Myoepithelial carcinoma (MECA) represents a rare malignant neoplasm accounting for less than 2% of all salivary tumors, with recurrent PLAG1 rearrangements comprising its predominant underlying molecular aberration.

A 48-year-old man presented with a 6-month history of a slow-growing, asymptomatic, pink-yellowish, submucosal nodule of the left upper lip measuring approximately 1.2 cm. An excisional biopsy was performed. Histologic examination revealed an infiltrative salivary neoplasm exhibiting a multilobulated growth pattern comprising numerous solid islands, nests, and anastomosing cords of lesional cells. A cribriform-like architecture was focally noted in association with pools of extracellular, amphiphilic, mucinous material. Neoplastic cells demonstrated predominantly epithelioid-to-plasmacytoid and in areas spindled cytomorphology, bland round-to-ovoid nuclei with granular chromatin, occasionally visible nucleoli, and abundant, eosinophilic, often vacuolated cytoplasm. Prominent nuclear pleomorphism and tumor necrosis were not present, while mitotic figures were infrequent (2 per 10 HPFs). Invasion of the adjacent adipose tissue was observed at the periphery of the lesion. The supporting stroma varied from fibrous-to-myxoid and featured mild acute and chronic inflammation. By immunohistochemistry, neoplastic cells were diffusely positive for CK7, SOX10, S100, and calponin, while p40 showed scattered/patchy immunoreactivity. They were negative for mammaglobin. The histomorphologic and immunophenotypic findings supported the diagnosis of low-grade MECA. RNA-based NGS revealed a CARMN/miR143HG::PLAG1 fusion, leading to a chimeric transcript between exons 1-2 of the long non-coding RNA host gene CARMN/miR143HG (chr5q32) and exons 3-5 of PLAG1 (chr8q12.1).

We report on the clinical, histopathologic and immunophenotypic characteristics of a low-grade MECA of the minor salivary glands with a novel CARMN/miR143HG::PLAG1 fusion, expanding the molecular landscape of salivary myoepithelial neoplasia.

While dietary therapies targeting individual amino acids in cancer show promise in modulating tumor metabolism, the issue of nutrient competition between tumors and the immune system remains unresolved. The current approaches face significant challenges, particularly in the context of metabolic adaptability and immune responses. Here, we demonstrate that the combined modulation of lysine (Lys) and arginine (Arg) balances tumor suppression and host fitness. Using a cross-species approach combining Drosophila and mouse models, we define a narrow therapeutic window for Lys and Arg. A balanced combination (0.5% Lys/0.5% Arg) reduces tumor burden, extends survival, and preserves host fitness in tumor-bearing mice, whereas an imbalanced formulation (0.25% Lys/1% Arg, LLHA) paradoxically accelerates tumor progression. Single-cell RNA sequencing revealed that LLHA was associated with increased B cells, M1-annotated macrophages and reduced T cells, consistent with systemic immune remodeling that may favor tumor progression, accompanied by decreased Rps6 and Rps29 and increased Hba-a1 and Hbb-bt expression, suggesting alterations in mechanistic target of rapamycin (mTOR), hemoglobin, and ribosomal/translational pathways in immune cells. By defining biphasic thresholds and identifying optimal Lys/Arg combinations, this work provides a preclinical framework for investigating how balanced Lys/Arg modulation may influence tumor control and host fitness. This represents a step towards potential future synergy with immunotherapies, contingent upon further validation of immune dependency.

To evaluate a biphasic CT clustering-based habitat radiomics approach for predicting the World Health Organization/International Society of Urological Pathology (WHO/ISUP) nuclear grade in clear cell renal cell carcinoma (ccRCC) and assess the discriminatory value of different tumor subregions.

This retrospective study collected 473 ccRCC patients (training: n = 337; test: n = 136). Thin-section corticomedullary phase (CMP) and excretory phase (EP) CT images were preprocessed and registered. NnU-Net was used for automated segmentation of tumor. Tumor habitats were generated via k-means clustering of three parameters: CMP attenuation values (CMP_HU), EP attenuation values (EP_HU), and their interphase difference (ΔHU). Radiomics features were extracted from whole-tumor volumes, individual subregions, and subregional combinations, followed by feature selection and model development.

