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The ability to remotely control the activity of chimeric antigen receptors (CARs) with small molecules can improve the safety and efficacy of gene-modified T cells. Split ON- or OFF-switch CARs involve the dissociation of tumor-antigen binding from T cell activation (i.e., CD3ζ) on the receptor (R-) and signaling (S-) chains, respectively, that either associate or are disrupted in the presence of a small molecule. Here, we have developed an inducible (i)ON-CAR comprising the anti-apoptotic B cell lymphoma protein 2 protein in the ectodomain of both chains which associate in the presence of venetoclax. We showed that inducible ON (iON)-CAR T cells respond to target tumors cells in the presence of venetoclax or the BH3 mimetic navitoclax in a dose-dependent manner, while there is no impact of the drugs on equivalent second generation-CAR T cells. Within 48 h of venetoclax withdrawal, iON-CAR T cells lose the ability to respond to target tumor cells in vitro as evaluated by Interferon-gamma (IFNγ) production, and they are reliant upon the presence of venetoclax for in vivo activity. Finally, by fusing a degron sequence to the endodomain of the iON-CAR S-chain we generated an all-in-one ON/OFF-switch CAR, the iONØ-CAR, down-regulated by lenalidomide within 4 to 6 for functionally inactive T cells (no IFNγ production) within 24 h. We propose that our remote-control CAR designs can reduce toxicity in the clinic. Moreover, the periodic rest of iON and iONØ-CAR T cells may alleviate exhaustion and hence augment persistence and long-term tumor control in patients., Competing Interests: Competing interests statement:Provisional intellectual property filing has been filed for iON and iONØ CAR designs with inventors including G.M.P.G.A., B.E.C., SS., and M.I.

Aerobic glycolysis and immune evasion are two key hallmarks of cancer. However, how these two features are mechanistically linked to promote tumor growth is not well understood. Here, we show that the glycolytic enzyme enolase-1 (ENO1) is dynamically modified with an O -linked β- N -acetylglucosamine (O-GlcNAcylation), and simultaneously regulates aerobic glycolysis and immune evasion via differential glycosylation. Glycosylation of threonine 19 (T19) on ENO1 promotes its glycolytic activity via the formation of active dimers. On the other hand, glycosylation of serine 249 (S249) on ENO1 inhibits its interaction with PD-L1, decreases association of PD-L1 with the E3 ligase STUB1, resulting in stabilization of PD-L1. Consequently, blockade of T19 glycosylation on ENO1 inhibits glycolysis, and decreases cell proliferation and tumor growth. Blockade of S249 glycosylation on ENO1 reduces PD-L1 expression and enhances T cell-mediated immunity against tumor cells. Notably, elimination of glycosylation at both sites synergizes with PD-L1 monoclonal antibody therapy to promote antitumor immune response. Clinically, ENO1 glycosylation levels are up-regulated and show a positive correlation with PD-L1 levels in human colorectal cancers. Thus, our findings provide a mechanistic understanding of how O-GlcNAcylation bridges aerobic glycolysis and immune evasion to promote tumor growth, suggesting effective therapeutic opportunities., Competing Interests: Competing interests statement:The authors declare no competing interest.

Introduction: CD38 and BCMA are proteins expressed at high levels in multiple myeloma cells, so they are targets for the development of mono- or multispecific antibodies., Areas Covered: patent US20240132615 describes anti-CD3/BCMA/CD38 trispecific antibodies and a method of treating relapsed/refractory multiple myeloma pharmaceutically. In vitro and preclinical results show that anti-CD3/BCMA/CD38 trispecific antibodies have stronger binding affinity and killing potency compared to daratumumab, isatuximab, and teclistamab antibodies., Expert Opinion: the trispecific structure and a silenced Fc is a pharmaceutical advantage of the anti-CD3/BCMA/CD38 antibody for the treatment of relapsed or refractory multiple myeloma.

Introduction: Fear of progression (FOP) is a significant psychological concern among cancer patients. The Fear of Progression Questionnaire-Short Form (FOPQ-SF) is one of the significant and reliable tools to evaluate FOP. This study aims to validate the psychometric features of the Persian version of FOPQ-SF in Iranian cancer patients., Methods: The translation of the FOPQ-SF was developed using a "forward-backward" approach. This cross-sectional study included 120 cancer patients who completed the questionnaires. The validity and reliability of the FOPQ-SF were evaluated, and the factor structure was examined using both exploratory factor analysis (EFA) and confirmatory factor analysis (CFA)., Results: The FOPQ-SF demonstrated high test-retest and internal reliability, with a Cronbach's alpha coefficient of 0.84. EFA revealed a one-factor structure consisting of 12 items. The FOPQ-SF exhibited high convergent validity, as indicated by significant correlations with anxiety, depression, the total score of HADS, and symptoms. It also demonstrated moderate divergent validity, with negative correlations observed between function and global health. Furthermore, FOP significantly differed among pre-defined groups based on cancer stages., Discussion: The results indicate that the Persian version of the FOPQ-SF is a reliable and valid questionnaire for assessing FOP in 20-60 Iranian cancer patients ages., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ethnopharmacological Relevance: Natural substance geraniol has anti-inflammatory and antioxidant qualities. It may be used to treat metabolic diseases such as diabetes, obesity, and cardiovascular illnesses. Innovations in nanoformulations enhance geraniol's absorption, stability, and targeted distribution, augmenting its therapeutic effectiveness and mitigating side effects, despite the limits of traditional treatment., Aim of the Review: The therapeutic potential of geraniol in the management of metabolic disorders such as diabetes, obesity, neuroinflammation, and cardiovascular disease is examined in this review. It highlights the anti-inflammatory, antioxidant, and lipid-lowering qualities of geraniol as well as the potential for nanoformulations to increase bioavailability and therapeutic efficacy., Materials and Methods: A collection of pertinent research articles about the potential of geraniol in metabolic illnesses, including obesity, type 2 diabetes, as well as cardiovascular diseases, was compiled from PubMed, Scopus, and Google Scholar. Terms such as "metabolic syndrome," "antioxidant," "anti-inflammatory," "geraniol," and "nanoformulations" were employed. Google Patents were also examined in order to offer insights into current and upcoming research., Results: The potential of geraniol to treat metabolic disorders, including obesity, diabetes, hyperlipidemia, and cardiovascular illnesses, is thoroughly reviewed in this article. Recent research has demonstrated the lipid-lowering, antioxidant, and anti-inflammatory properties of geraniol as well as its ability to improve endothelial function and reduce oxidative stress in preclinical animals. The paper delves into the various nanoformulations, including liposomes, nanoparticles, and nanoemulsions, which enhance geraniol's therapeutic efficacy and bioavailability, making it a viable option for managing metabolic syndrome., Conclusion: The antioxidant, anti-inflammatory, and lipid-lowering qualities of geraniol make it a promising treatment for metabolic diseases. Its bioavailability along with therapeutic efficacy are increased by nanoformulations, which makes it a compelling option for the treatment of conditions such as neuroinflammation, diabetes, and obesity., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Nanobodies (Nbs) are antibody fragments derived from heavy-chain-only IgG antibodies found in the Camelidae family as well as cartilaginous fish. Their unique structural and functional properties, such as their small size, the ability to be engineered for high antigen-binding affinity, stability under extreme conditions, and ease of production, have made them promising tools for diagnostics and therapeutics. This potential was realized in 2018 with the approval of caplacizumab, the world's first Nb-based drug. Currently, Nbs are being investigated in clinical trials for a broad range of treatments, including targeted therapies against PDL1 and Epidermal Growth Factor Receptor (EGFR), cardiovascular diseases, inflammatory conditions, and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. They are also being studied for their potential for detecting and imaging autoimmune conditions and infectious diseases such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A variety of methods are now available to generate target-specific Nbs quickly and efficiently at low costs, increasing their accessibility. This article examines these diverse applications of Nbs and their promising roles. Only the most recent articles published in the last five years have been used to summarize the most advanced developments in the field., (© 2024. The Author(s).)

Background: New diagnostic tools are needed to improve the diagnosis and risk stratification of cutaneous melanoma. Disease-specific microRNA signatures have been previously described via NanoString profiling of solid biopsy tissue and plasma. This study validated these signatures via next-generation sequencing technology and compared their performance against clinical metrics and other published melanoma signatures., Methods: RNA from 64 plasma and 60 FFPE biopsy samples from individuals with invasive melanoma or related benign/control phenotypes was extracted and enriched for microRNA. RNA sequencing was performed to compute MEL38/MEL12 signature scores. The results were evaluated with published NanoString and RNA sequencing datasets, comprising 548 solid tissue samples and 217 plasma samples, to predict disease status and patient outcome., Results: The MEL38 diagnostic signature classifies patients into discrete diagnostic groups via RNA sequencing in either solid tissue or plasma (P < 0.001). In solid tissue, the prognostic MEL12 signature stratifies patients into low-, intermediate- and high-risk groups, independent of clinical covariates. The hazard ratios for 10-year overall survival, based on observed survival intervals, were 2.2 (MEL12 high-risk vs low-risk, P < 0.001) and 1.8 (intermediate-risk vs low-risk, P < 0.001), outperforming other published prognostic models. MEL12 also exhibited prognostic significance in the plasma of 42 patients with invasive disease., Conclusions: The MEL38 and MEL12 signatures can be assessed in either solid tissue or plasma using RNA-seq and are strong predictors of disease state and patient outcome. Compared with other genomic methods, MEL12 was shown to be the strongest predictor of poor prognosis. MicroRNA expression profiling offers objective, accurate genomic information about a patient's likelihood of invasive melanoma and prognosis., (© 2024. The Author(s).)

