Search Results (517)

The tumor microenvironment (TME) is a highly adaptive and heterogeneous niche in which cancer stem cells (CSCs) promote immune evasion, metastatic dissemination, and therapy resistance. Among the mechanisms that support this phenotype, mitochondrial hijacking has emerged as a central strategy through which CSCs reprogram immune and stromal cells to favor tumor progression. This review synthesizes current evidence on how CSCs exploit mitochondrial transfer, particularly via tunneling nanotubes (TNTs) and extracellular vesicles (EVs), to impair antitumor immunity and remodel the metastatic niche. CSCs display marked metabolic plasticity, shifting between glycolysis and oxidative phosphorylation (OXPHOS) in response to environmental stress. They exploit this adaptability by transferring mitochondria and mitochondrial components to recipient cells, including tumor-associated macrophages (TAMs) and cytotoxic T cells, thereby disrupting ATP production, increasing oxidative stress, and skewing immune polarization. This mitochondrial hijacking contributes to an immunosuppressive milieu, stabilizes HIF-1α, and enhances PD-L1 expression, ultimately weakening T-cell activity and reinforcing CSC survival. EVs add another layer of regulation by transporting bioactive cargo, including oncogenic microRNAs (miRNAs) and mitomiRs such as miR-21, miR-210, and miR-34a. These molecules modulate mitochondrial gene expression, reshape immune signaling, and reinforce CSC phenotypes through autocrine and paracrine loops. Single-cell and spatial transcriptomic approaches have further revealed metabolic heterogeneity within CSC–immune synapses, identifying “metabolic hotspots” associated with profound immune dysfunction. Therapeutic strategies targeting OXPHOS, EV biogenesis, and miRNA activity are therefore being explored. In parallel, mitochondria-associated proteins such as TSGA10 may also contribute to CSC-driven immunometabolism regulation and deserve further investigation. Targeting downstream heterogeneity is like cutting the branches of a weed. Targeting the upstream mechanisms of mitochondrial hijacking and miRNA crosstalk aims to destroy the root (CSC plasticity) that generates the heterogeneity and drives therapy resistance in the first place. This review highlights mitochondrial hijacking and miRNA-mediated reprogramming as central determinants of CSC-driven immune escape and proposes a framework for precision interventions targeting CSC–immune interactions in metastatic cancer. Full article

Background: Accurate identification of complete or near-complete responders after total neoadjuvant therapy (TNT) is critical for selecting candidates for non-operative management in locally advanced rectal cancer (LARC). While static inflammatory biomarkers have been widely investigated, the predictive value of dynamic changes in systemic inflammation during TNT remains unclear. This study evaluated whether changes in the Pan-Immune Inflammation Value (PIV) correlate with magnetic resonance imaging tumor regression grade (mrTRG) and regrowth risk. Methods: Seventy-three patients with LARC treated with TNT between 2018 and 2024 were retrospectively analyzed. Patients were classified as complete/near-complete responders (C-NCRG; mrTRG1–2) or residual disease group (RDG; mrTRG3–5). The PIV was calculated as (platelet × monocyte × neutrophil)/lymphocyte at treatment initiation (first-PIV), three weeks after completion of chemotherapy (last-PIV), and at regrowth (Rg-PIV). Dynamic changes were defined as Δ-PIV (last-PIV minus first-PIV) and ΔRg-PIV (Rg-PIV minus first-PIV). Receiver operating characteristic analysis identified optimal cutoffs, and logistic regression assessed independent associations. Results: The baseline PIV did not differ between groups. Last-PIV and Δ-PIV were significantly lower in the C-NCRG compared with RDG (p = 0.006). A Δ-PIV cutoff of −36.9 discriminated responders (AUC = 0.705; sensitivity 53.7%; specificity 84.4%) and remained independently associated with MRI response in multivariate analysis. In the non-operative management cohort, ΔRg-PIV was significantly lower in patients without regrowth (p = 0.001), with a cutoff of −77.72 (AUC = 0.794; sensitivity 88.9%; specificity 66.7%). Overall survival was superior in the C-NCRG (p = 0.01). Conclusions: A dynamic reduction in the PIV during TNT is significantly associated with favorable MRI response and lower regrowth risk in LARC. PIV dynamics may serve as a noninvasive complementary biomarker to support response assessment and stratification in organ-preservation strategies. Full article

