Search Results (9,324)

Tuberculosis–diabetes mellitus (TB-DM) is increasingly recognized as a syndemic in which chronic metabolic dysregulation amplifies tuberculosis severity, delays treatment response, and increases relapse and mortality. However, conventional systemic correlates soluble cytokines and bulk whole-blood transcriptomic signatures often appear broadly similar between TB and TB-DM. This highlights a key gap: clinically meaningful immune dysfunction in TB-DM likely resides in specific lung and blood cell states that are poorly resolved by bulk assays. Small extracellular vesicles (EVs) in plasma and bronchoalveolar lavage (BAL) provide a tractable “liquid biopsy” layer because their RNA and protein cargo can integrate information from infected macrophages, neutrophils, and epithelial/endothelial compartments, and may also include pathogen-derived components. Yet most EV studies remain bulk and cell-agnostic, and interpretation is constrained by heterogeneous vesicle mixtures, selective cargo packaging, and co-isolated non-vesicular contaminants, issues that are especially problematic for nucleic-acid claims without rigorous controls. In this targeted narrative review (2010–2026), we argue that single-cell and multimodal immune reference atlases, including scRNA-seq/CITE-seq, provide a needed scaffold to link EV cargo patterns to specific immune cell states, pathways, and anatomic compartments in TB-DM, enabling prioritized candidates and testable hypotheses. We outline three complementary frameworks: reference-atlas anchoring to project EV cargo modules onto atlas-defined immune states; orthogonal triangulation combining computational inference with immunoaffinity enrichment, targeted validation, and functional assays; and cautious use of “droplet-era” extracellular signals as hypothesis-generating priors for EV-producing states. Implemented in longitudinal, clinically annotated cohorts with standardized EV workflows, atlas-guided EV profiling could yield cell-of-origin–resolved biomarkers of TB-DM immunopathology and treatment response, while prioritizing mechanistically plausible targets for host-directed intervention. Full article

Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer, with prognosis influenced by tumor location and primary status. This study evaluated clinicopathological features and survival outcomes in patients with MCC from multiple centers in Israel. Methods: Data on demographics, tumor characteristics, lymph node (LN) involvement, treatment, and survival were collected. Patients were stratified by primary tumor status (known vs. unknown) and tumor location (sun-exposed vs. non-sun-exposed). Disease-free survival (DFS) and overall survival (OS) were estimated using Kaplan–Meier analysis, and multivariate analyses were performed. Results: The cohort included 80 patients diagnosed with stage 3 (with LN involvement) MCC, of whom 52 (65%) had primary MCC with lymph node involvement, and 28 patients (35%) with unknown primary MCC. The majority were male (81.3%), with a median age of 71.2 years (range, 37–92). The median DFS and OS for the entire cohort were 24 and 32 months, respectively. Patients with unknown primary tumors had longer DFS (34 vs. 18 months; p = 0.0503) and OS (43 vs. 28 months; p = 0.0362) compared with those with known primary MCC. Non-sun-exposed tumors were associated with longer median DFS (32 vs. 18.5 months; p = 0.0663) and OS (41 vs. 23 months; p = 0.0353). Five-year survival analysis showed improved outcomes in patients with unknown primary tumors (DFS 54% vs. 35%, p = 0.04; OS 57% vs. 42%, p = 0.03) and in non-sun-exposed tumors (DFS 51% vs. 33%, p = 0.05; OS 57% vs. 40%, p = 0.04). Conclusions: Unknown primary status and non-sun-exposed tumor location are potentially associated with improved long-term survival in patients with MCC. These findings highlight the prognostic importance of tumor origin and anatomical site in MCC management. Full article