Background: Patients with cancer and an underlying autoimmune disease who are considering immune checkpoint blockers (ICBs) need to know about the benefits and risks of severe immune-related adverse events and flares of the autoimmune condition., Objective: This study aims to develop and alpha test an educational website for patients with cancer., Methods: Learning topics, images, and website architecture (including flow and requirements) were developed and iteratively reviewed by members of a community scientist program, a patient advisory group, and content experts. Alpha testing was performed, measuring the site's usability using the Suitability Assessment of Materials and its acceptability using the Ottawa Acceptability Measure., Results: The website included a home page; general information about ICBs; comprehensive modules on the benefits and risks of ICBs for patients with cancer and preexisting autoimmune diseases; general wellness information; and features such as a quiz, additional resources, and a glossary. For the alpha testing, 9 users assessed the newly developed website. Patient reviewers (n=5) had rheumatoid arthritis, Crohn disease, Sjogren syndrome, or vasculitis. Health care provider reviewers (n=4) were medical oncologists or rheumatologists. The median Suitability Assessment of Materials rating was 75 (IQR 70-79; range 0-100) for patients versus 66 (IQR 57-72; range 0-100) for providers (scores ≥70 indicate no substantial changes needed). Recommendations for improvement, mostly involving navigation and accessibility, were addressed. All participants expressed that the website was acceptable and balanced in terms of discussion of benefits and harms. Because half (2/4, 50%) of the providers suggested we increase the amount of information, we extended the content on the impact of having an autoimmune disease when considering ICB treatment, the probability of flares, and the management of flares in this context., Conclusions: The feedback led to minor revisions to enhance readability, navigation, and accessibility, ensuring the website's suitability as a decision-making aid. The newly developed website could become a supporting tool to facilitate patient-physician discussion regarding ICBs., (©Maria A Lopez-Olivo, Maria E Suarez-Almazor, Gabrielle F Duhon, McKenna Cherry, Huifang Lu, Cassandra Calabrese, Mehmet Altan, Hussain Tawbi, Alexa Meara, Clifton O Bingham, Adi Diab, Viola B Leal, Robert J Volk. Originally published in JMIR Cancer (https://cancer.jmir.org), 25.10.2024.)

Background: The effects of physical activity on the development of different types of cancers have not been comprehensively studied. This nationwide, population-based cohort study investigated the effects of leisure-time physical activity (LTPA) on the development of different types of cancer in Taiwanese adults. A total of 67,890 adult participants (≥ 18 y old) from five rounds (2001, 2005, 2009, 2013, and 2017) of the Taiwan National Health Interview Survey were included. LTPA was measured as the metabolic equivalent of task (MET) expenditure per week and was classified as inactive (< 1 MET-h), low (1-7.49 MET-h), or high (≥ 7.5 MET-h). The LTPA and other covariates were collected through in-person interviews at baseline. New-onset cancer was ascertained from histopathological reports. The Fine-Gray sub-distribution method, with death as a competing risk, was used to determine the impact of LTPA on incident cancer risk., Results: During the 844,337 person-years of follow-up, 4,435 individuals developed cancer. Compared to inactive adults, individuals engaging in high levels of LTPA (≥ 7.5 MET-h/week) were significantly associated with a reduced risk of developing cancer (adjusted hazard ratio [aHR] = 0.93; 95% confidence interval [CI] = 0.87-0.99). However, those with low levels of LTPA (1-7.49 MET-h/week) did not exhibit a significant association with a reduced risk of developing cancer (aHR = 1.00; 95% CI = 0.92-1.10). When considering specific types of cancers, participants with high levels of LTPA (≥ 7.5 MET-h/week) had a significantly lower risk of developing bladder cancer (aHR = 0.68; 95% CI = 0.47-0.99), cervical cancer (aHR = 0.48; 95% CI = 0.24-0.95), and thyroid cancer (aHR = 0.64; 95% CI = 0.44-0.93)., Conclusions: Our findings suggest that high LTPA (≥ 7.5 MET-h/week) is significantly associated with a low risk of incident bladder, cervical, and thyroid cancers., (© 2024. The Author(s).)

The Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1, also CD66a), a transmembrane glycoprotein of the immunoglobulin superfamily, is a pivotal mediator of various physiological and pathological processes, including oncologic disorders. However, its precise role in tumorigenicity is contradictory discussed by several clinical studies. This review aims to elucidate the clinical significance of CEACAM1 in different cancer entities focusing on tumour formation, progression and metastasis as well as on CEACAM1-mediated treatment resistance. Furthermore, we discuss the contribution of CEACAM1 to cancer immunity and modulation of the inflammatory microenvironment and finally provide a comprehensive review of treatment regimens targeting this molecule., (© 2024 The Author(s). European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Introduction: SOS1 is a crucial guanine nucleotide exchange factor for KRAS. It facilitates the transition of KRAS from inactive GDP-bound state to active GTP-bound state. The activation of KRAS triggers downstream signaling pathways, promoting tumor initiation and progression. Inhibiting SOS1 to prevent KRAS activation is an effective strategy for treating tumors driven by KRAS., Areas Covered: This review identified patents claiming to be SOS1 inhibitors or SOS1-KRAS interaction modulators published between January 2022 and June 2024 using Cortellis Drug Discovery Intelligence. A total of 15 patent applications from 5 different applicants were assessed., Expert Opinions: In KRAS-driven tumors, inhibiting SOS1 significantly affect cell proliferation and migration by modulating the RAS/MAPK and PI3K/AKT/mTOR signaling pathways. Since 2022, numerous patents for SOS1 inhibitors have been published. The majority of SOS1 inhibitors are currently in the preclinical phase of development, with only a few progressing to clinical trials. However, these inhibitors face significant challenges in clinical studies, including limited efficacy of monotherapies, safety concerns, and the necessity to enhance PK properties. Despite their excellent in vitro performance, SOS1 inhibitors must address issues related to safety, pharmacokinetics, and pharmacodynamics in clinical applications.