Advances in surgical techniques, radiographic imaging capabilities, radiotherapy, and chemotherapy have led to improved outcomes for patients with rectal adenocarcinoma. Treatment strategies have correspondingly evolved, as seen with total neoadjuvant therapy (TNT) and organ preservation approaches. TNT is a treatment strategy for primary, non-metastatic, resectable mismatch repair proficient rectal cancer where the intent is to administer all appropriate adjuvant therapy in the preoperative phase, including both systemic therapy and chemoradiotherapy/radiotherapy. In this setting, TNT is increasingly administered for the purposes of maximizing tumour response to facilitate resection, improving treatment compliance, thus increasing the likelihood of a complete response to allow for organ preservation and for the possibility of improving survival. While several recent randomized controlled trials have described the role of TNT in the contemporary treatment of rectal cancer, there is significant heterogeneity in sequencing of treatments, dosing, allowance for non-operative management, and the potential for over-treatment. Our objective here was to incorporate current evidence to develop a consensus-based institutional treatment algorithm to be used in the ambulatory and multidisciplinary team setting for the treatment of stage I–III rectal cancer. Full article

This study aims to investigate the effects of graphene oxide-modified titanium dioxide nanotube (TNT-GO) coatings on the biological behavior of Schwann cells and to evaluate their potential applications in dental implant surface modification and peripheral nerve regeneration. Titanium dioxide nanotubes (TNTs) were prepared by anodic oxidation, and graphene oxide (GO) was deposited on their surfaces by electrochemical deposition. The surface morphology and physicochemical properties were characterized by scanning electron microscopy (SEM), Raman spectroscopy, atomic force microscopy, X-ray diffraction, and contact angle measurements. The viability, proliferation, and adhesion of Schwann cells were assessed by cell counting kit-8 assay, live/dead staining, and SEM observation. The expression levels of nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF) were evaluated by immunofluorescence staining and real-time reverse-transcriptase polymerase chain reaction. The results indicated that TNT-GO surface significantly improved surface hydrophilicity and biocompatibility. Compared with the Ti and TNT groups, Schwann cells on TNT-GO surfaces exhibited enhanced proliferation, better spreading morphology, and significantly increased expression levels of NGF and GDNF. Overall, TNT-GO effectively promotes Schwann cell proliferation, adhesion, and neurotrophic factor secretion, suggesting its potential as a novel surface modification strategy to promote peri-implant nerve regeneration and improve osseoperception. Full article

In this study, TiO₂ nanotube (TNTs) array electrodes were fabricated by electrochemical anodization and subsequently modified through thermal annealing, hydrogenation heat treatment, and chemical decoration with copper species at various immersion times to enhance their electrochemical performance. The structural, morphological, semiconducting, and electrochemical properties of the modified nanotubes were systematically examined. FE-SEM and EDS analyses confirmed the formation of well-aligned TNTs and the successful deposition of copper species, with the most uniform surface distribution achieved for the sample decorated for 45 min. Raman spectroscopy and XRD results revealed that the anatase phase of TiO₂ remained stable after hydrogenation and copper decoration, while minor peak shifts indicated defect evolution and lattice distortion. Electrochemical evaluations, including linear sweep voltammetry, Tafel polarization, electrochemical impedance spectroscopy, and Mott–Schottky analysis, demonstrated a substantial enhancement in electrocatalytic activity following copper decoration. Compared with annealed and hydrogenated electrodes, the decorated samples exhibited markedly lower overpotentials, reduced cathodic Tafel slopes, and decreased charge-transfer resistance. Mott–Schottky analysis confirmed n-type semiconducting behavior for all electrodes, showing that hydrogenation increased donor density, whereas subsequent copper decoration slightly reduced it due to the partial substitution of oxygen vacancies by copper oxide species. Among all samples, the electrode decorated for 45 min (AA′HD45) exhibited the optimal balance between donor density, charge-transfer properties, and electrochemical performance. These results highlight the effectiveness of combining hydrogenation with optimized copper decoration to improve charge transport and interfacial kinetics in TNT electrodes for electrochemical applications. Full article

