Oral Radiology, Professor Kaan Orhan, who emphasized the need for detailed methodological reporting as well as raw data and source code sharing. Prof. Guzik highlighted data sharing tools such as GO Fair that aims to make raw data easily accessible to both humans and computers, the preprint servers bioRxiv and medRxiv and repositories such as the UK Biobank as a model for open access big data dissemination. He also tackled the role of AI within the open science model, addressing the good and the bad. The advantages of AI highlighted were manifold including its speed and efficiency, potential to reduce human-led analysis bias, enhanced pattern recognition, improved reproducibility and generation of robust predictive models. The drawbacks discussed included AI output quality control, intellectual property and data privacy issues, the introduction and perpetuation of analysis biases and the erosion of human user critical thinking. Although there are manifold benefits to the 'Open Science' model, the EiC of Pharmacology Research & Perspectives, Dr. Michael Jarvis, highlighted that the ethos is directly fuelling the rise of paper mills, predatory journals and a sidelining of the peer review process that is making it more challenging to identify high quality publications (Jarvis, 2024; Jarvis & Williams, 2016). Professor Roland Seifert, the EiC of the oldest pharmacology journal Naunyn-Schmiedebergs Arch Pharmacol (NSAP) founded in 1873, gave a detailed account of their ongoing war against the fraudulent publications generated by paper mills. Prof. Seifert detailed a three-step approach used by NSAP to identify fake papers which included checking NSAP rejected and withdrawn manuscripts against published literature using text mining tools, comparing the author lists of rejected/withdrawn NSAP submissions with their subsequently published versions in other journals and finally manual verification that the submission is the same if the author lists differed extensively. In this way, NSAP evaluated 2056 papers rejected/withdrawn between 2015 and 2021, finding that 952 were published elsewhere. Eleven of these 952 had radically different author lists than the NSAP submitted versions, and 10 of these were ultimately deemed to be fake papers (Wittau et al., 2024). Notably, the vast majority of the authors on these fake papers were Chinese highlighting paper mills as a geographic problem (Wittau & Seifert, 2024). Disappointingly, the journals that published the 10 fake papers have yet to take substantiative corrective action, highlighting that a massive change is necessary in how journals cooperate to maintain the scientific record. To combat paper mills, NSAP proposes the establishment of a database where all journals would submit their received manuscripts to enable cross-checking and flagging of potentially fraudulent papers. The best way to prevent overt publication fraud is to detect it at its earliest stages. To this end, the EiCs of Pathology Oncology Research (Dr. József Tímár), Physiology International (Dr. Zoltan Benyó), Pharmacological Research (Professor Emilio Clementi) and the European Journal of Mental Health (Professor Dávid Beáta) detailed the criteria they use to screen submissions. Immediate warning signs of potential fraud include all of the authors on a manuscript having 0–2 previous publications, use of non-institutional email addresses, the claimed institute not having an easily identified homepage, study funding undefined yet the submission contains expensive experiments and if the authors cannot suggest potential reviewers for their work. To help validate author identity, it is suggested that ORCIDs as well as work email addresses should be required. At the level of the manuscript itself, plagiarism should be screened for stringently with 0% text overlap occurring in the results section and <20% text overlap overall. Images should be checked for signs of manipulation and raw data such as uncut western blots submitted along with the manuscript. Additionally, only research that is ethically approved should be under consideration for publication that requires the submission of original internal review board (IRB) documents demonstrating study approval. Author contributions should also be declared using internationally recognized systems such as 'Contributor Roles Taxonomy' (CRediT) and the International Committee of Medical Journal Editors Acknowledgements criteria. The process of peer review is integral to the maintenance of scientific integrity. A general consensus of the meeting participants was that the double-blind review process is optimal for unbiased assessment and should involve at least two expert reviewers. Recognizing the wide scope of their portfolio, it is recommended that journals develop a robust network of consulting editors. These editors, specialists in key subfields, can provide their expertise on an as-needed basis, ensuring high-quality and relevant evaluations. A consensus view to emerge from this meeting was the need to foster a sense of community among authors, editors and reviewers. Indeed, if everyone has a direct stake in scientific integrity and is personally motivated to help maintain it, there is much less room for fraud to take root. This is especially relevant in the pharmacology research community that has a well-established history of requiring the reporting of clear and comprehensive reporting of research methodology and analysis (Jarvis, 2024). Professor Orhan correctly identified that this begins on the institute level that have to do much more to promote an environment of scientific cooperation and knowledge sharing. He further proposed that specific education at the institute level in publication ethics could go a long way to curbing unintentional ethical lapses and greatly improve outcomes for both authors, journals and ultimately the scientific record. Another crucial element in safeguarding scientific integrity is the continued support and development of society-affiliated journals as exemplified by ASPET, BPS and DGPT. These society-based journals benefit immensely from the interconnected community of members who regularly engage at society meetings and conferences. Such interactions facilitate a deeper understanding and familiarity with ongoing research in the field. When editors and reviewers are active participants in these scientific discussions, they gain first-hand insight into the nuances of the research and the reliability of the researchers themselves. This familiarity helps in making more informed decisions during the peer review process. Moreover, the society meetings serve as platforms for vibrant scientific debate, allowing potential issues and breakthroughs to be scrutinized collaboratively. By fostering a community that is both knowledgeable and engaged, society-affiliated journals inherently promote a culture of transparency and rigorous scholarly review, thereby enhancing the overall quality and credibility of published research. Additionally, these journals can further support the society's community-building efforts by publishing meeting proceedings (Murphy et al., 2022; Whitehead et al., 2022). This not only captures the spirit of the scientific debates held at these gatherings but also serves as a valuable archival resource that chronicles the progression of thought and discovery within the field. Professor Zoltan Ungvari of GeroScience highlighted an innovative approach to build community within the journal's network. As part of the American Aging Association (AGE), GeroScience utilizes members with high scientific standing from AGE to serve as handling editors, thereby enhancing the quality and depth of the feedback provided to authors. The journal also has instituted a mentorship program where seasoned reviewers guide less experienced ones, promoting a rigorous review culture. This system has not only increased reviewer reliability but also achieved a remarkable 96% author satisfaction rate, demonstrating the efficacy of community-oriented approaches in scientific publishing. Efforts to foster proactive engagement among junior scientists are a vital part of community-building within scientific societies. One particularly effective strategy highlighted by Professor Ungvari is the provision of incentives such as publication awards. These awards are given to junior scientists who author high-impact papers published in the society-affiliated journal. Additionally, award recipients are invited to attend the annual meeting of the society and are often recruited for the journal's peer reviewer training program. This involvement not only provides them with a platform to share their work and engage directly with leading figures in the field but also integrates them into the journal's operational processes, including open meetings held at the society's annual gatherings. Such initiatives strengthen the bond between the journal and the society while reinforcing the community as a whole. By supporting the development of emerging scientists in these ways, the journal and the society cultivate a rich environment of collaboration and scholarly exchange, enhancing the scientific community from the ground up. Notwithstanding all emphasis on scientific integrity and all efforts to prevent publication of fraudulent studies, authors and editors must also cooperate to set the record straight and avoid a positive publication bias in a specific field (Skyschally et al., 2024). Professor Gerd Heusch, EiC of Basic Research in Cardiology (BRiC), proposed that authors are encouraged to use a prospective, power analysis-based study design with appropriate randomization and blinding of investigators wherever possible. Editors should make sure that neutral studies and studies which contradict prior published data are published in equal right with positive, novel studies (Jarvis et al., 2023). In conclusion, the symposium at Semmelweis University marks a significant milestone in the ongoing battle against predatory journals and the broader challenges facing scientific publishing. The collaborative efforts discussed, and the strategies developed during the event underline a collective commitment to upholding scientific integrity. The measures outlined by the symposium's participants, from enhancing peer review to fostering transparency through society-affiliated journals and social media, set a path toward a more accountable and reliable scientific discourse. A key takeaway is the crucial need for non-predatory journals to form a united front, sharing resources, data and best practices to effectively combat the spread of unethical publications. This cooperation is essential not only for maintaining high standards within individual journals but also for fostering a global academic environment resistant to fraud and misconduct. As the academic community continues to evolve, the importance of robust review processes, community engagement and the implementation of innovative tools such as AI cannot be overstated. By continuing to engage, educate and innovate, we can ensure that scientific advancements remain a beacon of truth and progress. The authors would like to thank Evan E. Santo for compiling this editorial from author input. The authors would also like to thank Charles Whalley of the British Pharmacological Society for additional input.