Tertiary lymphoid structures (TLSs) are ectopic lymphocyte aggregates formed in non-lymphoid tissues, including cancers, and are loci for the generation of in situ anti-tumor immune responses, which play a crucial role in cancer control. The state of TLS presence in cancer and its composition can significantly impact the treatment response and prognosis of patients. TLSs have the potential to serve as predictive and prognostic biomarkers for cancer. However, the mechanisms underlying TLS formation in cancer and how the essential components of TLSs affect cancer are not fully understood. In this review, we summarized TLS formation in cancer, the value of the TLS in different states of existence, and its key constituents for cancer prediction and prognosis. Finally, we discussed the impact of cancer treatment on TLSs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The worldwide population is ageing, alongside an increase in cancer incidence rates. Over the past 10 years, there has been huge progress in the field of oncology with earlier diagnosis and an expansion of treatment options, leading to a growing number of older people living with cancer. That has meant that caring for older patients with cancer is now part of day-to-day oncology practices. This cohort often has geriatric syndromes and a higher prevalence of frailty and complex needs and preparing our clinical services to optimise care for these patients is essential. Whilst it is widely accepted that comprehensive geriatric assessments are of benefit to patients, only a small proportion of patients can access these through specialised teams during their cancer care. In the past few years there has been significant progress in this field throughout the United Kingdom (UK). The goal of this review is to inform other health care systems how to learn from what has been done in the UK. This paper provides an update from our previous review in 2020, detailing the new services being implemented and made available to patients and an expansion in the number of new pilot teams and research projects/trials throughout the four nations of the UK., Competing Interests: Declaration of Competing Interest Mark Baxter reports a relationship with Servier Monde that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Mark Baxter reports a relationship with Ipsen that includes: speaking and lecture fees and travel reimbursement. Mark Baxter reports a relationship with Bristol Myers Squibb Co that includes: speaking and lecture fees. Mark Baxter reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: speaking and lecture fees. Kirsty Balachandran reports a relationship with Bristol Myers Squibb Co that includes: speaking and lecture fees. Anne Barrell reports a relationship with Roche that includes: travel reimbursement. Anne Barrell reports a relationship with Bristol Myers Squibb Co that includes: speaking and lecture fees. Anne Barrell reports a relationship with Novartis AG that includes: speaking and lecture fees. Nicolo Matteo Luca Battisti reports a relationship with Pfizer Inc. that includes: board membership, speaking and lecture fees, and travel reimbursement. Nicolo Matteo Luca Battisti reports a relationship with Abbott that includes: board membership. Nicolo Matteo Luca Battisti reports a relationship with Sanofi that includes: board membership and speaking and lecture fees. Nicolo Matteo Luca Battisti reports a relationship with Astellas Pharma Inc. that includes: board membership. Nicolo Matteo Luca Battisti reports a relationship with Exact Sciences Corporation that includes: travel reimbursement. Nicolo Matteo Luca Battisti reports a relationship with Eli Lilly and Company that includes: speaking and lecture fees and travel reimbursement. Nicolo Matteo Luca Battisti reports a relationship with AbbVie Inc. that includes: speaking and lecture fees. Nicolo Matteo Luca Battisti reports a relationship with Roche that includes: speaking and lecture fees. Nicolo Matteo Luca Battisti reports a relationship with Servier Monde that includes: speaking and lecture fees. Nicolo Matteo Luca Battisti reports a relationship with Gilead Sciences Inc. that includes: speaking and lecture fees. Nicolo Matteo Luca Battisti reports a relationship with AstraZeneca Pharmaceuticals LP that includes: speaking and lecture fees. Kwok-Leung Cheung reports a relationship with Roche that includes: consulting or advisory. Kwok-Leung Cheung reports a relationship with Cancers that includes: travel reimbursement. Helen Brown reports a relationship with Roche that includes: funding grants. Fabio Gomes reports a relationship with AstraZeneca Pharmaceuticals LP that includes: speaking and lecture fees and travel reimbursement. Fabio Gomes reports a relationship with Roche that includes: speaking and lecture fees and travel reimbursement. Fabio Gomes reports a relationship with Boehringer Ingelheim GmbH that includes: speaking and lecture fees and travel reimbursement. Fabio Gomes reports a relationship with Pfizer Inc. that includes: speaking and lecture fees and travel reimbursement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The spatial organization of cells within tissues aids in understanding physiological and pathological processes, as well as elucidating the mechanisms of action underlying treatments. We present a protocol for analyzing image-based spatial proteomics data. To illustrate, we focus on whole-slide images of human multiplexed tumor tissues acquired using the PhenoCycler-Fusion 2.0 platform from Akoya Biosciences. We describe steps for cell segmentation, cell phenotyping, intercellular distance calculation, and data visualization. For complete details on the use and execution of this protocol, please refer to Franken et al. 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Smoking after cancer impairs cancer treatment outcomes and prognosis, regardless of cancer type. Prior data suggest that patients with cancers other than lung or head/neck cancer had lower cessation motivation, which in turn predicted lower smoking abstinence. This study evaluated feasibility for a future efficacy trial and assessed the acceptability of brief self-help materials, targeted by cancer type, to enhance cessation motivation., Methods: Patients had a diagnosis of skin melanoma, breast, bladder, colorectal, or gynecological cancers within ≤ 6 months, smoked ≥ 1 cigarette in the past month, and were not currently participating in a cessation program. After completing a baseline assessment, participants received the booklet corresponding to their cancer type. Follow-ups were conducted 1 week and 1 month post-intervention., Results: Among 118 patients potentially eligible, 109 were successfully contacted and 53 patients were eligible and all consented. Among consenting patients, 92.5% completed baseline, and 90.6% received the intervention. Among patients receiving the intervention, 91.7% completed all study procedures and follow-up. At 1 month, 87.5% reported reading the booklet and 92.8% rated it as good/excellent. Motivation to quit smoking increased over time among those with lower motivation at baseline, 33.3% sought smoking cessation assistance, and 25.0% were smoke-free 1 month post-intervention., Conclusion: This study demonstrated the feasibility and acceptability of the first intervention developed for patients with cancers not typically associated with smoking. This low-cost and easy to disseminate intervention has potential to increase motivation to quit smoking among patients with cancers not typically perceived as smoking-related., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Copper (Cu) is a transition metal that plays crucial roles in cellular metabolism. Cu+ homeostasis is upregulated in many cancers and contributes to tumorigenesis. However, therapeutic strategies to target Cu+ homeostasis in cancer cells are rarely explored because small molecule Cu+ chelators have poor binding affinity in comparison to the intracellular Cu+ chaperones, enzymes, or ligands. To address this challenge, we introduce a Cu+ chaperone-inspired supramolecular approach to disrupt Cu+ homeostasis in cancer cells that induces programmed cell death. The Nap-FFMTCGGCR peptide self-assembles into nanofibers inside cancer cells with high binding affinity and selectivity for Cu+ due to the presence of the unique MT/CGGC motif, which is conserved in intracellular Cu+ chaperones. Nap-FFMTCGGCR exhibits cytotoxicity towards triple negative breast cancer cells (MDA-MB-231), impairs the activity of Cu+ dependent co-chaperone super oxide dismutase1 (SOD1), and induces oxidative stress. In contrast, Nap-FFMTCGGCR has minimal impact on normal HEK 293T cells. Control peptides show that the self-assembly and Cu+ binding must work in synergy to successfully disrupt Cu+ homeostasis. We show that assembly-enhanced affinity for metal ions opens new therapeutic strategies to address disease-relevant metal ion homeostasis., (© 2024 Wiley‐VCH GmbH.)

In the current review, we aim to elucidate the advancements concerning the roles and fundamental mechanisms of intermittent fasting (IF) and fasting-mimicking diet (FMD) in cancers. As a dietary intervention,IF and FMD potentially impede tumor growth by modulating multiple signaling pathways, such as AKT, Nrf2, and AMPK pathways.Moreover, IF and FMD have been reported to be associated with the tumor immune response by regulating various immune cells including tumor-associated macrophages (TAMs), monocytic myeloid-derived suppressor cells (MDSCs), T cells, and B cells.Additionally, IF and FMD can enhance the efficacy and tolerability of therapy, concurrently reducing therapy-induced side effects. Furthermore, several clinical trials have underscored the safety, feasibility, and positive impact on the quality of life associated with IF and FMD, thereby augmenting the effectiveness of conventional anti-- tumor therapies while ameliorating treatment-related side effects. This review provides a comprehensive synthesis of findings and elucidates the underlying mechanisms of IF and FMD in cancer progression and therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

DNA methylation is a repressive epigenetic mark that is pervasive in mammalian genomes. It is deposited by DNA methyltransferase enzymes (DNMTs) that are canonically classified as having de novo (DNMT3A and DNMT3B) or maintenance (DNMT1) function. Mutations in DNMT3A and DNMT3B cause rare Mendelian diseases in humans and are cancer drivers. Mammalian DNMT3 methyltransferase activity is regulated by the non-catalytic region of the proteins which contain multiple chromatin reading domains responsible for DNMT3A and DNMT3B recruitment to the genome. Characterising disease-causing missense mutations has been central in dissecting the function and regulation of DNMT3A and DNMT3B. These observations have also motivated biochemical studies that provide the molecular details as to how human DNMT3A and DNMT3B mutations drive disorders. Here, we review progress in this area highlighting recent work that has begun dissecting the function of the disordered N-terminal regions of DNMT3A and DNMT3B. These studies have elucidated that the N-terminal regions of both proteins mediate novel chromatin recruitment pathways that are central in our understanding of human disease mechanisms. We also discuss how disease mutations affect DNMT3A and DNMT3B oligomerisation, a process that is poorly understood in the context of whole proteins in cells. This dissection of de novo DNMT function using disease-causing mutations provides a paradigm of how genetics and biochemistry can synergise to drive our understanding of the mechanisms through which chromatin misregulation causes human disease., (© 2024 The Author(s).)