Inflammation is associated with metabolic alterations that can lead to the release of volatile organic compounds (VOCs) reflecting cellular biochemical activity. Profiling these volatile metabolites may provide insight into cellular responses to inflammatory stimuli, although their characterization in skin-derived cells remains limited. In this exploratory proof-of-concept study, we investigated the volatile metabolite profiles of human skin fibroblasts exposed to different inflammatory stimuli. Fibroblast cell lines were stimulated with polyinosinic:polycytidylic acid (Poly I:C), tumor necrosis factor-alpha (TNF-α), and lipopolysaccharide (LPS) to model viral-, cytokine-, and bacterial-associated stress conditions. Headspace solid-phase microextraction coupled with comprehensive two-dimensional gas chromatography and time-of-flight mass spectrometry (HS-SPME-GC×GC-TOFMS) was applied to analyze volatile metabolites released from the cell cultures, enabling exploratory profiling of the fibroblast volatilome. A data-processing workflow including pairwise comparisons between experimental groups and statistical filtering was implemented to identify volatile features associated with the different conditions. Several VOCs were tentatively identified, mainly belonging to alcohol, ester, and hydrocarbon classes, and showed differential abundance patterns between stimulated and control samples. Multivariate analysis indicated a separation between stimulated and non-stimulated groups, suggesting stimulus-associated differences in the volatile profiles of fibroblast cultures. While these observations may reflect metabolic responses occurring under inflammatory stimulation, the chemical identity and biochemical origins of several detected features remain to be confirmed. All in all, this study demonstrates the feasibility of applying HS-SPME-GC×GC-TOFMS-based volatilome profiling to investigate stimulus-associated changes in fibroblast cultures. The detected VOC patterns should therefore be considered preliminary observations requiring further chemical characterization and independent validation. Future studies including larger sample numbers, complementary biological verification of the inflammatory response, and more physiologically relevant experimental models will be necessary to further assess the robustness and potential relevance of these volatile signatures in the context of inflammatory processes. Full article

Ovarian cancer (OC) remains one of the leading causes of gynecologic cancer mortality, largely due to late diagnosis, frequent relapse, and the emergence of chemoresistance. An important but often-overlooked contributor to treatment failure is the heterogeneous penetration of anticancer drugs within tumors. Structural and biochemical barriers—including abnormal vasculature, elevated interstitial pressure, dense extracellular matrix, drug efflux transporters, and malignant ascites—generate steep intratumoral concentration gradients that conventional preclinical models fail to capture. As a result, systemic pharmacokinetic measurements frequently provide limited insight into tumor-level drug exposure. Patient-derived organoids (PDOs) have emerged as physiologically relevant 3D models that preserve the genetic, architectural, and functional characteristics of the original tumor. These systems enable controlled investigation of pharmacokinetic and pharmacodynamic processes, including drug penetration, metabolism, retention, and exposure–response relationships. Adding cell-free malignant ascites supernatant enhances PDOs’ ability to mimic the metastatic peritoneal microenvironment of OC. This review discusses recent advances in PDO technologies and examines how PDO-derived data can inform intratumoral pharmacokinetics and dosing strategies using physiologically based pharmacokinetic modeling and in vitro–in vivo extrapolation. Emerging hybrid platforms, including organoid-on-chip systems, vascularized co-cultures, and multi-omics integration, are crucial to improve translational prediction and support precision oncology. Full article

Lactiplantibacillus plantarum MS11, isolated from traditionally fermented yak milk in the high-altitude Gannan region of the eastern Tibetan Plateau, was investigated for its technological and functional potential in food applications. Using whole-genome sequencing combined with targeted experimental verification, this study clarified the genetic determinants and metabolic capacity associated with its production of folate, lactic acid, bacteriocin, and exopolysaccharides (EPS). The MS11 genome consists of one circular chromosome and three plasmids, totaling 3,318,231 bp with a GC content of 44.48%, and encodes 3155 predicted open reading frames. Complete biosynthetic gene clusters were identified for folate (7 genes), L-lactic acid (13 genes), bacteriocin (14 genes), and EPS (17 genes). Phenotypic assays confirmed the strain’s high metabolite productivity, including folate (0.6043 μg/mL), L-lactic acid (76.24 mg/mL), and EPS (544.2 mg/L). The cell-free fermented supernatant exhibited strong antibacterial activity against Escherichia coli, supporting the functional relevance of its bacteriocin-associated gene cluster. To the best of our knowledge, this is the integrated genomic and experimental characterization demonstrating that a L. plantarum strain originating from a unique high-altitude fermented dairy niche can concurrently synthesize high levels of folate together with multiple beneficial metabolites. The multifunctional attributes of MS11—including nutrient fortification, acidification capacity, EPS formation, and antimicrobial activity—indicate substantial promise for its application as a composite starter culture, natural bio-preservative, and nutritionally enhanced probiotic in fermented food systems. Full article

