In this paper, the tumor-host interaction is modeled using a Lotka-Volterra framework. The critical parameters that define the possible dynamical regimes are identified through linear stability analysis. The effects of both constant and periodic perturbations are examined, along with their clinical implications. The treatment dose required to drive the system to a desired state is determined. It is also shown that aggressive tumors evolve toward a limit cycle when the host is under the action of low-frequency periodic treatment. As the frequency increases, a transition to a non-chaotic attractor occurs. This transition narrows as the frequency of the external periodic perturbation increases. No chaotic behavior is observed, even at higher values of both perturbation strength and frequency, as the maximum Lyapunov exponent remains negative. These results suggest that although aggressive tumors may not be completely eradicated by conventional anticancer therapies, they could potentially be controlled through external low-frequency periodic treatments that target directly only the host, such as immunotherapy.

The curative surgical treatment of older patients with oral cavity squamous cell carcinoma (OCSCC) is often personalized by incorporating subjective decisions on age and frailty. We aimed to determine here whether real-world recommended treatment, following official French guidelines only, versus deviation from recommended treatment was beneficial for older patients with OCSCC. To do this, we performed a retrospective evaluation of patients >70 years managed for treatment of p16-negative OCSCC in our tertiary hospital center in France between 2007 and 2017. The association between postoperative morbidity and deviation from recommended treatment was analysed using multivariate logistic regression. Cox Proportional Hazards Regression assessed the associations between deviation from recommended treatment and both the hazard of recurrence and mortality within 5 years. We included 185 patients who were recommended surgical resection of OCSCC: n = 147/185 (79%) patients underwent the recommended treatment and 38/185 (21%) patients underwent deviation from recommended treatment. Patients who underwent deviation from recommended treatment had a significantly lower recurrence-free survival (p = 0.0005) and overall survival (p = 0.008). Deviation from recommended treatment was found independently associated with increased development of 3-month postoperative morbidity (adjusted odds ratio 2.63 [1.23-5.82]; p = 0.02) and increased risk of recurrence within 5 years (adjusted hazard ratio 1.79 [1.14-2.83]; p = 0.01). Deviation from recommended treatment was not found independently associated with increased risk of mortality within 5 years (1.35 [0.82-2.23]; p = 0.2). Overall, deviation from recommended treatment was associated with worse outcomes and so we have identified a decision-making process biased by undocumented and subjective evidence. Preoperative risk models therefore require further validation in older patients with OCSCC to define more appropriate treatment regimens.

Lung cancer (LC) is the leading cause of cancer-related mortality worldwide, accounting for millions of deaths annually. Its major subtypes-lung squamous carcinoma (LUSC), lung adenocarcinoma, and small-cell LC-exhibit distinct risk factors and genetic susceptibilities, necessitating the use of subtype-specific biomarkers. Two-sample Mendelian randomization (MR) analyses were conducted using protein quantitative trait loci from the UK Biobank Pharma Proteomics Project and deCODE datasets. A robust analytical framework, including reverse MR, meta-analysis, summary-data-based MR tests, and colocalization, cisMR-cML, MR.CUE and phenotype scanning analyses were used to identify proteins associated with LC risk. We conducted a systematic review to contextualize our research findings. Follow-up analyses, including pathway enrichment, protein-protein interaction network analysis, and druggability evaluations, were used to explore the mechanisms and therapeutic potential of the identified proteins. Significant proteins were validated using population-level proteomic data from the UK Biobank (UKB). The results showed that twenty-five proteins were significantly associated with LC or its subtypes, including 15 novel findings. 60S ribosomal protein L14 (RPL14) and advanced glycosylation end-product-specific receptor (AGER) emerged as the strongest discovery, demonstrating consistent and significant associations across both MR and population-level analyses. RPL14 exhibited positive associations with overall LC risk (MR_meta: odds ratio [OR]: 2.012, 95% confidence interval [CI]: 1.297-3.119; UKB: OR: 1.509, 95% CI: 1.015-2.244). Similarly, AGER showed significant protective effects against LUSC risk (MR_meta: OR: 0.572, 95%CI: 0.368-0.889; UKB: OR: 0.366, 95% CI: 0.158-0.850). Pathway analysis revealed the involvement of these proteins in immune regulation and tumorigenesis. Among the 13 identified druggable targets, RPL14 and AGER showed therapeutic potential as approved or investigational drugs targeting these proteins. These findings offer new insights into the pathogenesis of LC and potential therapeutic targets.