The tumor suppressor gene Phosphatase and tensin homologue deleted on chromosome 10 (PTEN), possessing both protein and lipid phosphatase activities, is frequently mutated in various human cancers. PTEN aberrations disrupt critical cellular processes like proliferation, apoptosis, migration, and invasion, thereby promoting tumor growth. In the cells, PTEN localizes to the nucleus, cytoplasm, or cell membrane, and its roles depends on the subcellular localization. PTEN is regulated at the transcriptional, post-transcriptional, and post-translational levels, implying that its functions on the tumors are complex. The relationship between PTEN abnormalities and tumors has garnered significant interest in recent years. PTEN regulates essential cellular processes involved in tumorigenesis. Mutations or deletions in the PTEN gene often correlate with unfavorable prognosis and increased cancer recurrence. Numerous studies suggest that PTEN expression levels in tumors could be a valuable biomarker for cancer diagnosis, treatment, and predicting patient outcomes. This paper provides a comprehensive review of the biological function, regulatory mechanisms, and post-translational modifications of PTEN. Furthermore, this review explores the expression and regulation of PTEN in different tumor types, as well as its interactions with environmental factors in tumorigenesis. This comprehensive analysis aims to deepen our understanding of the signaling pathways between PTEN and cancer., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Introduction: Glycosylation, the process of glycan synthesis and attachment to target molecules, is a crucial and common post-translational modification (PTM) in mammalian cells. It affects the protein's hydrophilicity, charge, solubility, structure, localization, function, and protection from proteolysis. Aberrant glycosylation in proteins can reveal new detection and therapeutic Glyco-biomarkers, which help to improve accurate early diagnosis and personalized treatment. This review underscores the pivotal role of glycans and glycoproteins as a source of biomarkers in human diseases, particularly cancer., Areas Covered: This review delves into the implications of glycosylation, shedding light on its intricate roles in cancer-related cellular processes influencing biomarkers. It is underpinned by a thorough examination of literature up to June 2024 in PubMed, Scopus, and Google Scholar; concentrating on the terms: (Glycosylation[Title/Abstract]) OR (Glycan[Title/Abstract]) OR (glycoproteomics[Title/Abstract]) OR (Proteoglycans[Title/Abstract]) OR (Glycomarkers[Title/Abstract]) AND (Cancer[Title/Abstract]) AND ((Diagno*[Title/Abstract]) OR (Progno*[Title/Abstract]))., Expert Opinion: Glyco-biomarkers enhance early cancer detection, allow early intervention, and improve patient prognoses. However, the abundance and complex dynamic glycan structure may make their scientific and clinical application difficult. This exploration of glycosylation signatures in cancer biomarkers can provide a detailed view of cancer etiology and instill hope in the potential of glycosylation to revolutionize cancer research.

Aim: It remains unknown whether sodium-glucose cotransporter 2 inhibitors (SGLT2i) could be associated with incident cancer., Methods: We analyzed individuals having diabetes and newly prescribed SGLT2i or dipeptidyl peptidase 4 inhibitors (DPP4i) in a large-scale epidemiological database. The primary outcome was the incidence of cancer. A propensity score matching algorithm was employed to compare the subsequent development of cancer between the SGLT2i and DPP4i groups., Results: After 1:2 propensity score matching, 26,823 individuals (8,941 SGLT2i, 17,882 DPP4i) were analyzed. During the mean follow-up duration of 2.0 ± 1.6 years, 1,076 individuals developed cancer. SGLT2i administration was associated with a reduced risk of cancer (HR 0.80, 95% CI 0.70-0.91). Particularly, SGLT2i administration was related to a lower risk of colorectal cancer (HR 0.71, 95% CI 0.50-0.998). Our primary findings remained consistent across various sensitivity analyses, including overlap weighting analysis (HR 0.79, 95% CI 0.66-0.94), inverse probability of treatment weighting 0.75 (95% CI 0.65-0.86), and induction period settings 0.78 (95% CI 0.65-0.93). The risk of developing cancer was comparable among individual SGLT2is (P-value of 0.1738)., Conclusion: Our investigation using nationwide real-world data demonstrated the potential advantage of SGLT2i over DPP4i in reducing the development of cancer in individuals with diabetes., Competing Interests: Declaration of competing interest Research funding and scholarship funds (Hidehiro Kaneko and Katsuhito Fujiu) from Medtronic Japan CO., LTD, Boston Scientific Japan CO., LTD, Biotronik Japan, Simplex QUANTUM CO., LTD, and Fukuda Denshi, Central Tokyo CO., LTD. Hidehiro Kaneko owns stocks of PrevMed Co. Issei Komuro received remuneration for a lecture from AstraZeneca K.K, MSD K.K, Otsuka Pharmaceutical Co. Ltd., ONO PHARMACEUTICAL CO. LTD., DAIICHI SANKYO COMPANY LIMITED., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., BAYER YAKUHIN, LTD., Novo Nordisk Pharma Ltd., Pfizer Japan Inc and trust research/joint research funds from ONO PHARMACEUTICAL CO. LTD. and scholarship fund from Idorsia Pharmaceuticals Japan Ltd., MSD K.K., ONO PHARMACEUTICAL CO. LTD., Sanofi K. K., DAIICHI SANKYO COMPANY LIMITED., Dainippon Sumitomo Pharma Co. Ltd., Takeda Pharmaceutical Company Limited., Mitsubishi Tanabe Pharma Corporation, TEIJIN PHARMA LIMITED, TOA EIYO LTD.., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background: Carcinoma erysipeloides (CE) is a rare form of cutaneous metastasis appearing similar to erysipelas or cellulitis. Due to its rarity, little is known about CE., Method: We here initially reported a case of CE secondary to rectal carcinoma and then reviewed the literature and analyzed the basic characteristics of the cases reported previously., Results: Sixty-nine patients(including our case) with CE were identified. The mean age of diagnosis with CE was 60±15 yr(min:25 yr, max:91 yr), and 69.6% of the patients were female. Breast cancer, skin cancer, and gastroesophageal cancer were the three most commonly seen malignancies presented with CE(52.2 %, 11.6 %, and 10.1 %, respectively). Adenocarcinoma(81.2 %) was the primary histological subtype of the cases. While CE was the first presentation of the disease in 20.3% of patients, it was associated with recurrence or disease progression in 69.7 %. The median time from the first presentation of the disease to the diagnosis of CE was two years. More than half of the patients(55.1 %) have received local dermatological treatment with another differential diagnosis before diagnosis of CE. Only 21.7 % of the patients responded to the treatment, and median survival after diagnosis of CE was 4 months(min:0 mo, max:24 mo)., Conclusion: CE has a poor prognosis and is most common in individuals with breast cancer and adenocarcinoma. Patients generally receive local dermatological treatments with different diagnoses. CE should be considered in the differential diagnosis, especially in the presence of erysipelas/cellulitis-like lesions in patients with a history of malignancy or who do not respond to local treatments., Competing Interests: Declaration of competing interest The authors (İmdat Eroğlu, Aytug Uner, Fatih Gurler, Ozan Yazici, Ahmet Ozet, Nuriye Ozdemir) declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Cancer immunotherapies produce remarkable results in B cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor and normal tissues to identify biologically relevant cell surface immunotherapeutic targets for neuroblastoma, an often-fatal childhood cancer. Proteogenomic analyses reveal sixty high-confidence candidate immunotherapeutic targets, and we prioritize delta-like canonical notch ligand 1 (DLK1) for further study. High expression of DLK1 directly correlates with a super-enhancer. Immunofluorescence, flow cytometry, and immunohistochemistry show robust cell surface expression of DLK1. Short hairpin RNA mediated silencing of DLK1 in neuroblastoma cells results in increased cellular differentiation. ADCT-701, a DLK1-targeting antibody-drug conjugate (ADC), shows potent and specific cytotoxicity in DLK1-expressing neuroblastoma xenograft models. Since high DLK1 expression is found in several adult and pediatric cancers, our study demonstrates the utility of a proteogenomic approach and credentials DLK1 as an immunotherapeutic target., Competing Interests: Declaration of interests F. Zammarchi, K. Havenith, and P.H.v.B. are or were employed by ADC Therapeutics at the time the work was conducted and hold or previously held shares/stocks in ADC Therapeutics. The following patent is held: WO2018146199A1., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The pancreatic innervation undergoes dynamic remodeling during the development of pancreatic ductal adenocarcinoma (PDAC). Denervation experiments have shown that different types of axons can exert either pro- or anti-tumor effects, but conflicting results exist in the literature, leaving the overall influence of the nervous system on PDAC incompletely understood. To address this gap, we propose a continuous mathematical model of nerve-tumor interactions that allows in silico simulation of denervation at different phases of tumor development. This model takes into account the pro- or anti-tumor properties of different types of axons (sympathetic or sensory) and their distinct remodeling dynamics during PDAC development. We observe a "shift effect" where an initial pro-tumor effect of sympathetic axon denervation is later outweighed by the anti-tumor effect of sensory axon denervation, leading to a transition from an overall protective to a deleterious role of the nervous system on PDAC tumorigenesis. Our model also highlights the importance of the impact of sympathetic axon remodeling dynamics on tumor progression. These findings may guide strategies targeting the nervous system to improve PDAC treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Fusion among normal cells is tightly regulated and required for the developmental processes of an organism. Cancer cell fusion appears relatively rare but is associated with generating new hybrid cancer cells with aggressive properties. However, it remains unclear how cancer cells acquire aggressiveness via cell fusion. Here, we report changes in cell proliferative capacity, cell motility, anticancer drug resistance, and gene expression profiles when fusing human MCF-7 breast cancer cells and mesenchymal stem cells (MSCs). The fused cells were established using envelopes of a hemagglutinating virus of Japan, which increased cell proliferation, motility, and drug resistance. Comprehensive gene expression profile analysis revealed that the fused cells expressed higher levels of glycolysis-related genes than their parental cells. In fact, the fused cells relied more on glycolysis for ATP production (Warburg effect). HIF1A, which induces the expression of glycolysis-related genes, was upregulated in fused cells compared to MCF-7 cells. Allele-specific expression analysis of the fused cells indicated that MSC allele-derived HIF1A efficiently induces the expression of glycolysis-related genes in the MCF-7 allele. These findings indicate that the reorganization of gene expression by combining MSCs and MCF-7 alleles resulted in the predominant expression of glycolysis-related genes and increased malignancy in the fused cells., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Respiratory diseases such as asthma, acute respiratory distress syndrome (ARDS), influenza or COVID-19 often directly target the epithelium. Elevated immune levels and a 'cytokine storm' are directly associated with defective healing dynamics of lung diseases such as COVID-19 or ARDS. The infected cells leave wounded regions in the epithelium which must be healed for the lung to return to a healthy state and carry out its main function of gas-exchange. Due to the complexity of the various interactions between cells of the lung epithelium and surrounding tissue, it is necessary to develop models that can complement experiments to fully understand the healing dynamics. In this mathematical study we model the mechanism of epithelial regeneration. We assume that healing is exclusively driven by progenitor cell proliferation, induced by a chemical activator such as epithelial growth factor (EGF) and cytokines such as interleukin-22 (IL22). Contrary to previous studies of wound healing, we consider the immune system, specifically the T effector cells TH1, TH17, TH22 and Treg to strongly contribute to the healing process, by producing IL22 or regulating the immune response. We therefore obtain a coupled system of two ordinary differential equations for the epithelial and immune cell densities and two functions for the levels of chemicals that either induce epithelial proliferation or recruit immune cells. These functions link the two cell equations. We find that to allow the epithelium to regenerate to a healthy state, the immune system must not exceed a threshold value at the onset of the healing phase. This immune threshold is supported experimentally but was not explicitly built into our equations. Our assumptions are therefore sufficient to reproduce experimental results concerning the ratio TH17/Treg cells as a threshold to predict higher mortality rates in patients. This immune threshold can be controlled by parameters of the model, specifically the base-level growth factor concentration. This conclusion is based on a mathematical bifurcation analysis and linearization of the model equations. Our results suggest treatment of severe cases of lung injury by reducing or suppressing the immune response, in an individual patient, assessed by their disease parameters such as course of lung injury and immune response levels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Gynaecological cancers, especially ovarian cancer, remain a critical public health issue, particularly in regions like India, where there are challenges related to cancer awareness, variable pathology, and limited access to screening facilities. These challenges often lead to the diagnosis of cancer at advanced stages, resulting in poorer outcomes for patients. The goal of this study is to enhance the accuracy of classifying ovarian tumours, with a focus on distinguishing between malignant and early-stage cases, by applying advanced deep learning methods. In our approach, we utilized three pre-trained deep learning models-Xception, ResNet50V2, and ResNet50V2FPN-to classify ovarian tumors using publicly available Computed Tomography (CT) scan data. To further improve the model's performance, we developed a novel CT Sequence Selection Algorithm, which optimises the use of CT images for a more precise classification of ovarian tumours. The models were trained and evaluated on selected TIFF images, comparing the performance of the ResNet50V2FPN model with and without the CT Sequence Selection Algorithm. Our experimental results show the Comparative evaluation against the ResNet50V2 FPN model, both with and without the CT Sequence Selection Algorithm, demonstrates the superiority of the proposed algorithm over existing state-of-the-art methods. This research presents a promising approach for improving the early detection and management of gynecological cancers, with potential benefits for patient outcomes, especially in areas with limited healthcare resources., (© 2024. The Author(s).)