Tongue squamous cell carcinoma (TSCC) is clinically heterogeneous, and patients with a similar TNM stage can experience markedly different outcomes. We systematically reviewed omics-driven studies to identify prognostic TSCC biomarkers. Although fundamentally prognostic, we discussed their theoretical translational relevance regarding future clinical decisions—such as treatment stratification or surveillance intensity—while strictly framing them as preliminary, hypothesis-generating targets. PubMed, Scopus, Web of Science, and Cochrane were searched for original human studies published between 2014 and 2024 using high-throughput genomic or transcriptomic profiling. Study selection followed referred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), data were extracted with a structured workbook, and risk of bias was assessed using QUIPS and PROBAST, with reporting completeness appraised using REMARK. Seventeen studies were included, identifying 85 distinct biomarkers. Across biomarkers supported by multivariable overall survival analyses, higher-risk associations were reported for NELL2, PDE4D, CTTN, HBEGF, and CA9, whereas lower-risk associations were reported for AC139530.1, LINC01711, CCDC96, CYP2J2, and SPAG16. Recurrent biological themes included IL-17 signaling, ECM-receptor interaction, and focal adhesion. CA9 was the only biomarker reported in more than one included study, supporting its prioritization for validation. Although the evidence remains heterogeneous and largely hypothesis-generating, these markers may support the future validation of response-oriented therapeutic stratification in TSCC. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is the most common chronic liver disease in the world. The disease progresses from steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The modern concept of “multiple parallel hits” interprets disease progression as the result of the synergistic action of lipotoxicity, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, proinflammatory signals, and gut–liver axis dysfunction. Against the background of the limited translation of preclinical data from animal models due to interspecies differences, the importance of human-oriented in vitro platforms compatible with controlled design and high-throughput screening is increasing. The current review analyzes MASLD models based on the HepG2 cell line, systematizing steatosis induction protocols, evaluating the metabolic characteristics and limitations of this cell, and comparing 2D monocultures, 3D systems, and co-cultures. HepG2 has been shown to demonstrate a predictable steatogenic response to free fatty acids (FFAs) and is convenient for reproducing early stages of pathogenesis and primary pharmacological selection of compounds. At the same time, key limitations of the model are highlighted, namely tumor origin, glycolytic shift (Warburg effect), reduced β-oxidation, impaired very-low-density lipoprotein (VLDL) assembly and secretion, and sharply reduced cytochrome P450 (CYP450) activity, as well as limited reproducibility of fructose-induced de novo lipogenesis (DNL). Comparative analysis demonstrates an increase in physiological relevance with the transition from 2D to 3D and multicomponent co-cultures, accompanied by increased complexity and cost, but allowing for the modeling of inflammation and fibrogenesis. The review justifies approaches to selecting the appropriate platform based on the specific research task. Full article

Background/Objectives: Central Nervous System (CNS) relapse represents a severe and often fatal complication of Diffuse Large B-Cell Lymphoma (DLBCL). This study aimed to evaluate clinical, biological, and treatment-related factors associated with progression-free survival (PFS) until CNS relapse in patients with DLBCL. Methods: A retrospective cohort study was conducted using clinical data from adult DLBCL patients evaluated and treated at the Regional Institute of Oncology, Iași, Romania, between 2015 and 2023. Associations between clinical, biological, and treatment-related variables and CNS relapse were evaluated using univariate and multivariable Cox proportional hazards models, Fine–Gray competing-risk analyses, and propensity score-based methods to address confounding by indication for CNS prophylaxis. Results: Twenty-six CNS relapse events (6.3%) and 72 deaths without prior CNS relapse occurred over a median follow-up of 12 months. In the prespecified reduced multivariable Cox model, non-R-CHOP regimens (HR 4.57, 95% CI 1.67–12.52; p = 0.003) and high CNS-IPI scores (HR 4.70, 95% CI 1.14–19.46; p = 0.033) were independently associated with CNS relapse. The 20-month cumulative incidence of CNS relapse was 7.0% in the R-CHOP-like group versus 35.2% in the non-R-CHOP group (Gray’s test p < 0.001). Fine–Gray modeling confirmed the association for non-R-CHOP regimens (SHR 3.38, 95% CI 1.21–9.45; p = 0.02). Cell-of-origin subtype, double-expressor phenotype, and Ki-67 were not significantly associated with CNS relapse. Conclusions: High CNS-IPI and treatment with non-R-CHOP regimens independently predicted earlier CNS relapse. Future multicenter studies with molecular profiling are needed to refine CNS risk stratification. Full article

