Search Results (23,450)

Tumor-infiltrating lymphocytes (TILs) are thought to play important roles in tumor shrinkage and survival prolongation in patients with breast cancer receiving neoadjuvant chemotherapy (NAC). TILs are mononuclear immune cells such as lymphocytes and plasma cells, including CD4+ and CD8+ T cells, natural killer cells, B cells, macrophages, regulatory T cells (Tregs), and myeloid/dendritic cells. The pre-NAC presence of more T cells and fewer Tregs in biopsy samples of primary breast tumors is known to contribute to tumor shrinkage and prolonged survival. This review was conducted to elucidate these roles in patients with breast cancer treated with NAC. Publications selected for inclusion in this review were identified by a PubMed search for articles published in English, performed using the terms “breast cancer”, “neoadjuvant chemotherapy”, “tumor-infiltrating lymphocyte”, “pathological complete response”, and “immune response”. The search was completed in July 2024. The functional roles of TILs in the achievement of these outcomes may vary by tumor subtype; increases and decreases in TIL levels before and after NAC have been shown to have conflicting effects. Biomarkers have been reported to predict local responses in the tumor microenvironment (e.g., immune-related gene signatures) and systemic immune responses (e.g., neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios). Immune gene signatures and immune cell infiltration do not appear to be universally associated with tumor response or outcome in patients with breast cancer treated with NAC. The functional roles of TILs in breast tumor response and breast cancer survival may vary by tumor subtype, and conflicting results for the same subtypes may be due to differences in NAC regimens, immune responses, tumor heterogeneity, sample size, and the technical methods used to evaluate TILs in tumor samples. Full article

Cryptococcus neoformans (C. neoformans) has emerged as a global pathogen of concern. While much is known about its pathobiology, its management is complicated by strains displaying non-fluconazole susceptibility. This contribution assessed the repurposing of artemisinin (ART) as an anti-Cryptococcus antifungal. An in vitro susceptibility assay was performed to assess the drug response of cells. To establish the ART mode of action, assays examining mitochondrial health were set up. The phagocytosis efficiency of a murine macrophage cell line towards ART-treated and non-treated cells was determined. To complement this, the immunomodulatory effects of ART were further characterised in Galleria mellonella (G. mellonella) by assessing haemocytes’ phagocytosis and expression of immune genes, i.e., insect metalloproteinase inhibitor (IMPI) and hemolin, essential for the insect antimicrobial response. In the end, the survival rate of infected larvae was calculated. We established that ART was antifungal, with cell death triggered by the uncoupling of the cytochrome c (cyt c) from the mitochondria, leading to activation of caspase-3-dependent-like apoptosis. Moreover, treatment induced ultrastructural changes with treated cells appearing more deformed than non-treated cells (p < 0.05). Treatment also increased the susceptibility of cells towards both macrophage and haemocyte phagocytosis compared to non-treated cells (p < 0.05). Importantly, treatment seemed to weaken the cells, decreasing their virulence potential based on analysis of the expression of the immune gene markers, which translated into treatment rescuing 75% of the larvae infected with 0.1 ART-treated cells. These preliminary findings support the repurposing of ART as an anti-Cryptococcus antifungal. Full article

Background: Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy. Complete tumor resection (R0) is critical for prognosis and may require multivisceral resection in locally advanced cases. However, data on outcomes after multivisceral resection for ACC remain limited. This study evaluates the perioperative and oncologic outcomes of patients undergoing multivisceral resection for suspected ACC. Methods: We retrospectively analyzed 21 patients who underwent multivisceral resection with curative intent for suspected ACC. Three were later diagnosed with other tumor entities (sarcoma, non-small cell lung carcinoma metastasis and ganglioneuroma). The remaining 18 patients with histologically confirmed ACC were compared with 19 patients who underwent isolated adrenalectomy during the same study period. Results: Patients undergoing multivisceral resection were significantly younger (p = 0.003), had larger (p < 0.001) and more advanced tumors according to ENSAT classification (p < 0.001). All but one had open surgery; laparoscopic or hybrid approaches were more common in the isolated adrenalectomy group. Multivisceral resections were associated with longer operative times (p = 0.002), all required an ICU admission (p < 0.001), and had longer hospital stays (p = 0.001). Lymphnode metastases were observed only in the multivisceral group (p = 0.002). No significant differences were found in complication rates (p = 0.081), resection status (p = 0.091), progression-free survival (p = 0.095), or overall survival (p = 0.71). Conclusions: Multivisceral resection is a safe and feasible approach in specialized centers and may achieve comparable oncologic outcomes to isolated adrenalectomy, even in patients with more advanced disease. It should be considered when R0 resection is required and technically achievable. Full article

Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by chronic joint inflammation. Its pathophysiology involves complex interactions among immune cells, leading to joint damage, primarily in the synovial membrane. MicroRNAs (miRs), single-stranded non-coding RNAs, play a critical role in regulating pathways affecting RA progression, particularly in fibroblast-like synoviocytes and peripheral blood mononuclear cells. Key pathways influenced by miRs include NF-κB, apoptosis, PI3K/AKT signaling, and cytokine production. Dysregulated miRs impact cell proliferation, survival, and inflammatory responses. This review explores not only the role of miRs in RA pathogenesis, but also highlights their potential as biomarkers for early detection and severity prediction. Moreover, therapeutic approaches targeting miRs, including mimics and inhibitors, show promise in animal models, with methods like intra-articular administration being favored due to better efficacy and reduced side effects. While early studies highlight potential pathways for RA treatment, challenges remain in translating these findings into safe and effective clinical therapies. Full article

Cholangiocarcinoma (CCA) is an aggressive malignancy of the biliary tract with rising global incidence and limited treatment options. Its pathogenesis involves a complex interplay of genetic mutations, epigenetic dysregulation, inflammatory signaling, and environmental influences. Emerging evidence highlights the pivotal role of the gut–liver axis and microbiota dysbiosis in shaping biliary homeostasis and disease progression. Alterations in microbial composition disrupt apoptosis and autophagy, two key processes regulating cell survival and death, thereby contributing to tumorigenesis, metastasis, and therapy resistance. Specific taxa, including Enterococcus, Escherichia coli, Pseudomonas, Bifidobacterium, and Bacillus, demonstrate strain-dependent effects, acting either as tumor promoters through genotoxic metabolites and immune evasion or as potential tumor suppressors by inducing apoptosis and immune activation. These findings underscore the context-dependent roles of microbiota in CCA biology. Importantly, microbiota modulation offers novel therapeutic opportunities. Dietary interventions such as probiotics, prebiotics, and nutritional strategies, alongside innovative microbiome-targeted therapies, hold promise for restoring microbial balance, enhancing antitumor immunity, and improving patient outcomes. This review integrates current molecular and microbiological evidence to propose the gut microbiota as both a biomarker and a therapeutic target in CCA, opening avenues for precision medicine approaches in hepatobiliary oncology. Full article

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that influence cancer progression via extracellular matrix (ECM) remodeling and secretion of growth factors and cytokines. Endothelial-to-mesenchymal transition (EndMT) is emerging as an important axis among the heterogeneous origins of CAFs. This review introduces the diverse methods used to induce EndMT in cancer—mouse tumor models, conditioned-medium treatment, co-culture, targeted gene perturbation, ligand stimulation, exosome exposure, irradiation, viral infection, and three-dimensional (3D) culture systems—and summarizes EndMT cell-type evidence uncovered using transcriptomic and proteomic technologies. Hallmark EndMT features include spindle-like morphology, increased motility, impaired angiogenesis and barrier function, decreased endothelial markers (CD31, VE-cadherin), and increased mesenchymal markers (α-SMA, FN1). Reported mechanisms include signaling via TGF-β, cytoskeletal/mechanical stress, reactive oxygen species, osteopontin, PAI-1, IL-1β, GSK-3β, HSP90α, Tie1, TNF-α, HSBP1, and NOTCH. Cancer-induced EndMT affects tumors and surrounding TME—promoting tumor growth and metastasis, expanding cancer stem cell-like cells, driving macrophage differentiation, and redistributing pericytes—and is closely associated with poor survival and therapy resistance. Finally, we indicate each study’s stance: some frame cancer-induced EndMT as a source of CAFs, whereas others, from an endothelial perspective, emphasize barrier weakening and promotion of metastasis. Full article