Ubiquitin-specific peptidase 7 (USP7) is a deubiquitinating enzyme that mediates the stability and activity of numerous proteins. At basal expression levels, USP7 stabilizes p53 protein, even in the presence of excess MDM2. However, its overexpression leads to the deubiquitination of MDM2 at a rate faster than p53, leading to p53 degradation and pro-tumorigenic roles. Consequently, it is an attractive target for anticancer drug discovery via the modulation of its allosteric site from which the protein is activated. In this study, molecular modeling techniques and cheminformatics approaches were employed to unravel the potential of eighty compounds to serve as its allosteric site modulators. The compounds were initially subjected to virtual screening. Subsequently, the binding free energies of the top four compounds with the highest binding affinities were calculated, and their drug-likeness, and pharmacokinetic and toxicity profiles were evaluated. Ultimately, the complexes of the protein and hit compounds were subjected to a 100 nanoseconds (ns) molecular dynamics simulation. The results of the study revealed eight compounds from the compound library with docking scores ranging from - 7.491 to -11.43 kcal/mol, compared to P217564, which exhibited a docking score of -5.671 kcal/mol. The top four compounds with the highest affinities possessed drug-like properties, and good pharmacokinetic and toxicity profiles, and their predicted inhibitory potentials showed they will be effective at minimal concentration. Also, molecular dynamics simulation confirmed the stability of the protein-ligand complexes. Conclusively, the compounds identified in this study are worthy of further evaluation for the development of allosteric site modulators of USP7., (© 2024. The Author(s).)

Introduction: Omacetaxine, a semisynthetic form of Homoharringtonine (HHT), was approved for the treatment of Chronic Myeloid Leukemia (CML). Previously, we have published the synthesis of this natural alkaloid and three of its derivatives: Deoxyharringtonine (DHT), Deoxyhomoharringtonine (DHHT), and Bis(demethyl)-deoxyharringtonine (BDHT), and reported its refractory activity against the HL-60/RV+ cells over-expressing P-glycoprotein 1 (MDR1)., Methods: In this study, we have explored the extent of this resistance by first expanding the panel of established cell lines and using a panel of 21 leukemia patient-derived primary cells., Results: Herein, we have reported consistent resistance to HTT of K562-derived cells and to mitoxantrone of MES-SA/MX2-derived cells; all of them have been found to overexpress MDR1, while we have found U87MG-ABCG2 and H69AR cells to be very sensitive to HTT. In contrast, DHT, DHHT, and BDHT seemingly overcame this resistance due to the changes made to the acyl chain of HTT, rendering the derivatives less susceptible to efflux. Surprisingly, the leukemia primary cells were very sensitive to HHT and its derivatives with low nanomolar potencies, followed by a new class of CDC7 kinase inhibitors, the anthracycline class of topoisomerase inhibitors, the DNA intercalator actinomycin-D, and the vinca alkaloid class of microtubule inhibitors. The mechanism of cell death induced by HTT and DHHT was found to be mediated via caspase 3 cleavage, leading to apoptosis., Conclusion: Taken together, our results confirm that HHT is a substrate for MDR1. It opens the door to a new opportunity to clinically evaluate HHT and its derivatives for the treatment of AML and other cancers., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

RNAscope staining of breast cancer tissue allows pathologists to deduce genetic characteristics of the cancer by inspection at the microscopic level, which can lead to better diagnosis and treatment. Chromogenic RNAscope staining is easy to fit into existing pathology workflows, but manually analyzing the resulting tissue samples is time consuming. There is also a lack of peer-reviewed, performant solutions for automated analysis of chromogenic RNAscope staining. This paper covers the development and optimization of a novel deep learning method focused on accurate segmentation of RNAscope dots (which signify gene expression) from breast cancer tissue. The deep learning network is convolutional and uses ConvNeXt as its backbone. The upscaling portions of the network use custom, heavily regularized blocks to prevent overfitting and early convergence on suboptimal solutions. The resulting network is modest in size for a segmentation network and able to function well with little training data. This deep learning network was also able to outperform manual expert annotation at finding the positions of RNAscope dots, having a final F 1 -score of 0.745. In comparison, the expert inter-rater F 1 -score was 0.596., (© 2024. The Author(s).)

Background: Ascites in malignancies is usually associated with poor prognosis, but the predictive value may vary between different cancer types. Objectives: The aim was to map the frequency and temporal pattern of paracentesis in patients with malignancies in relation to time to death and to evaluate the occurrence of ascites as a predictive factor in different cancer types, with a limitation to the last year of life. Design: A retrospective study based on registry data covering all care visits in the Stockholm Region, Sweden, for seven years was performed. All deceased subjects that had at least one registered paracentesis in the last year of life were included. Results: Of 23,056 subjects dying from cancer, 1863 had undergone paracentesis in the last year of life (8.0%). Ascites requiring paracentesis was most frequently seen in appendiceal cancer (38%), ovarian cancer (35%), cholangiocarcinoma (26%), hepatocellular carcinoma (19%), and pancreatic cancer (17%). The median time for the first paracentesis in all cancer types varied between 248 and 20 days before death. For ovarian cancer, the median time for first paracentesis differed significantly compared with upper gastro-intestinal (GI) cancers, 81 days compared with 30 days ( p < 0.0001). Ascites in prostate cancer was rare,1.9%, but when present, a pronounced increase in the frequency of paracentesis was observed in the last three months of life. Conclusion: The occurrence of paracentesis in patients with advanced cancer is generally a sign that death is approaching within the coming months, especially in upper GI cancer. For ovarian and appendiceal cancers, ascites is less useful as a predictive tool.