Mixed hepatocellular carcinoma (HCC)–neuroendocrine carcinoma (NEC) is a major type of liver mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN). Primary liver NEC, which is very rare, is mostly associated with HCC rather than pure NEC. To characterize the cancer cell heterogeneity of the HCC and NEC components, we comprehensively analyzed the protein expression of three cancer cell biological markers (TERT, Ki-67, and p53) and five differentiation markers (one hepatocyte marker and four neuroendocrine markers) via immunohistochemistry and immunofluorescence using curative resection tissues from three patients with liver MiNEN. TERT/Ki-67/p53 proteins, which are related to cell proliferation and malignancy, were independently expressed in the HCC and NEC components; Ki-67 was highly expressed among the three proteins in both cancer components, and the expression of all three markers was higher in the NEC component than in the HCC component. Despite the intracomponent and intercomponent heterogeneity, the expression signatures of the three markers were similar between the two components, potentially suggesting a common origin of mixed HCC-NEC. An in-depth exploration of intracomponent heterogeneity using differentiation markers revealed multiple intermediate phenotypes of cancer cells, i.e., HCC-like and NEC-like cells, mainly in the HCC component. Histologically NEC-like cells rather than HCC-like cells tended to have an intermediate percentage of Ki-67-positive cells, compared with NEC cells. The spatial distribution of various intermediate cancer cell phenotypes suggests that mixed HCC-NEC may involve the transdifferentiation from HCC cells to NEC cells through the dedifferentiation of HCC. Full article

Particulate matter (PM) is a complex mixture of airborne solid particles and liquid droplets originating from various environmental sources, and it has been implicated in the initiation, development, and progression of pulmonary inflammation and respiratory diseases. However, the underlying associated molecular mechanisms remain unclear. Adenophora divaricate Franch. & Sav. (AD) is a medicinal herb classified within the Campanulaceae family and genus Adenophora, with a broad geographic distribution across East Asia, including Korea, Asia, and Russia. In this study, we investigated the mechanisms underlying the effects of AD on PM-induced lung inflammation in both PM-stimulated RAW264.7 cells and PM-exposed mice. Considering that the reactive oxygen species (ROS)-mediated thioredoxin-interacting protein (TXNIP) and NOD-like receptor pyrin domain containing (NLRP3) inflammasome pathway plays a role in PM-induced inflammatory responses, we focused on determining whether AD exerts its anti-inflammatory effects through modulation of this signaling pathway. The anti-inflammatory properties of the methanolic extract of AD were evaluated using PM-stimulated RAW264.7 cells and PM-exposed mice. PM was administered intranasally to mice for 7 days, whereas AD or dexamethasone was orally administered for the same duration. AD treatment significantly attenuated pulmonary inflammation, as evidenced by reduced inflammatory cell counts and decreased cytokine levels in bronchoalveolar lavage fluid. In addition, AD decreased oxidative stress marker (ROS and thiobarbituric acid reactive substances) while increasing glutathione content, leading to suppression of TXNIP/NLRP3 inflammasome expression. Histopathological analysis revealed a marked alleviation of inflammatory responses in lung tissue, characterized by diminished inflammatory cell infiltration and reduced alveolar wall thickening. Collectively, these findings suggest ROS-mediated TXNIP serves as a key regulatory factor, and AD may serve as a potential therapeutic agent for pulmonary inflammation. Full article