Circadian rhythms are endogenous ~24 h oscillations that regulate diverse biochemical processes. Although stress responses can exhibit circadian modulation, evidence for rhythmic regulation of stress granules (SGs)—cytoplasmic RNA–protein condensates formed under stress—remains limited. We investigated sodium arsenite-induced SG dynamics in NIH/3T3 cultures. SG number, eIF3 signal intensity—an established SG marker—and area oscillated with a period of ~24 h. These rhythms persisted in Bmal1^−/− mouse embryonic fibroblasts (MEFs), despite lacking a transcription–translation feedback loop (TTFL) that constitutes the canonical circadian clock, but with altered amplitude and phase, indicating partial dependence on the molecular clock. Several SG-associated RNA-binding proteins (TIA-1, BRF1, hnRNP Q, and LARK) exhibited time-dependent changes at the mRNA and/or protein level, suggesting potential mechanisms for rhythmic SG modulation. Unlike previous in vivo reports linking SG variation to eIF2α phosphorylation, no temporal changes in phosphorylated eIF2α were observed, highlighting differences between isolated cells and tissues. Our results show that SG rhythmicity can persist without BMAL1, supporting alternative oscillatory mechanisms that contribute to the temporal organization of stress responses. Given their role in cell survival and the association of SG dysfunction with disease, these rhythms provide insight into how cellular stress responses are temporally regulated. Full article

Background: p73, a member of the p53 family of transcription factors, plays important roles in DNA repair, cell proliferation, angiogenesis, invasion, metastasis, immune evasion, and cytotoxic therapy response. The clinicopathological significance of p73 in breast cancer, particularly in the context of TP53 mutation, remains largely unknown. Methods: Clinicopathological significance of p73 and p53 protein expression was evaluated in 1369 invasive BC and 317 ductal carcinomas in situ (DCIS), including in p53 wild-type or p53 mutant tumours. p73 transcripts and splice variants were investigated in breast cancer genomes (TCGA). Results: High cytoplasmic p73 was significantly associated with high tumour grades, high pleomorphism scores, high mitotic scores, high risk Nottingham prognostic index, negative expression of oestrogen receptors (ERs), triple negative phenotypes (all p values ≤ 0.01), and poor breast cancer specific survival (BCSS) (p = 0.013). In TP53 mutant breast cancers, high p73 was significantly associated with aggressive histopathological features (all p ≤ 0.001) and poor BCSS (p = 0.001) but not in p53 wild-type tumours. Conclusions: Cytoplasmic p73 may be a marker of aggressive phenotype and worse prognosis, particularly in p53 mutant breast cancer. p73, in conjunction with altered p53 expression, may be involved in breast cancer pathogenesis. Full article

Background/Objectives: Colorectal neuroendocrine carcinomas (NECs) are rare, aggressive tumors with poorly defined clinicopathologic and molecular features. Their biological behavior and optimal treatment strategies remain unclear. Additionally, a subset of anorectal NECs may be associated with high-risk human papillomavirus (HPV) infection, suggesting potential heterogeneity in pathogenesis. Methods: We retrospectively reviewed 12 cases of colorectal NECs. Clinical outcomes, histologic morphology, immunohistochemistry, molecular profiling, including common oncogenic mutations, and HPV status were analyzed. Results: Seven cases demonstrated small cell NECs, and five showed large cell NECs. The majority of NECs (n = 9) arose in the rectum. TP53 mutations were the most common (75%), followed by KRAS, RB1, FBXW7, and BRAF mutations. One case demonstrated mismatch repair (MMR) deficiency. High-risk HPV was detected in one rectal NEC, which lacked common oncogenic mutations and was the only long-term survivor (54 months). p16 expression did not correlate consistently with HPV in situ hybridization (ISH) status. Among small cell NECs with follow-up, platinum-based chemotherapy resulted in significantly longer survival than FOLFOX (13.5 vs. 4 months, p = 0.0209). Conclusions: Colorectal NECs display histologic and molecular heterogeneity. The tumors of small cell NECs potentially benefit more from platinum-based chemotherapy. HPV-associated NECs may represent a distinct subset with better prognosis, but p16 is not a reliable surrogate marker. Routine subclassification into small vs. large cell types and comprehensive molecular profiling, including HPV testing, may aid clinical decision-making and prognostication. Full article