Somatic variant testing through next-generation sequencing (NGS) is well integrated into Swiss molecular pathology laboratories and has become a standard diagnostic method for numerous indications in cancer patient care. Currently, there is a wide variation in reporting practices within our country, and as patients move between different hospitals, it is increasingly necessary to standardize NGS reports to ease their reinterpretation. Additionally, as many different stakeholders-oncologists, hematologists, geneticists, pathologists, and patients-have access to the NGS report, it needs to contain comprehensive and detailed information in order to answer the questions of experts and avoid misinterpretation by non-experts. In 2017, the Swiss Institute of Bioinformatics conducted a survey to assess the differences in NGS reporting practices across ten pathology institutes in Switzerland. The survey examined 68 reporting items and identified 48 discrepancies. Based on these findings, the Swiss Society of Molecular Pathology initiated a Delphi method to reach a consensus on a set of recommendations for NGS reporting. Reports should include clinical information about the patient and the diagnosis, technical details about the sample and the test performed, and a list of all clinically relevant variants and variants of uncertain significance. In the absence of a consensus on an actionability scheme, the five-class pathogenicity scheme proposed by the ACMG/AMP guideline must be included in the reports. The Swiss Society of Molecular Pathology recognizes the importance of including clinical actionability in the report and calls on the European community of molecular pathologists and oncologists to reach a consensus on this issue., (© 2024. The Author(s).)

Purpose: Dyslipidemia and statin use are associated with an increased risk of various cancers. However, the association in head and neck cancer (HNC) remains unclear. Therefore, this study aimed to investigate the impact of dyslipidemia and statin use on the development of HNC., Methods: Using data from the Korean National Health Insurance Service-National Sample Cohort from 2002 to 2019, we compared two groups HNC patients (n = 1006) and matched control participants (n = 4024) after propensity score overlap weighted balancing. The odds ratios (ORs) for HNC development according to dyslipidemia and statin use duration were assessed using propensity score overlap-weighted multivariable logistic regression., Results: Individuals with untreated dyslipidemia had significantly lower odds of developing HNC than those of normal participants (OR 0.70, 95% confidence interval [CI] 0.59-0.82). Conversely, patients with dyslipidemia who received statin therapy (< 60 days) showed a nearly two-fold increase in the odds of HNC (OR 1.94, 95% CI 1.29-2.90). Long-term statin use (≥ 60 days) aligned the odds with those of normal participants (OR 0.89, 95% CI 0.76-1.04)., Conclusions: The adverse effect of short-term statin use on HNC development requires further study, and long-term statin use for dyslipidemia treatment does not increase the odds of HNC., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Tumors caused by failure of the DNA-mismatch repair system generally show microsatellite instability (MSI). High-frequency MSI cancers have been shown to be susceptible to immuno-oncology therapies. The aim of this study was to evaluate the clinical reliability of a rapid immunohistochemistry (IHC) technique for intraoperatively assessing molecular status through detection of tumoral deficiencies in the expression of mismatch repair proteins (dMMR; MLH1, MSH2, MSH6, and PMS2)., Methods: The rapid IHC method uses non-contact alternating current (AC) mixing to achieve more rapid/stable staining within a minimum of 13 min during surgery. Sixteen formalin-fixed paraffin-embedded (FFPE) tumor samples from 3 dMMR patients with Lynch syndrome and 6 FFPE samples from 6 dMMR-cancer patients were collected to establish an IHC protocol for MMR proteins. Next, 26 surgical patients treated and whose MSI status was determined using PCR-based tests were retrospectively analyzed. The concordance of dMMR diagnoses for thoracic tumors between the conventional (frozen section (FS)- and FFPE-IHCs) and rapid AC-mixing IHC with FSs were compared., Results: A rapid IHC protocol using primary antibodies against four MMR proteins (mixed 5-10 min) was established (entire process within 40 min). The concordance rate for MMR-IHC between the conventional and rapid IHC was 100%. dMMR diagnoses including an MSI-high pulmonary sarcoma patient entirely matched between FS- and FFPE-IHC., Conclusion: Rapid MMR-IHC could potentially serve as a clinical tool for intraoperative determination of tumor MSI/dMMR status. AC-mixing technology will contribute to improving pathological diagnostic capability through the development of an original and innovative rapid IHC., (© 2024. The Author(s), under exclusive licence to The Japanese Association for Thoracic Surgery.)

Background/aims: The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE ® ) was developed to capture symptomatic adverse events from the patient perspective. We aim to describe statistical properties of PRO-CTCAE items and summary scores and to provide evidence for recommendations regarding PRO-CTCAE administration and reporting., Methods: Using data from the PRO-CTCAE validation study (NCT02158637), prevalence, means, and standard deviations of PRO-CTCAE items, composite scores, and mean and maximum scores across attributes (frequency, severity, and/or interference) of symptomatic adverse events were calculated. For each adverse event, correlations and agreement between attributes, correlations between attributes and composite scores, and correlations between composite, mean, and maximum scores were estimated., Results: PRO-CTCAE items were completed by 899 patients with various cancer types. Most patients reported experiencing one or more adverse events, with the most prevalent being fatigue (87.7%), sad/unhappy feelings (66.0%), anxiety (63.6%), pain (63.2%), insomnia (61.8%), and dry mouth (60.0%). Attributes were moderately to strongly correlated within an adverse event ( r  = 0.53 to 0.77, all p  < 0.001) but not fully concordant (κ weighted  = 0.26 to 0.60, all p  < 0.001), with interference demonstrating lowest mean scores and prevalence among attributes of the same adverse event. Attributes were moderately to strongly correlated with composite scores ( r  = 0.67 to 0.97, all p  < 0.001). Composite scores were moderately to strongly correlated with mean and maximum scores for the same adverse event ( r  = 0.69 to 0.94, all p  < 0.001). Correlations between composite scores of different adverse events varied widely ( r  = 0.04 to 0.68) but were moderate to strong for conceptually related adverse events., Conclusions: Results provide evidence for PRO-CTCAE administration and reporting recommendations that the full complement of attributes be administered for each adverse event, and that attributes as well as summary scores be reported., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Histopathological features of hepatocellular carcinoma (HCC) induced by diethylnitrosamine (DEN) in mice display strong similarities with those seen in humans, including the higher tumor prevalence in males than in females. Previous studies have demonstrated that continual production of the pro-inflammatory IL-6 by Kupffer cells is involved in the initiation and progression of DEN-induced HCC and that estrogen-mediated reduction of IL-6 secretion would decrease its incidence in females. Given the predominant utilization of male mice in hepatic carcinogenesis research, the objective of this study was to examine histopathological and immunological parameters in the DEN-induced liver carcinogenesis model in female C3H mice. We observed a significant prevalence of hepatocellular hyperplasias and adenomas alongside a minimal infiltration of inflammatory cells and a scarcity of senescent areas in females. Further, a low expression of immunosuppression markers is observed in females - such as neutrophil/lymphocyte ratio, PD-1 expression in CD8 T cells, and PD-L1 in myeloid cells - compared to males. Comparative studies between susceptible and resistant hosts to chemical carcinogenesis may help to unveil novel therapeutic strategies against cancer.