Human liver stem cells (HLSCs) are a mesenchymal stromal cell (MSC)-like population isolated from adult liver biopsies. HLSCs share key characteristics with MSCs, including phenotype and differentiation capabilities. Previous studies have demonstrated that HLSCs promote regeneration in different experimental models of acute and chronic tissue injury and that HLSC-derived extracellular vesicles (HLSC-EVs) recapitulate the therapeutic effects of the cells of origin. This study aimed to determine whether HLSC-EVs, obtained and characterized under good manufacturing practice (GMP) conditions, can influence the progression of liver fibrosis in vivo. The EV production process was carried out under GMP conditions to generate batches of HLSC-EVs by tangential flow filtration. To assess their therapeutic potential, an in vivo model of hepatic fibrosis was established through administration of thioacetamide (TAA). In TAA-treated mice, EV administrations attenuated fibrosis progression. Molecular analyses showed a significant reduction in the expression levels of key pro-fibrotic genes. At the functional level, EV administration resulted in a significant reduction in plasma alanine aminotransferase levels and an increase in albumin levels, indicating improved liver function. These data indicate that HLSC-EVs, produced under GMP conditions, display antifibrotic effects in a chronic liver disease model, leading to improved liver function and histology. Full article

Background: Malignant salivary gland tumors represent a highly diverse group of neoplasms, their heterogeneity likely arising due to variable origin in different tissue components. Emerging evidence suggests that SOX-2 and EZH-2 play critical roles in salivary gland carcinogenesis, being related to tumor cell stemness potential, along with accelerated tumor progression and unfavorable clinical outcomes. The aim of this study was to assess the association between SOX-2 and EZH-2 expression, survival parameters, and tumors’ pathological characteristics in a group of patients with primary epithelial malignant salivary gland tumors (MSGTs) and to evaluate their value as diagnostic and prognostic markers. Methods: Our study group comprised 104 patients with primary epithelial MSGTs diagnosed in “Sf. Spiridon” County Hospital, Iasi, over a period of fifteen years. Pathological parameters and survival evaluation, along with SOX-2 and EZH-2 immunohistochemistry assessment and scoring, were conducted, and the associations between different parameters were analyzed. Results: High SOX-2 immunoexpression was significantly associated with lymphatic invasion (LY) (p = 0.003), pT stage (p = 0.010), histological tumor type (p = 0.003), and tumor grading (p = 0.037), while high EZH-2 immunoexpression was significantly associated with perineural invasion (PnI) (p < 0.001), vascular invasion (p = 0.038), LY (p = 0.001), tumor grading (p = 0.002), and pathological extranodal extension (pENE) (p = 0.018). The tumors with high SOX-2 and EZH-2 expressions were associated with a reduced overall survival (OS) (p = 0.013 and p = 0.011). Cox regression analysis revealed that pT (HR = 1.826, p = 0.019), LY (HR = 0.318, p = 0.007), and tumor grade (HR = 0.505, p = 0.021) added to high SOX-2 and EZH-2 immunoexpression independently predicted a poor survival outcome (HR = 2.373, p = 0.016 and HR = 2.746, p = 0.015). Conclusions: Our findings suggest that SOX-2 and EZH-2 may serve as biomarkers of aggressive behavior and a poor prognosis in primary epithelial MSGTs, providing potential opportunities for precision-targeted therapies. Full article

Cultured meat holds the potential to reduce environmental impacts and offer ethical advantages while replicating the nutritional, taste, and texture attributes of conventional meat. To date, most research on consumer acceptance of meat has focused on European and North American markets. In contrast, Muslim-majority countries remain underexplored, particularly regarding the compatibility of cultured meat with Islamic dietary laws. These societies are experiencing rising meat consumption, and countries such as Saudi Arabia and Malaysia rely heavily on meat imports. This narrative perspective article aims to systematically examine how specific stages of cultured meat production align with, or challenge, Islamic dietary (halal) principles. To this end, we adopt a stage-based analytical approach, mapping key technological steps in cultured meat production onto core requirements of Islamic jurisprudence. To this end, we critically and comprehensively examine the intersection between cultured meat production methods and the Islamic concept of halal, which extends beyond ingredient permissibility to encompass ethical, spiritual, and hygienic dimensions of food production. Key challenges to halal certification include the origin and status of starter cells, whether donor animals were slaughtered according to Islamic law, the permissibility of biopsied tissue, and the use of fetal bovine serum in growth media. The analysis indicates that while halal-compliant cultured meat is scientifically feasible, its adoption remains constrained by unresolved religious interpretations, regulatory fragmentation, and limited availability of halal-certified inputs. We emphasize the need for interdisciplinary collaboration among Islamic scholars, food scientists, certification bodies, and policymakers. From a policy perspective, harmonized halal standards, targeted investment in serum-free and animal-free culture media, and early regulatory engagement with Islamic authorities are essential to facilitate responsible market entry. Therefore, we suggest a multi-level governance and stage-gated halal decision framework for cultured meat. Proactive regulation and open dialogue with religious leaders are vital to ethically introduce cultured meat into Muslim markets, aligning innovation with Islamic values while supporting national sustainability and food security goals. Full article