Introduction: Renal cell carcinoma (RCC) develops metastatic disease in 30–50% of patients during their disease course, with approximately one quarter presenting with metastases at diagnosis. While the lungs, liver, bones, brain, and adrenal glands are the most frequent metastatic sites, duodenal involvement is exceptionally rare. This uncommon presentation poses diagnostic and therapeutic challenges, particularly regarding the role of surgical resection in the metastatic setting. Objective: We aim to evaluate the clinical presentation, management strategies, and outcomes of patients with duodenal metastasis from RCC, with particular emphasis on the potential role of surgery, through a systematic review of the literature. Methods: A comprehensive electronic search of Medline, Embase, and Scopus was conducted according to PRISMA guidelines. The following MeSH terms were applied: Kidney Neoplasms [MeSH] AND Duodenal Neoplasms/metastasis [MeSH]. Eligible studies included original reports or case series describing RCC with duodenal metastasis. Demographic, clinical, surgical, and survival data were extracted and synthesized. Results: Of 89 records identified, 83 underwent full-text review and 51 met inclusion criteria, representing 55 patients. The median age at diagnosis was 64 years, and 80% of primary tumors arose from the right kidney. Nearly all patients (98%) were symptomatic, most commonly with upper gastrointestinal bleeding, anemia, or obstructive features. Pancreaticoduodenectomy was the predominant surgical approach, performed with curative intent in selected cases. Patients undergoing surgery achieved a 5-year overall survival of 70%, compared with 0% among non-operated patients. Conclusions: Duodenal metastasis from RCC remains an uncommon entity, limiting the strength of available evidence. Nevertheless, our findings suggest that surgical management—when feasible and decided within a multidisciplinary framework—can provide meaningful survival benefit and should be considered as a complement to contemporary systemic therapies for metastatic RCC Full article

Oxidative stress (OxS) is a central factor in neurodegenerative diseases (NDs), including Parkinson’s disease (PD). Phenolic compounds, including flavonoids and coumarins, counteract reactive species and modulate key intracellular survival pathways, highlighting their therapeutic potential. Parastrephia quadrangularis (Pq), a plant from the Atacama Desert traditionally used by Andean communities, contains phenolic compounds with antioxidant, antifungal, and anti-inflammatory activities. However, its neuroprotective potential remains unexplored. Here, a hydroalcoholic extract (HAE) of Pq and four subfractions (MeOH, EtOAc, DCM, and n-hex) were obtained and assessed for in vitro antioxidant activity, with HAE selected for its consistent activity. In SH-SY5Y cells, HAE-Pq lowered basal reactive oxygen species and attenuated hydrogen peroxide-induced OxS. The UHPLC-MS analysis of HAE-Pq unveiled a high abundance of flavonoids, followed by coumarins and phenolic acids, and identified 16 additional metabolites, including jaceidin as the most abundant. In vivo assays using a Drosophila genetic PD model induced by overexpression of human α-synuclein, showed that HAE-Pq was non-toxic and non-aversive and that it delayed the onset of motor defects by one week in female flies. This study provides the first evidence of the neuroprotective potential of Pq, supporting its value as a source of bioactive metabolites relevant to NDs and reinforcing its ethnopharmacological validation. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by its aggressive clinical behavior and intricate microenvironment regulation, leading to dismal prognosis. Elucidating the molecular mechanisms underlying PDAC pathogenesis is crucial for developing improved therapeutic approaches. The functional significance and molecular basis of transcobalamin 1 (TCN1) in PDAC remain largely unexplored. Methods and Results: Through integrated analysis of TCGA and GTEx datasets combined with 80 clinical specimens, we identified significant TCN1 overexpression in PDAC, showing a positive association with tumor stage and negative associations with histological differentiation and overall survival. Functional investigations showed that TCN1 enhanced pancreatic cancer cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) in both in vitro and in vivo models. Mechanistically, TCN1 physically interacts with signal transducer and activator of transcription 4 (STAT4) to enhance its transcriptional activity. Chromatin immunoprecipitation (ChIP) assays showed that STAT4-mediated transcriptional activation of dual oxidase 2 (DUOX2) occurs through direct promoter binding. As a pivotal reactive oxygen species (ROS)-generating enzyme, DUOX2 overexpression elevates intracellular ROS levels, thereby promoting EMT progression and activating proliferation-related signaling cascades. Antioxidant treatment effectively abrogated TCN1-driven oncogenic phenotypes, establishing ROS as the critical downstream mediator. Conclusions: Collectively, our findings reveal a novel TCN1/STAT4/DUOX2 regulatory axis that exacerbates PDAC progression by remodeling redox homeostasis. This signaling cascade may serve as a prognostic biomarker and a potential therapeutic target for ROS-directed precision therapy in PDAC. Full article