Five distinct subregions were identified. Subregion 4 ( representing the tumor viable-necrosis transition zone ) -based Random Forest model achieved diagnostic performance statistically comparable to whole-tumor-based model in both CMP ( AUC: 0.773 vs. matched whole-tumor AUC 0.819, DeLong' p = 0.152 ) and EP ( AUC: 0.810 vs. matched whole-tumor AUC 0.827, DeLong' p = 0.593 ). Subregion 2 ( necrotic core ) -based model showed similar efficacy to whole-tumor model in EP ( AUC: 0.771 vs. matched whole-tumor AUC 0.802, DeLong' p = 0.219 ). Multi-subregion models containing Subregion 4 maintained statistically comparable performance with whole-tumor models, with Subregion 1+4 demonstrating optimal performance.

Biphasic CT clustering-based habitat analysis reveals that specific tumor subregions-particularly the tumor viable-necrosis transitional zone-can approximate whole-tumor diagnostic performance for ccRCC nuclear grading. This method provides spatial mapping of tumor heterogeneity through visualizable CT subregions, offering a potential complementary tool for non-invasive ccRCC characterization. Further prospective multicenter validation with histopathological correlation is needed before clinical implementation.

Uveal melanoma (UM) is a rare but aggressive cancer arising from cells of the uveal tract that is highly resistant to therapy once it has metastasized. In drug screening experiments, we identified a high sensitivity of primary UM cell lines to the pan-histone deacetylase (HDAC) inhibitor panobinostat and addressed the question whether two class IIa HDACs, HDAC4 and HDAC5, could serve as potential therapeutic targets in UM. Selective pharmacological inhibition of HDAC4/5, as well as stable knockdown of HDAC4 or HDAC5, did not strongly affect cell viability, differentiation, apoptosis or necrosis, and did not sensitize cells to other HDAC or MEK inhibitors. Proteogenomics analysis revealed 73% concordance and only 7% discordance in the expression of transcripts and proteins. Concordance reached 92% for significant transcripts. Despite the lack of severe global gene and protein expression changes in HDAC4- or HDAC5-knockdown UM cell lines, the expression of individual cancer-related genes and signaling pathways was differently regulated following HDAC4 or HDAC5 knockdown. This was particularly evident in the NF-κB pathway, which showed decreased NF-κB p65 phosphorylation in UM cell lines with monosomy in chromosome 3 (M3) genotype and mutations in BRCA1-associated protein 1 (BAP1). In summary, our results suggest that HDAC4/5 inhibitors alone are insufficient for monotherapy in UM cells, but the identification of HDAC4/5-regulated genes involved in cancer progression provides a rationale for exploring combination strategies that include HDAC4/5 inhibition.

Mutations in the untranslated region (UTR) of a gene dysregulate its expression by disrupting the regulatory elements. Defective EGFR, AKT1, and HRAS are known to promote colorectal cancer (CRC) by activating oncogenic signaling pathways. The current study aimed to screen the Pakistani CRC patients for UTR mutations of EGFR, AKT1, and HRAS genes and investigate the functional impact of detected mutations on regulatory elements. The genomes of CRC patients were analyzed by whole-exome sequencing. All the identified UTR mutations were subjected to extensive in silico analysis to study the functional consequences on pathogenicity, oncogenicity, regulatory elements, mRNA structure, transcription factor binding sites, and miRNA binding sites. Moreover, miRNA expression, pathway, protein-protein interaction and gene enrichment analysis were also performed. The present study identified UTR mutations of EGFR (n = 5), AKT1 (n = 6), and HRAS (n = 3) in Pakistani CRC patients. Among 5' UTR mutations of EGFR, c.-216G > T causes loss of TF and motif sequences, c.-191 A > C increases strength of the motif sequences, AKT1: c.-463dupG, c.-47 C > T, and c.-478G > C, and HRAS: c.-101 C > T mutations stabilize the mRNA structure and alter the motif sequence and transcription factor binding sites. Whereas 3' UTR mutations of EGFR c.*281dupA and c.*774T > C and AKT1 c.*301C > T cause loss of oncomiR sites. PPI and pathway enrichment analysis show that EGFR, AKT1, and HRAS interact with other oncogenes. This study reported the presence of damaging mutations in the regulatory region, which may alter the expression of EGFR, AKT1, and HRAS. The information thus generated could facilitate designing personalized therapy.