Developing membranes with superior antifouling properties is crucial for efficient and sustainable water treatment. In this study, polysulfone (PSM) composite membranes were fabricated by incorporating hydroxylated titanium nanotubes (TNT@OH) via the non-solvent-induced phase separation method. The hydroxylation of TNTs enhanced their dispersion in the polymer matrix and promoted strong polymer–nanoparticle interactions. Comprehensive characterization using FTIR, XRD, TGA, FESEM, and AFM confirmed the successful integration of TNT@OH, resulting in membranes with improved hydrophilicity, porosity, and thermal stability. The contact angle decreased from ~88° for neat PSM to ~50° at 7 wt% TNT@OH, while surface free energy increased significantly. Mechanical strength and flexibility were also enhanced at optimal TNT@OH loadings (3–5 wt%), owing to uniform dispersion and strong interfacial bonding. Filtration experiments using humic acid (HA) and natural organic matter (NOM) demonstrated remarkable improvements in water flux, rejection efficiency, and fouling resistance. The composite membranes achieved HA rejection rates of up to 98%, with reduced irreversible fouling and higher flux recovery ratios across multiple filtration–cleaning cycles. The proposed antifouling mechanism is attributed to the formation of a stable hydration layer by surface hydroxyl groups, which prevents foulant adhesion and facilitates cleaning. These findings suggest that incorporating TNT@OH into polysulfone membranes is a promising approach for developing high-performance ultrafiltration membranes with enhanced permeability, mechanical robustness, and long-term antifouling stability, thereby making them suitable for advanced water purification applications. Full article

Toxoplasma gondii, the causative agent of toxoplasmosis, a disease widely distributed, is an intracellular parasite that invades host cells of different tissues using specialized endocytic activity. Recent studies suggest that tunneling nanotubes (TNTs), thin cell-surface projections, may participate in the parasite–host cell interaction. Here we report results that suggest the involvement of host-cell TNTs in the adhesion of T. gondii tachyzoites to epithelial LLC-MK² cells. Microscopy analysis showed that incubating cells in a medium containing 0.45 M sucrose induces reversible assembly of TNTs without affecting cell viability. The presence of extended TNTs correlated with increased parasite adhesion and reduced parasite entry, thus suggesting a structural or signaling role in mediating adhesion. TNTs assembled following sucrose incubation contain both actin and tubulin components as determined by immunofluorescence microscopy. These results highlight a possible functional relevance of TNTs in T. gondii host cell interaction, especially in parasite adhesion, opening new perspectives for understanding T. gondii-host cell interaction. Full article

The protection of leaves from photoinhibition and berries from dehydration and sunburn has become an increasingly important objective in response to the rising frequency and intensity of heat waves worldwide. This research investigated the effect of a white nonwoven geotextile sheet (TNT) installed in the fruiting zone in the white cultivar ‘Verdicchio’ (Vitis vinifera L.) during critical summer periods with the aim of protecting leaves and berries from extreme heat. The study was conducted over two seasons (2020–2021) in a rainfed vineyard in central Italy using a randomized block design. Physiological and yield parameters were recorded. Vines protected with TNT did not show any changes in net photosynthesis, stomatal conductance, and water use efficiency, compared to unshielded vines. However, TNT reduced leaf temperature and increased berry total acidity and malic acid concentration while reducing sugar content, leading to wines with higher freshness and reduced alcohol levels. The use of TNTs shows significant potential as a practical tool for viticulturists to mitigate the effects of excessive heat, allowing for better management of berry ripening and ultimately improving final wine characteristics. Additionally, TNT is economically feasible, especially if applied only to the afternoon-exposed side of the canopy, and its cost can be amortized, especially in vineyards affected by frequent heat waves and/or dedicated to the production of premium wines. Full article