PD-L1 expression for the prediction of response to immune-checkpoint blockade remains the most broadly utilised clinically validated biomarker in a range of tumour types. In this study, we aimed to assess, in a prospectively collected matched cohort, the impact of sampling technique and both formalin and alcohol fixation on PD-L1 expression and heterogeneity in non-small cell lung carcinoma (NSCLC). Patients undergoing surgical resection for NSCLC were consented. Surgical specimens were received directly from theatre and sampled fresh to produce two sets of core biopsies, two fine-needle aspirates (FNAs) and two whole-block tissue sections from each specimen. A matched biopsy, FNA, and whole-block were placed into formalin or an alcohol-based fixative (Cytolyt™) prior to PD-L1 immunohistochemistry assessment. A total of 114 specimens from 57 patients were included. All whole-block cases (100%), 92% of core biopsies, and 88% of FNAs were adequate for PD-L1 expression analysis. Fixation had no significant impact on adequacy, but cytology specimens fixed in alcohol showed a significant reduction in PD-L1 expression, with 25% of cases placed into different clinically relevant categories of PD-L1 expression. PD-L1 expression by immunochemistry is an exemplar of the challenges of utilising a heterogeneously expressed protein-based predictive biomarker. Regardless of sampling technique, a good quality biopsy or FNA is likely to give a statistically representative PD-L1 expression, although expression ranges close to clinically relevant cut-offs of 1% and 50% remain a source of potential discordance.

Molecular targeted therapy and immunotherapy have shown promise in managing gastric adenocarcinoma. The amplified expression of Human epidermal growth factor receptor-2 (HER-2) and microsatellite stable (MSI) status serve as indicators of response to targeted therapy and immunotherapy, respectively.

Brain metastasis represents the most prevalent form of brain tumors in adults, with a rising incidence resulting from significant advancements in cancer detection and therapeutic interventions. Current treatment protocols advocate for whole brain radiotherapy (WBRT) for patients who are not candidates for either surgical resection or stereotactic irradiation. However, cognitive decline remains a major side effect of this treatment modality. Hippocampal-sparing WBRT (HA-WBRT) has been shown to decrease brain toxicity, with the main concern being the probability of developing new brain metastasis in the hippocampal avoidance region.

Recent evidence suggests that EpCAM and CD44 could serve as diagnosis or prognosis markers in pancreatic cancer (PC). In this meta-analysis, we evaluated their associations with clinicopathologic features. Specifically, we compared immunohistochemical-positive and -negative PC patients for T stage (T3-T4 vs. T1-T2), N stage (N1 vs. N0), M stage (M1 vs. M0), tumor grade (well/moderately vs. poorly differentiated), UICC Stage (III, IV vs. I, II), and overall survival (OS). The diagnostic meta-analysis was performed analysing the pooled sensitivity and specificity and evaluating overall accuracy to indicate the diagnostic efficacy of the markers. The protocol of this systematic review and meta-analysis was registered on the PROSPERO website under the registration number of CRD42024568390. A systematic search of PubMed, Scopus, and ISI Web of Science was conducted on January 30th, 2025. The statistical analysis was performed using the Review Manager 5.4 software and R language (R package Mada and Metafor). The quality of the studies included was assessed using the Newcastle-Ottawa scale and the QUADAS-2 tool. Data from relevant studies were independently screened and extracted using Rayyan, by at least two authors. A total of 19 studies were eligible (9 studies for EpCAM, 9 studies for CD44, and 2 studies for both EpCAM and CD44), comprising a total of 1370 patients. The diagnostic meta-analysis demonstrated moderate accuracy for EpCAM (AUC, 95% CI of 0.802, 0.69-0.96). A statistically significant association was found for CD44 expression and T-status (OR = 2.04, 95%CI = 1.18-3.51), or N-stage (OR = 2.68, 95%CI = 1.86-3.85), or TNM stage (OR = 3.79, 95%CI = 2.14-6.71). CD44v6 overexpression predicted worse OS (HR = 2.33, p < 0.00001), while EpCAM + CD44 + co-expression was prognostic (HR = 2.02, p = 0.02). Heterogeneity was not observed among the studies included, but further research is warranted to better understand the clinical implications of these markers' positivity in PC diagnosis and prognosis.