Background: Obstructed hemivagina and ipsilateral renal anomaly (OHVIRA) syndrome, also known as Herlyn–Werner–Wunderlich syndrome (HWWS), is a rare Müllerian malformation. Gynaecologic malignancies reported in association with OHVIRA syndrome/HWWS are exceptional and scattered across isolated case reports and small case series, leading to significant challenges for screening, early diagnosis, and optimal management. The primary aim of this study was to comprehensively review and synthesize the clinicopathologic features, treatment approaches, and reported outcomes of patients with OHVIRA-associated gynaecologic neoplasms. Methods: A systematic review of published cases of gynecologic malignancies in OHVIRA/HWWS was conducted using PubMed/MEDLINE and Scopus from database inception through January 2026. To expand the current evidence, an illustrative novel institutional case is also presented and integrated into the analysis. Results: A total of 21 cases were identified and analysed; reported tumours predominantly involved the lower genital tract (vagina/cervix), with a recurrent representation of adenocarcinoma, particularly clear cell histology, and a frequent origin from the obstructed or non-visible compartment when side was described. Endometrial and ovarian involvement was uncommon. Conclusions: The anatomical complexity of OHVIRA syndrome creates a diagnostic blind spot that warrants heightened clinical suspicion, rigorous MRI-based anatomic delineation, and side-specific evaluation in symptomatic patients. By synthesizing the available literature, this review underscores the necessity for tailored, multidisciplinary management and proactive surveillance strategies in this rare population. Full article

Oocyte competency is a crucial determinant of fertilisation success and the initial development of embryos in assisted reproductive technologies. The metabolic and biochemical environment of the ovarian follicle is crucial for determining oocyte developmental potential, alongside genetic integrity. The follicular microenvironment includes a complex network of signalling chemicals that regulate mitochondrial activity, steroidogenesis, oxidative balance, and cellular energy metabolism. Recently, metabolic hormones originating from adipose tissue and skeletal muscle, namely, adipokines and myokines, have received considerable focus as crucial regulators of ovarian physiology. Adiponectin, irisin, and the recently identified hormone asprosin have emerged as crucial metabolic regulators influencing granulosa cell activity, mitochondrial bioenergetics, insulin signalling pathways, and redox homeostasis inside the follicular niche. Adiponectin mostly provides metabolic protection by activating AMP-activated protein kinase (AMPK) and improving insulin sensitivity, which in turn enhances mitochondrial efficiency and steroidogenic function in granulosa cells. Irisin, derived from the breakdown of fibronectin type III domain-containing protein 5 (FNDC5), aids the developing oocyte by facilitating mitochondrial biogenesis, augmenting oxidative phosphorylation, and altering cellular defence mechanisms against oxidative stress. Conversely, asprosin has been associated with glucogenic signalling, metabolic stress, and probable mitochondrial malfunction, suggesting a possible relationship between systemic metabolic problems and negative reproductive consequences. Clinical and experimental research indicate that the levels of these metabolic regulators in follicular fluid may correlate with ovarian response, oocyte quality, fertilisation rates, and embryo development during in vitro fertilisation cycles. This review consolidates current molecular, cellular, and clinical information, clarifying the pathways by which adipokines and myokines influence follicular metabolism and impact oocyte competency. Understanding the metabolic connections between systemic endocrine signals and the follicular milieu may provide novel indicators for reproductive prognosis and provide new treatment targets to improve assisted reproduction outcomes. Full article