Cytokines are important regulators of immune responses, making them attractive targets for autoimmune diseases and cancer therapeutics. Yet, the significance of cytokine glycosylation remains underestimated. Many cytokines carry N- and O-glycans and some even undergo C-mannosylation. Recombinant cytokines produced in heterologous host cells may lack glycans or exhibit a different glycosylation pattern such as varying levels of galactosylation, sialylation, fucosylation or xylose addition compared to their human counterparts, potentially impacting critical immune interactions. We focused on cytokines that are currently utilized or designed in advanced therapeutic formats, including immunocytokines, fusokines, engager cytokines, and genetically engineered 'supercytokines.' Despite the innovative designs of these cytokine derivatives, their glycosylation patterns have not been extensively studied. By examining the glycosylation of the human native cytokines, G-CSF and GM-CSF, interferons β and γ, TNF-α and interleukins-2, -3 -4, -6, -7, -9, -12, -13, -15, -17A, -21, and - 22, we aim to assess its potential impact on their therapeutic derivatives. Understanding the glycosylation of the native cytokines could provide critical insights into the safety, efficacy, and functionality of these next-generation cytokine therapies, affecting factors such as stability, bioactivity, antigenicity, and half-life. This knowledge can guide the choice of optimal expression hosts for production and advance the development of effective cytokine-based therapeutics and synthetic immunology drugs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lise Hafkenscheid reports financial support was provided by Technical University of Denmark. Giulia Scapin reports financial support was provided by Technical University of Denmark. Ece Cagdas reports financial support was provided by Technical University of Denmark. Lise Grav reports financial support was provided by Technical University of Denmark. Nathan Lewis reports financial support was provided by University of California San Diego. Steffen Goletz reports financial support was provided by Technical University of Denmark. Lise Hafkenscheid reports a relationship with Technical University of Denmark that includes: employment. Giulia Scapin reports a relationship with Technical University of Denmark that includes: employment. Ece Cagdas reports a relationship with Technical University of Denmark that includes: employment. Lise Grav reports a relationship with Technical University of Denmark that includes: employment. Nathan Lewis reports a relationship with University of California San Diego that includes: employment. Steffen Goletz reports a relationship with Technical University of Denmark that includes: employment. Nathan Lewis is a co-founder of NeuImmune and Augment Biologics, which both work on glycoengineered biotherapeutics. Steffen Goletz is founder and shareholder of Glycotope GmbH which works on antibody and glycoengineered biotherapeutics including immunocytokines. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Data on maternal and fetal outcomes in patients diagnosed with cancer during pregnancy are limited. Given expected increase in patients diagnosed with cancer during pregnancy, there is a growing need to evaluate clinical outcomes., Objective: To evaluate obstetric outcomes among women with early-stage gynecologic or breast cancer who were diagnosed during pregnancy compared to women without cancer in a population-based cohort., Methods: We performed a population-based study of women aged 18-45 years with stage I gynecologic or stage I-III breast cancer reported to the California Cancer Registry for the years 2000-2012. Data were linked to the 2000-2012 California birth data to produce a database with cancer characteristics and obstetric outcomes. We included patients who had a delivery within the 10 months following cancer diagnosis. The primary outcome was severe maternal morbidity (SMM). Secondary outcomes included pre-term birth (PTB) and neonatal morbidity. Propensity scores were used to match similar controls to cases in a 2:1 ratio based on demographic attributes and medical comorbidities included in the Obstetric Comorbidity Index (OB-CMI). Logistic regressions were used to evaluate outcomes., Results: The cohort consisted of 503 women with cancer in pregnancy (319 breast, 125 ovarian, 59 cervical), and 1,006 matched controls. Cancer during pregnancy was associated with higher odds of SMM (6.8% vs <1.1%; odds ratio [OR] 8.03, 95% CI 3.82-16.88), PTB between 32-36 weeks (32.6% vs 8.3%, OR 5.38, 95% CI 4.02-7.20), and neonatal morbidity (12.5% vs 6.1%; OR 2.22, 95% CI 1.53-3.21) compared to matched controls. In sub-analysis of SMM indicators, hysterectomy and sepsis were significantly associated with cancer during pregnancy (4.8% vs <1.1%, P<.001; <2.2% vs 0.0%, P=.037, respectively)., Conclusion: Cancer during pregnancy is associated with increased risk of maternal and neonatal morbidity. These findings highlight the need for careful management and consideration of obstetric outcomes in these patients., (Copyright © 2024. Published by Elsevier Inc.)

RNA-binding proteins (RBPs) and non-coding RNAs are crucial trans-acting factors that bind to specific cis-acting elements in mRNAs, thereby regulating their stability and translation. The trans-activation response (TAR) RNA-binding protein (TRBP) recognizes precursor microRNAs (pre-miRNAs), modulates miRNA maturation, and influences miRNA interference (mi-RNAi) mediated by the RNA-induced silencing complex (RISC). TRBP also directly binds and mediates the degradation of certain mRNAs. Thus, TRBP acts as a hub for regulating gene expression and influences a variety of biological processes, including immune evasion, metabolic abnormalities, stress response, angiogenesis, hypoxia, and metastasis. Aberrant TRBP expression has been proven to be closely related to the initiation and progression of diseases, such as viral infection, chronic metabolic diseases, brain disorders, and cancer. This review summarizes the roles of TRBP in cancer and other diseases, the therapeutic potential of TRBP inhibition, and the current status of drug discovery on TRBP., Competing Interests: Declaration of competing interest The authors have declared that no competing interest exists., (Copyright © 2024. Published by Elsevier Inc.)

We present a protocol to generate a liver tumor murine model utilizing orthotopic ultrasound-guided intrahepatic injections of tumor cells and a partial hepatectomy. We describe cell and animal preparation and ultrasound-guided intrahepatic injections. We then depict how to conduct a partial hepatectomy addressing solutions to potential problems. This approach introduces a rapid and reproducible orthotopic implantation model of liver tumor model in a minimally invasive manner, allowing the surgical procedure to be optimized with minimal intra-abdominal injury. For complete details on the use and execution of this protocol, please refer to Brown et al. 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Toxic metals in PM 2.5 represent a growing public health concern because of their potential health effects. Ambient PM 2.5 samples were collected from five provinces around Bangkok from December 2020 to December 2021. The concentrations of PM 2.5 and metals (arsenic, cadmium, chromium, cobalt, nickel, lead, and vanadium) were analyzed. The noncarcinogenic and carcinogenic risks were evaluated via Monte Carlo simulations in four age groups (0 to <6, 6 to <12, 12 to <18, 18-70 years), with a dataset comprising 2282 heavy metal assays within the particulate matter. Significantly higher PM 2.5 concentrations were detected in provinces with higher factory densities, as well as higher concentrations during haze periods than during non-haze periods. The HI values for all age groups and provinces were lower than 1, indicating acceptable noncarcinogenic risks. The carcinogenic risks from PM 2.5 -bound metals varied between 7.08×10 -7 and 4.29×10 -6 , indicating increased cancer risks, for preschool children and adults. Cancer risk was highest in industrial areas, followed by areas with dense traffic, and lowest in agricultural areas. The results indicated that Thailand's current air quality regulations, which primarily provide only lead limits, are insufficient considering the high carcinogenic potential of other metals. The Monte Carlo simulation results confirmed that lowering Thailand's 24-h PM 2.5 standard from 37.5 to either 25 or 15 µg m -3 , as specified in the 2021 World Health Organization guidelines, would decrease cancer risk by 9.63-43.18 %., Competing Interests: Declaration of Competing Interest All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with intellectual and developmental disabilities (IDD) face unique challenges resulting in disparities in their health care. We sought to define the effect that IDD had on achievement of a "textbook outcome" (TO) following a cancer operation among a nationally representative cohort of patients., Methods: Data on patients who underwent surgery for a malignant indication, including lung, breast, liver, biliary tract, pancreas, and colorectal, between 2014 and 2020 were extracted from the 100% Medicare Standard Analytical Files database. The association of IDD with TO (defined as the absence of postoperative complications, extended length of stay, 90-day readmission, and 90-day mortality), expenditures, and discharge status was assessed using multivariable logistic regression., Results: Among 500,472 Medicare beneficiaries, 4,326 (0.9%) with IDD had a cancer diagnosis (breast, n=481; lung, n=419; hepatobiliary, n=194; pancreas, n=145; colorectal, n=3,087). Although overall incidence of TO was 50.5%, patients with IDD were less likely to achieve a TO than those without (37.1% vs 50.6%, respectively; odds ratio [OR], 0.50; 95% CI, 0.46-0.53; P<.001). On multivariable regression, patients with IDD had higher odds of a postoperative complication (OR, 1.53; 95% CI, 1.43-1.64), extended length of stay (OR, 2.06; 95% CI, 1.93-2.21), 90-day readmission (OR, 1.15; 95% CI, 1.07-1.24), 90-day mortality (OR, 1.90; 95% CI, 1.70-2.13), and discharge to a skilled nursing facility (OR, 4.28; 95% CI, 3.97-4.62) (all P<.001)., Conclusions: Patients with IDD had a much lower chance of a postoperative TO, as well as discharge to a nonhome setting. The data highlight the need to improve the care of patients with IDD to assure equitable oncologic surgical care.

The elevated level of replication stress is an intrinsic characteristic of cancer cells. Targeting the mechanisms that maintain genome stability to further increase replication stress and thus induce severe genome instability has become a promising approach for cancer treatment. Here, we identify histone deacetylase 8 (HDAC8) as a drug target whose inactivation synergizes with the inhibition of checkpoint kinases to elicit substantial replication stress and compromise genome integrity selectively in cancer cells. We showed that simultaneous inhibition of HDAC8 and checkpoint kinases led to extensive replication fork collapse, irreversible cell-cycle arrest, and synergistic vulnerability in various cancer cells. The efficacy of the combination treatment was further validated in patient tumor-derived organoid (PDO) and xenograft mouse (PDX) models, providing important insights into patient-specific drug responses. Our data revealed that HDAC8 activity was essential for reducing the acetylation level of structural maintenance of chromosomes protein 3 (SMC3) ahead of replication forks and preventing R loop formation. HDAC8 inactivation resulted in slowed fork progression and checkpoint kinase activation. Our findings indicate that HDAC8 guards the integrity of the replicating genome, and the cancer-specific synthetic lethality between HDAC8 and checkpoint kinases provides a promising replication stress-targeting strategy for treating a broad range of cancers.