The Greatwall kinase inhibits PP2A-B55 phosphatase activity during mitosis to stabilise critical Cdk1-driven mitotic phosphorylation. Although Greatwall represents a potential oncogene and prospective therapeutic target, our understanding of the cellular and molecular consequences of chemical Greatwall inactivation remains limited. To address this, we introduce C-604, a highly selective Greatwall inhibitor, and characterise both immediate and long-term cellular responses to the chemical attenuation of Greatwall activity. We demonstrate that Greatwall inhibition causes systemic destabilisation of the mitotic phosphoproteome, premature mitotic exit and pleiotropic cellular pathologies. Importantly, we show that the cellular and molecular abnormalities associated with reduced Greatwall activity are specifically dependent on the B55α isoform, rather than other B55 variants, underscoring PP2A-B55α phosphatases as key mediators of the cytotoxic effects of Greatwall-targeting agents in human cells. Additionally, we establish that sensitivity to Greatwall inhibition varies in different cell line models and that dependency on Greatwall activity reflects the balance between Greatwall and B55α expression levels. Our findings highlight Greatwall dependency as a cell-specific vulnerability and propose the B55α-to-Greatwall expression ratio as a predictive biomarker of cellular responses to Greatwall-targeted therapeutics.

Epithelial ovarian cancer (EOC) remains one of the most lethal gynecological malignancies. Although treatment options for newly diagnosed advanced EOC include primary debulking surgery (PDS) or neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS), the comparative effectiveness of these strategies remains uncertain across different disease stages.

RPS20 is a proposed colorectal cancer (CRC) predisposition gene, with only four families with putative loss-of-function (pLoF) variants published. The prevalence, phenotypic spectrum, and clinical management recommendations for RPS20 heterozygotes remain unknown.

This Special Article provides a comprehensive review and expert commentary on the prospective clinical implementation of artificial intelligence (AI) in the detection of prostate cancer from digital prostate biopsies, as presented in the original research by Flach et al. It contextualizes the study within broader developments in digital pathology and AI, addressing barriers to adoption and the implications for diagnostic workflows and pathology practice.

Infection with tick-borne encephalitis virus (TBEV) can lead to severe neurological complications largely associated with the activation of innate immunity and inflammatory reactions in the tissues of the nervous system. In this regard, the study of factors, including viral factors, influencing these processes is underway. We analyzed the possible role of nonstructural protein 1 (NS1) of TBEV in the activation of innate immune response reactions in cells of the nervous system. SH-SY5Y neuroblastoma and DBTRG-05MG glioblastoma cells were transfected with a plasmid encoding NS1 or treated with extracellular vesicles of NS1-expressing HEK293T cells and then stimulated with polyinosinic-polycytidylic acid [poly(I:C)] to activate the innate immune response. It was found that poly(I:C) stimulation of NS1-expressing SH-SY5Y cells resulted in lower mRNA levels of the pro-inflammatory cytokines interleukin-1β(IL-1β) and tumor necrosis factor-α(TNF-α), as well as the innate immune response of the cytokine interferon-1β(IFN-β) and the interferon-stimulated gene 15 product (ISG15), compared to stimulated cells without NS1 expression. In addition, transcription of the sensor gene MDA5, which is responsible for activating gene transcription of these cytokines, was reduced in these cells. In NS1-expressing DBTRG-05MG stimulated cells, only the IL-1β mRNA content was reduced. Treatment of SH-SY5Y cells with extracellular vesicles from NS1-expressing cells followed by poly(I:C) stimulation resulted in increased mRNA levels of IL-6, TNF-α, and IFN-β, compared with stimulated cells treated with vesicles from non-NS1-expressing cells. No differences were detected in DBTRG-05MG cells with similar treatment. Based on these data, we can assume that TBEV NS1 plays a dual role in the formation of neuroinflammation during the infection, and we can consider this protein as a potential therapeutic target.