Background/Objectives: Total neoadjuvant therapy (TnT) has emerged as a treatment option for locally advanced rectal cancer. Few studies have evaluated specifically the use of chemotherapy and short-course radiation therapy (SCRT) in obtaining a complete clinical response (cCR) or near-complete clinical response (nCR) and offering non-operative management (NOM). This phase II study sequences FOLFOX followed by SCRT with the primary aim of evaluating the rate of cCR or nCR. Methods: Treatment-naïve adults with non-metastatic clinical T2-3N0 or T1-3 with N1-2a rectal adenocarcinoma deemed candidates for total mesorectal excision (TME) were eligible for this open-label, single-arm clinical trial. This trial evaluated TnT with 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) followed by SCRT. The primary endpoint was the rate of cCR or nCR. Those with cCR or nCR after TnT were offered NOM and close surveillance; all others underwent TME. Secondary endpoints included 1-year disease-free survival (DFS), overall survival (OS), and R0 surgical resection rate. Results: Twelve patients of a planned 40 were enrolled with a median follow-up duration of 4.1 years. The study was closed early after results of the OPRA trial suggested a benefit of sequencing radiation prior to chemotherapy when seeking organ preservation. Four of the twelve patients (33%, 95% CI = (9.9%, 65.1%)) achieved cCR or nCR after TnT and underwent NOM; one patient had local regrowth 5.5 months after the completion of TnT and underwent TME. All four were free of disease at time of analysis. The 1-year DFS was 100%. The median OS was not reached. All surgical resections were R0 with no local recurrence after TME. Conclusions: This paper suggests that TnT with FOLFOX followed by SCRT is a safe and effective approach for treating locally advanced rectal cancer. This approach can be considered in select patients. The 33% of patients offered NOM is lower than the published 74% in OPRA, however, suggesting that chemotherapy followed by SCRT may not be the most optimal approach if organ preservation is the primary treatment aim. Full article

Breast cancer brain metastasis (BCBM) affects up to 30% of patients with metastatic disease and carries a median survival of only 4–18 months. Emerging evidence reveals that BCBM cells are not passive survivors, but active participants that hijack core neurotransmitter networks, GABA (gamma-aminobutyric acid) and glutamate, to fuel their growth. BCBM, particularly triple-negative breast cancer (TNBC), frequently switch to a GABAergic mode utilizing brain-derived GABA as an oncometabolite. In parallel, BCBM cells can also form direct synapses with neurons, tapping into excitatory input through glutamatergic receptors to drive tumor cell proliferation and survival. Concurrently, reprogrammed astrocytes establish gap junctions, secrete growth factors, and provide metabolic support. Together, tumor cells, neurons, and astrocytes form a pathological partnership locked in feedback loops sustaining metastatic progression. This review focuses on the unique mechanisms employed by distinct breast cancer subtypes and maps the metastatic progression from pre-metastatic to mature brain metastatic niche formation of BCBM. We highlight opportunities to repurpose neurological drugs to disrupt these communication axes. Full article