Malignant pericardial effusion (MPE) is a life-threatening condition in patients with cancer, with common recurrences after simple pericardiocentesis. Consequently, the intrapericardial instillation of sclerosing or cytotoxic agents has been explored, with limited evidence from small studies with different methodologies. We undertook an observational, retrospective, single-centre study, including all patients diagnosed with a solid neoplasm and clinically significant and/or recurrent, cytology-confirmed MPE, treated with Intrapericardial Instillation of Cisplatin (IPIC), between 2009 and 2022. Patients with hematological malignancies were excluded. The procedure followed a multidisciplinary approach and a standardized protocol. Variables collected included baseline patient characteristics, neoplasm details, MPE impact, adverse events (AEs) from procedures (pericardiocentesis and IPIC) and outcomes (time to MPE recurrence and survival). This study adhered to the STROBE guidelines. A total of 41 patients were included, 51% female, with a median age of 61 (51–69) years. Non-small cell lung cancer (NSCLC) was the predominant primary tumour (78%) and in 44% of the cohort, MPE was identified at cancer diagnosis. Most patients (90.2%) presented symptoms related to MPE at diagnosis, and 88% had cardiac tamponade on echocardiography. IPIC was administered a median of four times. IPIC-related AEs occurred in 10 patients (24.4%), with transient atrial fibrillation (AF) being the most frequent one. Two patients (4.9%) experienced MPE recurrence within 30 days after IPIC. The median survival time from MPE diagnosis was 161 days (5.4 months; IQR 73–455 days). IPIC appears to be a feasible, effective and safe option for reducing the risk of MPE recurrence, mainly in NSCLC. Full article

Allergic contact dermatitis (ACD) is a common inflammatory skin disease induced by exposure of the skin to contact allergens. Classically, ACD is defined as a delayed-type (type IV) hypersensitivity reaction mediated by allergen-specific T cells, with symptoms peaking 48–72 h after exposure to the contact allergen. This delayed response to the contact allergen is seen during patch testing, where allergen-naïve, unaffected skin of allergic individuals is exposed to the contact allergen. However, in daily life and in certain occupational settings, allergic individuals often experience rapid flare-ups/exacerbations with intensely itching erythema, oedema, and often vesicles within hours after re-exposure to the specific contact allergen. These rapid flare-ups only develop at skin sites previously exposed to the contact allergen. Thus, it is important to distinguish between the rapid-onset reaction typically experienced by the allergic individual and the delayed-type reaction typically seen after patch testing. This review summarizes current insights into the immunopathology of rapid- versus delayed-type ACD reactions and outlines potential therapeutic opportunities, as well as their current limitations, against rapid-onset ACD, including modulation of cytokine signaling, T cell survival, checkpoint pathways, and redox balance. Full article

Background: Small cell lung cancer (SCLC) is a malignant carcinoma characterized by high proliferative rate and early metastatization with limited treatment options and poor prognosis. The approval of ICIs has established a new standard of care for extensive-stage (ES)-SCLC (5). Atezolizumab, an anti PD-L1 monoclonal antibody, has been the first immune checkpoint inhibitor (ICI) to be approved for SCLC patients. This study aims to retrospectively evaluate the real-world effectiveness and safety of atezolizumab in a cohort of patients with ES-SCLC. Methods: We conducted a monocentric retrospective analysis of SCLC patients who received atezolizumab in addition to chemotherapy, between January 2020 and December 2023. Study design endpoints included progression-free survival (PFS), overall survival (OS), and adverse events. Results: A total of 134 patients were included in this study. Out of 134 patients who began the CEA protocol, 100 continued maintenance. Currently, 25 are alive, 17 still on atezolizumab, 5 on second-line therapy, and 3 receiving best supportive care. The median age was 65 years. Patients received a median of four cycles of CEA (range 1–6 cycles), while the median number of atezolizumab maintenance cycles was eight (range 0–75). The overall median survival was 15 months, with patients who received more than 30 cycles of atezolizumab showing OS of 46.7% at 48 months. Common adverse events included skin disorders, pneumonitis, colitis, alanine, and aspartate deaminase increment, dysthyroidism, and blood disorders with only 3% of patients experiencing grade 3 or higher toxicities. Conclusions: In this real-world cohort, atezolizumab demonstrated comparable effectiveness to clinical trial results, with a manageable safety profile. These findings support the use of atezolizumab as a viable treatment option for ES-SCLC in routine clinical practice. Full article