The discovery of a class of long noncoding RNAs (lncRNAs), including lncRNAs of the small nucleolar RNA (snoRNA) host gene family, SNHG, has led to growing interest in the study of both snoRNAs themselves and the genes encoding them. Currently, of the 232 known snoRNA genes, only 32 have been confirmed to have lncRNAs. At the same time, a positive correlation has been shown between the expression of lncRNAs and snoRNAs encoded by a common host gene of the SNHG family. Thus, lncRNA of the SNHG1 gene correlates with snoRNAs SNORD22 and SNORD25-31, and lncRNA of the SNHG16 gene, with snoRNAs SNORD1A, SNORD1B, and SNORD1C. There is evidence that SNHG lncRNAs can participate in oncogenesis both through regulatory functions inherent to lncRNAs and by influencing ribosome biogenesis. At the same time, information has accumulated on the "extraribosomal" functions of snoRNAs. In addition to a brief excursion into the biological functions of snoRNAs and SNHG lncRNAs, we present a comprehensive review of data on the role of these two types of noncoding RNAs in the pathogenesis of ovarian cancer, the most insidious cancer of the female reproductive system. The influence of these regulatory RNAs on the main processes of ovarian oncogenesis, such as apoptosis, epithelial-mesenchymal transition, cell cycle control, and DNA methylation mechanisms in this type of cancer is considered. The prospects for clinical application of regulatory RNAs due to their influence on the level of drug resistance are also discussed.

In single-cell datasets, patient labels indicating disease status (e.g., "sick" or "not sick") are typically available, but individual cell labels indicating which of a patient's cells are associated with their disease state are generally unknown. To address this, we introduce mixture modeling for multiple-instance learning (MMIL), an expectation-maximization approach that trains cell-level binary classifiers using only patient-level labels. Applied to primary samples from patients with acute leukemia, MMIL accurately separates leukemia from nonleukemia baseline cells, including rare minimal residual disease (MRD) cells; generalizes across tissues and treatment time points; and identifies biologically relevant features with accuracy approaching that of a hematopathologist. MMIL can also incorporate cell labels when they are available, creating a robust framework for leveraging both labeled and unlabeled cells. MMIL provides a flexible modeling framework for cell classification, especially in scenarios with unknown gold-standard cell labels.

Thyroid nodules are primarily diagnosed using ultrasound imaging (USI), but its low specificity leads to unnecessary fine-needle aspiration biopsies (FNABs). In particular, USI's limited ability to differentiate follicular neoplasms from benign nodules contributes to suboptimal biopsy decision-making. We propose a dual-modal imaging approach that combines multiparametric photoacoustic imaging (PAI) and USI to support smarter biopsy decisions. In 106 patients with 29 benign nodules, 45 papillary thyroid carcinomas, and 32 follicular neoplasms, three PAI-derived parameters-the photoacoustic spectral gradient, oxygen saturation, and skewness of the oxygen saturation distribution-were combined using a support vector machine. Following USI-based American Thyroid Association (ATA) guidelines, they were used to develop the ATA-Photoacoustic (ATAP) scoring system. The ATAP score achieved 97% sensitivity and 38% specificity in distinguishing nodules requiring FNAB. Our approach enabled better identification of benign nodules, reducing unnecessary FNAB in 11 of the 29 benign cases. This dual-modal strategy can assess thyroid nodules, effectively reducing unnecessary biopsies while maintaining high diagnostic accuracy.