Titanium and its alloys are widely used for orthopedic implants, but their intrinsic bioinertness may hinder osseointegration. In this study, titanium dioxide nanotube (TNT) arrays were fabricated on Ti-6Al-4V scaffolds via anodization, and their effects on the adhesion behavior of human bone marrow mesenchymal stem cells (hBMSCs) were investigated. Surface characterization showed that anodization successfully generated ordered TNT layers, increased surface roughness, enhanced protein adsorption, and induced an apparent superhydrophilic wetting response. Compared to the untreated scaffold and TNT50, the small-diameter TNT10 surface significantly promoted hBMSC adhesion and proliferation. Microscope imaging further revealed enhanced cell spreading, F-actin organization, and vinculin expression on TNT surfaces, with the most prominent focal adhesion-related staining observed in TNT10. Quantitative proteomic analysis showed that TNT10 was associated with coordinated remodeling of adhesion- and cytoskeleton-related molecular programs, including focal adhesion, cell–substrate junction, and regulation of the actin cytoskeleton. In contrast, TNT50, despite supporting obvious cytoskeletal remodeling, was more compatible with a dynamic, higher-turnover adhesion state. Overall, these findings suggest that small-diameter TNTs provide a more favorable interfacial microenvironment for stable early hBMSC adhesion on porous titanium scaffolds. Full article

Background/Objectives: Total neoadjuvant therapy (TNT), integrating systemic chemotherapy and radiotherapy before surgery or surveillance, has become a standard approach for locally advanced rectal cancer (LARC). However, optimal sequencing strategies and long-term outcomes of watch-and-wait (W&W) following sandwich TNT remain insufficiently characterized. We evaluated oncologic outcomes and treatment response in patients treated with an institutional sandwich TNT protocol. Methods: We conducted a retrospective cohort study of consecutive patients with LARC treated with sandwich TNT (induction chemotherapy followed by hypofractionated intensity-modulated radiotherapy with simultaneous integrated boost [IMRT-SIB] chemoradiotherapy and consolidation chemotherapy) at the Institute of Oncology Ljubljana between 2016 and 2023. The primary endpoint was an overall complete response (CR; pathological [pCR] and clinical [cCR]). Secondary endpoints included tumor regression grade (TRG), major pathological response (MPR), R0 resection rate, organ preservation, overall survival (OS), and disease-free survival (DFS). Results: Among 205 patients (median age 61 years), overall CR was 29.5% (pCR 19.3% and cCR 10.2%). Major pathological response (TRG 3–4) occurred in 37.6%. R0 resection was achieved in 94.5%. In the W&W cohort (n = 21), local regrowth occurred in 33.3% (95% CI, 14.6–57.0%) over a median follow-up of 4.96 years. Total mesorectal excision (TME)-free survival at 5 years was 73.1% (95% CI, 55.0–97.2%). Estimated 5-year OS was 81.1% (95% CI, 75.5–87.2%) and 5-year DFS was 75.2% (95% CI, 69.0–82.0). In multivariable analysis, non-R0 resection (HR 6.06, 95% CI, 1.99–18.42), MRI circumferential resection margin positivity (HR 3.11, 95% CI, 1.53–6.33), and MRI extramural vascular invasion positivity (HR 1.97, 95% CI, 1.05–3.91) remained independent predictors of DFS. Conclusions: Institutional sandwich TNT yields meaningful tumor response and durable survival in MRI-defined high-risk LARC. Structured W&W offers organ preservation with acceptable oncologic control under intensive surveillance. Full article

With the introduction of total neoadjuvant therapy (TNT) in locally advanced rectal cancer treatment, multidisciplinary treatment options have become more diverse than before, and many challenges remain unresolved. A randomized clinical study in intermediate-risk locally advanced rectal cancer showed that neoadjuvant full-dose systemic chemotherapy with response-adapted omission of radiation therapy is non-inferior to concurrent chemoradiotherapy. Given that preoperative systemic chemotherapy provides an additional layer of local disease control, the traditional role and extent of neoadjuvant radiation therapy could be strategically re-evaluated within the TNT framework. In this context, a risk-adapted approach featuring selective reduction in elective nodal irradiation volume, particularly of the lateral pelvic lymph nodes, may offer a promising middle ground for treatment personalization. Drawing parallels from surgical practice—where total mesorectal excision is standard but lateral pelvic lymph node dissection is reserved for selected cases—this perspective advocates for similar selectivity in radiation therapy targeting, focusing on mesorectal and presacral regions while judiciously omitting lateral nodes in appropriately selected patients. This approach could maintain oncologic safety by focusing radiation therapy on limited but essential volumes. With modern intensity-modulated radiation therapy, reducing the target volume translates directly to enhanced organs-at-risk sparing, thereby mitigating radiation-induced toxicity. When combined with induction chemotherapy response assessment to refine patient selection, this approach can offer a biologically informed, personalized treatment paradigm that balances disease control with quality of life. Full article