Circulating RNAs have been investigated systematically for over 20 years, both as constituents of circulating extracellular vesicles (EVs) or, more recently, non-EV RNA carriers, such as exomeres and supermeres. The high level of variability and low reproducibility rate of EV/extracellular RNA (exRNA) results generated even on the same biofluids promoted several efforts to limit pre-analytical variability by standardizing sample collection and sample preparation, along with instrument validation, setup and calibration. Anticoagulants (ACs) are often chosen based on the initial goal of the study and not necessarily for the later EV and/or exRNA analyses. We show the effects of blood collection on EV size, abundance, and antigenic composition, as well on the miRNAs. Our focus of this work was on the effect of ACs on the number and antigenic composition of circulating EVs and on a set of circulating miRNA species, which were shown to be relevant as disease markers in several cancers and Alzheimer's disease. Results show that while the number of plasma EVs, their relative size, and post-fluorescence labeling profile varied with each AC, their overall antigenic composition, with few exceptions, did not change significantly. However, the number of EVs expressing platelet and platelet-activation markers increased in serum samples. For overall miRNA expression levels, EDTA was a better AC, although this may have been associated with stimulation of cells in the blood collection tube. Citrate and serum rendered better results for a set of miRNAs that were described as circulating markers for Alzheimer's disease, colon, and papillary thyroid cancers., Competing Interests: John Tigges is consulting for Acoerela., (© 2024 The Author(s). Journal of Extracellular Biology published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

Background: Cancer is regarded as one of the main causes of death globally. Future predictions indicate that the death rate from cancer will keep rising, which may reach 11.4 million in 2030. Carcinogenesis refers to the phenomenon of transforming a normal cell into a cancer cell. Cancer is characterized by unregulated and uncontrolled cell division due to alterations at the molecular and genetic levels. Gene mutations can speed up the rate of cell division, which leads to cancer. Metastasis entails the dissemination of cancer cells from the primary site to distant regions of the body via the circulatory or lymphatic systems., Objective: This review is mainly focusing on the anticancer properties of terpenoids. In the case of human beings, several types of cancers can be treated clinically based on the form and phase of the cancer. So, there are different types of treatment regimens available for the management of cancer, such as immunotherapy, hormonal therapy, radiation therapy, and chemotherapy., Methods: Several problems are associated with cancer therapy, including chemoresistance, severe toxicity, relapse, and metastasis. To minimize these complications, natural products like terpenoids seem to be beneficial for the effective management of cancer., Results: Experimental results revealed that the anticancer potential of terpenoids is due to activation of apoptosis and stimulation of cell cycle arrest. Some of the terpenoids exhibit anticancer effects by inhibiting angiogenesis and metastasis via the regulation of several signaling pathways intracellularly. Certain terpenoids have been shown to work in concert with anticancer medications (doxorubicin, cisplatin, paclitaxel, and 5-fluorouracil) to provide synergistic effects. These terpenoids have also been shown to be effective against cancer cells that are resistant to several drug therapies., Conclusion: The current study will focus on signaling pathways and mode of action of several types of terpenoids as anticancer agents. Further, it will provide insights into the ongoing clinical trials and prospective pathways for the advancement of terpenoids as possible anti-cancer agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Cancer is a leading cause of death worldwide, posing a substantial threat to human well-being. Microplastics (MPs) exposure can harm human health and the carcinogenicity of MP remains uncertain. In this study, we investigated carcinogenesis by MPs exposure. We observed MP significantly exacerbated hepatic injury in infectious conditions. In addition, cancer-related p53 and p21 signals are activated by MPs. Analysis of the liver transcriptomic landscape uncovered a noteworthy intensification of the carcinogenesis pathway by MPs compared with pre-infection. The transcription factor SALL2 could act as an oncogenic promoter in the promotion of cancer regulated by MPs. Further, big data analysis presents the correlation between MPs pollution and human hepatocellular carcinoma. This work revealed a toxic amplification effect of the non-bioactive MPs on the bioactive pathogens. This finding provides new insight into understanding the potential toxicity of the MPs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Champions are integral across research in cancer, yet studies exploring their roles are limited and have produced mixed results. The current review examines and synthesizes descriptions of how champions emerged and the types of activities they most often performed. By examining evidence from across the translational research continuum, this scoping review aims to characterize the role of champions and strategies that facilitate their involvement in the implementation of cancer care interventions in both clinical and community-based settings., Methods: This scoping review was designed and implemented in compliance with PRISMA-ScR. The review focused on peer-reviewed articles in English-language journals. We searched five databases: PubMed (including MEDLINE), Scopus (including EMBASE), CINAHL, PsycINFO, and the Cochrane Library. Articles published from 1971 to 2022 were included. Two members of the team reviewed in duplicate each article and then a single member of the team extracted the data in Covidence, with a second member comparing the extraction to the original article. Qualitative and quantitative data were extracted and then synthesized. These data were used to summarize core champion activities and implementation strategies and to characterize barriers and facilitators to using champions in research., Results: A total of 74 articles were included in the review. The qualitative synthesis highlighted facilitators and barriers to the effective use of champions. Facilitators included consideration of an individual's characteristics when identifying champions, time spent planning for the specific responsibilities of champions, working within a supportive environment, and identifying champions embedded in the target setting. Major barriers included constrained time, low self-efficacy among champions, inadequate training, high turnover rates of champions, and a lack of buy-in from organizational leadership toward the intervention. Champions also were mostly assigned their roles, had varied core activities, and used complementary strategies to empower their target populations. Champions' most frequent core activities include facilitation, outreach/promotion, and recruitment of participants into studies., Conclusions: Champions were used in research of many cancer types and often serve similar roles regardless of where they are located within the translational research process. Despite their critical role, evidence is lacking on the impact of champions specifically on outcomes of many of the research studies that include them. Future research is needed to understand the nuances of champion-driven approaches across diverse cancer care settings., (© 2024. The Author(s).)

As an AAA + ATPase, thyroid hormone receptor interacting protein 13 (TRIP13) primarily functions in DNA double-strand break repair, chromosome recombination, and cell cycle checkpoint regulation; aberrant expression of TRIP13 can result in chromosomal instability (CIN). According to recent research, TRIP13 is aberrantly expressed in a variety of cancers, and a patient's poor prognosis and tumor stage are strongly correlated with high expression of TRIP13. Tumor cell and subcutaneous xenograft growth can be markedly inhibited by TRIP13 knockdown or TRIP13 inhibitor administration. In the initiation and advancement of human malignancies, TRIP13 seems to function as an oncogene. Based on available data, TRIP13 may function as a biological target and biomarker for cancer. The creation of inhibitors that specifically target TRIP13 may present novel approaches to treating cancer., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Physical inactivity is a global issue for cancer survivors. Wearable activity trackers are promising to address physical inactivity by providing real-time feedback on physical activity and offering opportunities for self-monitoring and goal setting. Meta-analysis has reported the effects of interventions that incorporate wearable activity trackers on improved physical inactivity and related health outcomes (eg, BMI, anxiety and depression, and self-rated health status). However, wearable activity trackers were often used as an adjunct to physical activity interventions, and the effectiveness of wearable activity trackers alone is unknown., Objective: This study aims to determine the association of wearable activity trackers with physical activity and health outcomes in patients with cancer., Methods: Data from 957 cancer survivors from the Health Information National Trends Survey-Surveillance, Epidemiology, and End Results (HINTS-SEER) were analyzed. The outcome variables examined were time spent in moderate to vigorous physical activity, weekly frequency of strength training, BMI, anxiety and depression levels, and self-assessed health status. The primary independent variable was whether cancer survivors had used wearable activity trackers within the past 12 months. Design-based linear regression for continuous outcome variables and ordinal logistic regression for ordinal outcome variables were conducted to determine the associations after controlling for sociodemographic, cancer-related, and health-related factors. All data analyses accounted for the complex survey design and sample weights., Results: Only 29% of cancer survivors reported wearable activity tracker use. Bivariate analyses showed that younger age (P<.001), higher education (P=.04), higher income (P<.001), and an employed status (P<.001) were significantly associated with wearable activity tracker use. Wearable activity tracker use was significantly associated with higher time spent in moderate to vigorous physical activity (adjusted =37.94, 95% CI 8.38-67.5; P=.01), more frequent strength training per week (adjusted odds ratio [OR] 1.50, 95% CI 1.09-2.06; P=.01), and better self-rated health status (adjusted OR 1.58, 95% CI 1.09-2.29; P=.01), but not with BMI or anxiety and depression., Conclusions: This study suggests that the uptake of wearable activity trackers is low and highlights the digital divide among patients with cancer. This study has confirmed the associations of wearable activity tracker use with physical activity and self-rated health, supporting using wearable activity trackers as a promising tool to facilitate physical activity promotion., (©Weijiao Zhou, Shaomei Shang, Youmin Cho. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 22.10.2024.)