How cancers regulate endoplasmic reticulum (ER) pH and minimize ER stress remains unclear. Here we show that in breast cancer, these processes are governed by the anion channel GPR89. While normally localized to the Golgi, we find GPR89 is also present in the ER of tumor cells, where it collaborates with vacuolar H⁺ ATPase to regulate pH, and reduces ER stress via IRE1α-HSP47-XBP1s, ATF6 and ATP2A2 pathways. This ER localization of GPR89 drives a tumor-specific dependency, rendering breast cancer cells, but not normal tissues, dependent on this anion channel. Structural modeling and mutagenesis identify five key amino acids essential for GPR89's ER pH regulatory function and tumor cell survival. Consistent with its cancer-specific functions, GPR89 cooperates with Myc to accelerate mammary tumorigenesis. These findings uncover how breast cancers adapt to oncogenic stress by co-opting Golgi mechanisms of pH regulation to support ER homeostasis and survival.

Sleep is essential for metabolic homeostasis and overall health. NAFLD, recently reclassified as MASLD, is the most prevalent chronic liver disease globally (~ 25% prevalence) and is strongly linked to metabolic comorbidities. Growing evidence associates adverse sleep conditions including short sleep duration, OSA, and circadian misalignment with NAFLD onset and progression. However, data from Iranian and Middle Eastern populations remain scarce, and no study has simultaneously evaluated sleep quality and OSA risk in a large Iranian NAFLD cohort. This study aimed to address this gap using the PSQI and STOP-BANG questionnaire.

This cross-sectional study utilized registry data from the PERSIAN Organizational Cohort Study (POCS) at Mashhad University of Medical Sciences. A total of 958 NAFLD patients diagnosed by abdominal ultrasonography were included.

Among 958 participants (69.6% male; mean age 46.7 ± 9.1 years), 35.4% had sleep disturbance (31.6% mild; 3.8% moderate). Over half (53.4%) were at intermediate OSA risk. Sleep disturbance was significantly associated with female sex (p = 0.022), single marital status (p = 0.019), higher BMI (p = 0.026), and hypertension (p = 0.007). BMI correlated weakly but significantly with PSQI scores (r = 0.072, p = 0.036). Hepatic steatosis grade was not associated with sleep disturbance (p = 0.193) but correlated positively with STOP-BANG scores (r = 0.232, p < 0.001).

Sleep disturbance and elevated OSA risk are common among patients with NAFLD and were associated, in unadjusted analyses, with female sex, elevated BMI, hypertension and single marital status. These findings support consideration of sleep assessment in this population on case-finding grounds; whether identifying or treating these conditions improves hepatic or metabolic outcomes cannot be determined from a cross-sectional study.

Streptococcus pneumoniae remains the leading bacterial cause of community-acquired pneumonia (CAP) and a major source of morbidity and mortality in adults. Pneumococcal conjugate vaccines (PCVs) have substantially reduced invasive pneumococcal disease, but serotype replacement has led to shifts in pneumococcal CAP epidemiology. In addition, the identification of S. pneumoniae remains challenging. This study investigated pneumococcal serotype distribution, vaccine coverage, and the diagnostic yield of a serotype-specific urinary antigen detection assay (ssUAD) among adults with CAP in Switzerland between 2016 and 2021.

Adult patients enrolled in the Swiss CAPNETZ cohort with available urine samples were analyzed using the Pfizer 24-serotype ssUAD assay. Results were compared with conventional diagnostic methods, including the pneumococcal urinary antigen test (pUAT) and cultures. Serotype distribution, vaccine coverage (PCV13, PCV15, PCV20 and PCV21), and temporal trends were assessed.