Vision Transformers (ViTs), owing to their strong capability in modeling global contextual dependencies, have been widely adopted in hyperspectral image unmixing (HU). However, standard ViTs process images by partitioning them into non-overlapping patches, which disrupts spatial continuity at the pixel level and neglects the fine-grained structural relationships among pixels within local regions. Consequently, effectively capturing the detailed spatial–spectral features required for accurate unmixing remains challenging. Furthermore, the high computational complexity of global self-attention and its sensitivity to noise limit the applicability of conventional Transformers to HU. To address these issues, we propose a spatial–spectral similarity guided Transformer-in-Transformer (SSTNT) framework. The proposed network adopts a modified TNT architecture, in which the inner Transformer employs a linear self-attention (LSA) mechanism to efficiently exploit pixel-level local features within sliding windows, while the outer Transformer preserves global attention to aggregate contextual information, thereby forming a cooperative local–global optimization scheme. Furthermore, a lightweight spatial–spectral similarity module is introduced to enhance the modeling of neighborhood structures. Finally, spectral reconstruction is achieved through a trainable endmember decoder and a normalized abundance estimation module. Extensive experiments conducted on both synthetic and real hyperspectral datasets demonstrate the effectiveness and robustness of the proposed method. Full article

Background: Total neoadjuvant therapy (TNT) is increasingly administered in rectal cancer, but compared with concurrent chemoradiotherapy (CRT), data regarding the gastrointestinal (GI) toxicity profile and clinical predictors remain limited. Objectives: To evaluate GI toxicity associated with TNT compared with CRT and to explore clinical predictors of these adverse events (AEs). Methods: This retrospective study included 201 patients with rectal cancer treated with TNT (n = 157) and CRT (n = 44). GI AEs (nausea, vomiting, diarrhea) were graded according to CTCAE v5.0. In the analysis of factors associated with GI AEs, multiple clinical and pathological variables were included using multivariable logistic regression. Results: The composite endpoint “any GI AEs grade ≥ 1” was more frequent in the TNT group compared with the CRT group (33.1% vs. 15.9%; RR = 2.08; 95% CI 1.02–4.25; p = 0.038). Nausea was significantly more frequent in the TNT group (28.7% vs. 9.1%; RR = 3.15; 95% CI 1.20–8.30; p = 0.012), whereas vomiting (9.6% vs. 2.3%; p = 0.203) and diarrhea (17.8% vs. 9.1%; p = 0.242) did not reach statistical significance. In multivariable logistic regression, TNT (OR = 2.65; 95% CI 1.08–6.53; p = 0.032) and female sex (OR = 2.03; 95% CI 1.05–3.77; p = 0.033) were identified as independent predictors of grade ≥ 1 GI AEs. For nausea, TNT remained significant (OR = 4.37; 95% CI 1.45–13.20; p = 0.0089). Upper rectal tumor location was significantly associated with vomiting (p = 0.0054). No grade 3–4 GI AEs were observed in either treatment group. Conclusions: TNT was associated with a higher incidence of mild GI AEs, predominantly driven by nausea, without an increase in severe toxicities. TNT and female sex were identified as independent clinical predictors of an increased risk of GI AEs, while tumor location in the upper third of the rectum was associated with a higher occurrence of vomiting. Full article