Intratumoral low oxygen tension promotes cancer cell invasion and metastasis. Hypoxia-Inducible Factor 1-alpha (HIF1α) is the principal transcription factor orchestrating cellular responses to hypoxic stress, mediating the regulation of genes implicated in adapting to perturbations in oxygen homeostasis. Here, we describe our findings that functionally demonstrate a nucleolar localization domain in HIF1ɑ that enables HIF1ɑ to translocate to the nucleolus. Nucleolar HIF1ɑ binds the ribosomal DNA promoter and upregulates RNA Polymerase I activity leading to dysregulated ribosomal RNA transcription and consequently enhanced ribosome biogenesis. Ribosome biogenesis is important in supporting cellular metabolic processes and invasion and metastasis. Our findings are recapitulated in breast tumors wherein upregulated HIF1ɑ and rRNA biogenesis are associated with poor prognosis. Finally, our studies demonstrate that inhibition of RNA Polymerase I impedes aggressive traits of hypoxia-driven cancer progression, highlighting the potential of this approach as a therapeutic strategy in breast cancer. Cumulatively our work unravels an unprecedented role of HIF1ɑ in regulating rRNA biogenesis in breast cancer.

Recent evidence has highlighted immune checkpoint inhibitors as among the most promising immunotherapies for various malignancies. However, a significant proportion of HCC patients exhibit poor responses. Lipid metabolic heterogeneity is considered a key driver of cancer progression. However, the role of lipid metabolic reprogramming in HCC immunotherapy resistance remains poorly understood. Herein, we aimed to illuminate the potential relationship between lipid metabolic reprogramming and ICI resistance and provide novel strategies to increase the HCC immunotherapy response. Patients who received PD-1/PD-L1 inhibitors were enrolled. The effect of TACC3 on the tumor microenvironment was validated via single-cell RNA sequencing in HCC-bearing mouse models. Targeted metabolomics was performed to analyze the regulatory role of TACC3 in HCC metabolism. To address HCC immunotherapy resistance, we developed a targeted nucleic acid therapeutic utilizing N-acetylgalactosamine (GalNAc) to conjugate siTACC3. Through clinical cohort analysis, we found that TACC3 was overexpressed in HCC patients with poor response to immunotherapy. Furthermore, we demonstrated that silencing tumor-derived TACC3 optimizes the cytotoxicity of infiltrating CD8+ T lymphocytes. Both in vitro and in vivo assays suggested that TACC3 maintains ACSL4-mediated polyunsaturated fatty acid (PUFA) metabolism in HCC cells. Additionally, TACC3 accelerates ACSL4 expression by interacting with LARP1 and PABPC1, which stabilize ACSL4 mRNA. The results of preclinical models demonstrated the satisfactory efficacy of GalNAc-conjugated siTACC3 combined with PD-1 inhibitor therapy for HCC. In summary, tumor-derived TACC3 impairs the tumor-killing activity of CD8+ T lymphocytes through PUFA metabolism-associated crosstalk. Targeting TACC3 represents a novel and practicable strategy to augment ICI efficacy against HCC.

Mitosis is a critical phase of the cell cycle and a vulnerable point where cancer cells can be disrupted, causing cell death and inhibiting tumor growth. Challenges such as drug resistance persist in clinical applications. During mitosis, mRNA translation is generally downregulated, while non-canonical translation of specific transcripts continues. Here, we show that mitotic cancer cells redistribute ribosomes toward the 5' untranslated region (5' UTR) and beginning of the coding sequence (CDS), enhancing translation of thousands of upstream open reading frames (uORFs) and upstream overlapping open reading frames (uoORFs). This mitotic induction of uORF/uoORF enriches human leukocyte antigen (HLA) presentation of non-canonical peptides on the surface of cancer cells after mitotic inhibitor treatment. Functional assays indicate these epitopes provoke cancer-cell killing by T cells. Our findings highlight the therapeutic potential of targeting uORF/uoORF-derived epitopes with mitotic inhibitors to enhance immune recognition and tumor cell elimination.

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.

Repeated oncogenic mutations and polyclonal proliferation are evident in cancers. However, little is known about the polyclonal principles governing the systemic cancerous lineage during immunotherapy. Here, we examine a unique autopsy case of metastatic urothelial carcinoma that exhibits different treatment responses to anti-PD-1 therapy at each tumor site. By performing in-depth analyses of different multiregional bulk tumor masses, we reveal that subsets of subclones acquire potential driver mutations under treatment selection pressure. Spatial transcriptomics analysis reveals that subclones resistant to immunotherapy form distinct immunosuppressive environments consistent with their habitats. Furthermore, different cancer hallmarks are identified in each of the subclones that expand under immunotherapy at single-cell level; for example, one subclone is more proliferative, and another is more stem-cell-like. In summary, this study provides an overall picture of the polyclonal competition and changes in the immune microenvironment that are related to resistance to immunotherapy in patients with malignancies.

The efficacy, safety and ideal treatment duration of an adjuvant epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for patients with resected EGFR-mutated non-small-cell lung cancer (NSCLC) were not known until 2014, when this study was initiated. In this phase 3 ICTAN trial (GASTO1002, NCT01996098), patients with completely resected, EGFR-mutated, stage II-IIIA NSCLC after adjuvant chemotherapy were assigned in a 1:1:1 ratio to receive icotinib (125 mg, three times daily) for 12 months, to receive icotinib for 6 months, or to undergo observation. The primary endpoint was disease-free survival (DFS). This trial was terminated early. A total of 251 patients were randomized. Adjuvant icotinib for 12 months significantly improved DFS (hazard ratio [HR]: 0.40, 95% confidence interval [CI], 0.27-0.61; P < 0.001) and overall survival (OS; HR: 0.55, 95% CI, 0.32-0.96; P = 0.032) compared with observation. Adjuvant icotinib of 6 months also significantly improved DFS (HR: 0.41, 95% CI, 0.27-0.62; P < 0.001) and OS (HR: 0.56, 95% CI, 0.32-0.98; P = 0.038) compared with observation. Adjuvant icotinib for 12 months did not improve DFS (HR: 0.97; P = 0.89) or OS (HR: 1.00; P = 0.99) compared with 6 months of this drug. Rates of adverse events of grade 3 or higher were 8.3%, 6.0% and 2.4% for the 12-month icotinib, 6-month icotinib, and observation groups, respectively. Adjuvant icotinib for 12 months or 6 months following adjuvant chemotherapy improved DFS and OS compared with observation in patients with resected EGFR-mutated stage II-IIIA NSCLC with a manageable safety profile, supporting it as a potential treatment option.

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.

Malignant transformation of fibrous dysplasia in McCune-Albright syndrome is observed in less than 1% of cases, thus osteosarcoma is developing more frequently. According to the search in the PubMed database over the last 5 years, 13 publications were found, but none of them described cerebral cranium damage.

Craniopharyngiomas are benign tumors of the chiasmal-sellar region of adults and children, prone to local invasion and recurrence. There are two morphological types of craniopharyngiomas - adamantinomatous (in children and adults) and papillary (PCPs) (mainly in adults). PCPs are a rarer type (15-20%). In the literature of recent years devoted to PCPs, two main variants of these tumors are distinguished: 1) solid intraventricular (III ventricle) and 2) monocystic with a small tumor component located outside III ventricle.