Neurofibromin/NF1 is a RAS (rat sarcoma virus) GTPase-activating protein and estrogen receptor (ER) transcriptional corepressor. NF1low status, identified by copy number loss or low mRNA/protein expression, is associated with endocrine therapy resistance in ~20% of ER+/HER2- (human epidermal growth factor receptor 2) early-stage breast cancers. The identification of targeted treatments for NF1low ER+/HER2- breast cancer is therefore a priority. In this study, proteogenomic analysis of ER+/HER2- breast cancer demonstrated that NF1low tumors exhibited elevated cyclin-dependent kinase 4/6 (CDK4/6) activity. In cell lines, NF1 deletion had a dual effect on CDK4 activity: first, by promoting ER recruitment to CCND1 (cyclin D1), thereby increasing CDK4-cyclin D1 complex formation, and second, by activating C-RAF (rapidly accelerated fibrosarcoma), which drove phosphorylation of the CDK4 activation loop. Preclinical modeling demonstrated that NF1low ER+ cancer cells were more sensitive to fulvestrant combined with a CDK4/6 inhibitor versus fulvestrant alone, with the induction of cell death in vitro and durable tumor regressions in ER+ NF1low patient-derived xenograft models in vivo. Furthermore, NF1low ER+/HER2- tumors were more sensitive to neoadjuvant aromatase inhibitor (AI) plus palbociclib than to neoadjuvant AI alone, as indicated by suppression of mRNA-based proliferation scores. These data are consistent with a model whereby ER and RAS coactivation upon NF1 loss can drive CDK4/6 activity and endocrine therapy resistance but renders NF1low ER+ tumors susceptible to CDK4/6 inhibition. Development of clinical-grade NF1 diagnostics should be prioritized to determine whether NF1low ER+ breast cancers should receive adjusted adjuvant treatment recommendations that reflect increased responsiveness to CDK4/6 inhibition.

A 17-year-old male presented with a painful subungual mass, which was clinically diagnosed as a subungual exostosis prior to surgical referral. Few reported cases of subungual osteochondroma exist in the literature, and those published describe skin or nail deformities resulting from the lesion. These deformities can easily be misdiagnosed as subungual exostosis by clinical examination alone. The characteristic findings in this case resulted in a diagnosis of subungual osteochondroma, which was successfully resolved following surgical excision. This report highlights the clinical, radiographic, and histopathologic characteristics of subungual osteochondroma, and differentiates it from subungual exostosis. The results report on the success of a 2-year post-surgical audit of patient-related outcomes.

The main functional parts of the glymphatic system are perivascular spaces and surrounding astrocytes. Cerebrospinal fluid enters the brain parenchyma from subarachnoid cisterns through perivascular Virchow-Robin spaces and passes into the interstitium through aquaporin channels in astrocytes. Then, cerebrospinal fluid removes metabolic products and mixes with interstitial fluid. Outflow of cerebrospinal fluid with metabolic products from the brain parenchyma occurs in three ways. The first route is periarterial through intermuscular spaces in the middle layer of cerebral arteries. The second route is perivenous. The third route is lymphatic through meningeal or sinus-associated lymphatic vessels. They provide drainage of macromolecules and immunocompetent cells from the brain to the cervical lymph nodes. Gliomas are accompanied by inhibition of normal cerebrospinal fluid outflow pathways, mainly due to additional intracranial tissue, and compensatory cerebrospinal fluid outflow along the spinal cord. Reduced cerebrospinal fluid release with impaired outflow contribute to accumulation of toxic metabolic products, proinflammatory cytokines and chemokines. Transport of antigens to lymph nodes is inhibited that disrupts antitumor immunity. Impaired cerebrospinal fluid circulation also reduces the effectiveness of intracranial drug delivery. One of the mechanisms of pathogenesis of glioma metastasis is based on migration of tumor cells along classical and meningeal lymphatic pathways. Damage to the latter contributes to metastasis.

The majority of meningiomas - benign tumors with an extremely low metastasis tendency. Only singular observations of extracranial metastasis of WHO Grade I benign meningiomas are described in the literature. Despite the intensive study of meningiomas' molecular biology, there are currently no reliable markers indicating the possibility of their metastasis.

Surgery of meningiomas of the craniocervical region is one of the most difficult parts of neurosurgery due to the closeness of the brainstem, caudal group of the cranial nerves (CNs) and vertebral artery. According to the literature, suffering of the caudal group of CNs is between 20 and 55% according to different authors. In their dysfunction, the recovery of CNs is long-term and requires joint efforts by both the medical team and the patient and his family.