Among 234 CAP patients, S. pneumoniae was identified by conventional diagnostics (pUAT and cultures combined) in 37 (15.8%). The ssUAD was positive in 35 patients (15.0%). Among patients with available results from both conventional diagnostics and ssUAD (n = 161), the addition of ssUAD increased pneumococcal CAP detection from 18.6% to 29.2% (p = 0.036). Among ssUAD-positive patients, the most frequent serotypes detected by ssUAD were 3 (n = 12), 8 (n = 5), and 11A (n = 4). Based on ssUAD-derived serotype distribution, vaccine coverage was 54.3% for PCV13, 60.0% for PCV15, 91.4% for PCV20, and 85.7% for PCV21. During 2020-2021, the proportion of serotypes not covered by PCV13 increased from 10/28 (35.7%) to 6/7 (85.7%) (p = 0.018).

The addition of ssUAD improved S. pneumoniae detection beyond standard methods. Although based on a small number of cases, the shift toward non-PCV13 serotypes underscores the potential benefit of higher-valency vaccines such as PCV20 and PCV21 for adult pneumococcal disease prevention in Switzerland.

Chronic obstructive pulmonary disease (COPD) is a progressive heterogeneous lung disease driving global illness and death, yet reliable biomarkers for its early diagnosis, molecular subtyping and prognosis are lacking. Here, we conduct targeted plasma metabolomic profiling in two independent, deeply phenotyped cohorts comprising 1344 participants across the full spectrum of COPD severity, with 3-year longitudinal follow-up for 651 subjects. Machine learning integration screens metabolite signatures associated with disease presence, clinical subtypes, and longitudinal outcomes. We identify unique plasma metabolic profiles distinguish COPD patients from healthy people and separate emphysema and small-airway-dominant subtypes with high accuracy in test and validation cohorts. A 27-metabolite panel detects early COPD by capturing metabolic shifts prior to lung function loss. Moreover, specific metabolite subsets independently predicted lung function decline, occurrence of acute exacerbations, and dyspnoea severity. Together, plasma metabolomics yields robust multi-purpose COPD biomarkers, offering an accessible strategy for early screening and personalized clinical risk stratification.

Pseudomonas aeruginosa (PA) pneumonia is occasionally misdiagnosed as invasive pulmonary aspergillosis (IPA) in immunocompromised patients because of shared risk factors and overlapping radiologic manifestations. However, this topic has not been systematically investigated.

We retrospectively reviewed immunocompromised patients diagnosed with PA pneumonia between 2014 and 2023. Patients with confirmed or probable PA pneumonia were analyzed. For comparison, control patients with proven or probable IPA diagnosed between 2018 and 2023 were randomly selected. First, we tested whether two thoracic radiologists could differentiate PA pneumonia from IPA based on computed tomography (CT) findings. Second, we identified clinical and radiologic features that could help differentiation.

Thirty-three PA patients (15 confirmed and 18 probable) and 75 IPA control patients (15 proven and 60 probable) were analysed. Two radiologists blindly scored 33 PA and 25 IPA cases which were randomly selected from control patients. Among PA pneumonia cases, 36% (12/33) were unanimously misclassified as IPA by the two radiologists. The sensitivities of radiologist A and B for PA were 61% and 33%, respectively (fair agreement, kappa value = 0.38). We then compared the clinical features and CT findings of the 33 PA and 75 IPA patients. Clinical factors such as solid organ transplantation beyond 6 months and an acute clinical course favored PA diagnosis. PA pneumonia frequently exhibited IPA-like features, including macronodules (39%), mass-shaped consolidation (49%), and cavitation (24%). However, ill-defined centrilobular nodules and peribronchial consolidation were significantly more common in PA pneumonia (67% vs. 21% and 58% vs. 21%, respectively, P < 0.001). In multivariate analysis, solid organ transplantation, peribronchial consolidation, and ill-defined centrilobular nodules were independent predictors of PA pneumonia.

Approximately one-third of patients with PA pneumonia exhibited CT findings resembling IPA. Integration of clinical contexts, especially transplant history and detailed interpretation of radiologic signs, may improve differential diagnosis between PA pneumonia and IPA.