EDITORIAL Pathol. Oncol. Res., 14 February 2024 https://doi.org/10.3389/pore.2024.1611691

Pancreatic adenocarcinoma is one of the deadliest forms of cancer with no effective therapeutic options. A KRAS mutation can be found in up to 90% of all pancreatic tumors, making it a promising therapeutic target. The introduction of new KRAS inhibitors has been a milestone in the history of KRAS mutant tumors; however, therapeutic resistance limits their efficacy. Thus, new therapeutic options, including combination therapies, are urgently needed. Recently, we have shown that KRAS G12C inhibitors in combination with farnesyl-transferase inhibitors exert synergistic antitumor effects. Here, we provide evidence for the feasibility of this combinational approach to break down resistance in KRAS G12D mutant pancreatic cancer. Although we have shown that the 3D environment dramatically sensitizes cells to MRTX1133 treatment, the synergistic effect of this drug combination is present in both 2D and 3D in the PANC1 pancreatic adenocarcinoma model, which showed high resistance to MRTX1133 in 2D. The effects of the combination treatment show an association with the inhibition of farnesylated regulatory proteins, including HRAS and RHEB, along with the expression level of KRAS. Our study warrants further investigation for the potential applicability of KRAS G12D inhibitors in combination with farnesyl-transferase inhibitors for the treatment of KRAS mutant pancreatic adenocarcinoma.

Current clinical guidelines recommend mismatch repair (MMR) protein immunohistochemistry (IHC) or molecular microsatellite instability (MSI) tests as predictive markers of immunotherapies. Most of the pathological guidelines consider MMR protein IHC as the gold standard test to identify cancers with MMR deficiency and recommend molecular MSI tests only in special circumstances or to screen for Lynch syndrome. However, there are data in the literature which suggest that the two test types may not be equal. For example, molecular epidemiology studies reported different rates of deficient MMR (dMMR) and MSI in various cancer types. Additionally, direct comparisons of the two tests revealed relatively frequent discrepancies between MMR IHC and MSI tests, especially in non-colorectal and non-endometrial cancers and in cases with unusual dMMR phenotypes. There are also scattered clinical data showing that the efficacy of immune checkpoint inhibitors is different if the patient selection was based on dMMR versus MSI status of the cancers. All these observations question the current dogma that dMMR phenotype and genetic MSI status are equal predictive markers of the immunotherapies.