Search Results (9)

Cell wall invertases (CINs) establish sucrose gradients between source and sink tissues, essential for the allocation of photoassimilates. Rice possesses nine CIN genes, among which OsCIN1 and OsCIN2 have been reported as key regulators of sink strength. To test whether increasing CIN activity enhances grain yield, we generated OsCIN1 overexpression lines in rice driven by the CaMV 35S promoter. Subcellular localization analysis of OsCIN1–GFP confirmed its apoplastic localization. OsCIN1 promoter::GUS analyses verified expression in vascular tissues and revealed predominant signals in the ovular vascular and lateral stylar vascular traces during seed development. Although CIN activity was markedly elevated throughout the plant, the resulting phenotypes were unexpected. Sugar profiling of flag leaves at the flowering stage showed almost complete sucrose depletion in the overexpression (OX) lines, accompanied by increased hexose and starch accumulation. Under field conditions, OsCIN1 OX plants exhibited ~50% fewer tillers and a lower 1000-grain weight relative to wild type (WT), resulting in reduced productivity. Ectopic expression of OsCIN1 disrupted the sucrose concentration gradient, weakened carbon partitioning to sink tissues, and impaired key agronomic traits. Collectively, sugar flux is governed by the spatiotemporal patterning of CINs, highlighting that precise spatial and temporal control of CIN activity is required to increase yield. Full article

Cervical cancer ranks third among malignant diseases of the female reproductive system and progressively develops through a series of pathological changes known as cervical intraepithelial neoplasia (CIN). Despite being extremely aggressive and causing increased mortality, the main treatment options include surgery or a combination of chemotherapy and radiotherapy, often based on cisplatin-based chemotherapy and external beam radiotherapy or brachytherapy. Cervical dysplasia is an abnormal growth of cells on the surface of the cervix that could lead to cervical cancer. CIN most commonly occurs at the squamocolumnar junction of the cervix, a transitional zone between the squamous epithelium of the vagina and the columnar epithelium of the endocervix. The primary cause of CIN is chronic infection of the cervix with Human Papillomavirus (HPV). Oxidative stress (OS) and chronic inflammation are associated with HPV-induced cervical dysplasia. Reactive oxygen species (ROS) facilitate the progression of CIN through DNA damage, immune evasion, and cellular mutations. Thus, the inflammatory environment, characterized by increased expression of proinflammatory cytokines, contributes to epithelial transformation. Given these mechanisms, antioxidants, including vitamins A, C, D, E, polyphenols, and carotenoids, are being investigated for their potential as adjunctive therapies in CIN management. This review aims to provide a comprehensive analysis of the influence of oxidative stress, antioxidants, and inflammation on cervical cancer. Full article

Background/Objectives: Gastric cancer (GC) is a highly aggressive malignancy with diverse molecular subtypes. While microsatellite instability (MSI) GC generally carries a favorable prognosis, a subset of patients experiences poor outcomes, highlighting the need for refined prognostic markers. Methods: This study utilized transcriptomic and clinical data from two independent cohorts, The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG), to identify novel prognostic genes in MSI-GC. Results: Through rigorous survival analysis, we identified high MAP4K4 expression (MAP4K4^high) as an independent and robust predictor of poor overall survival (OS) and disease-free survival (DFS) specifically within the MSI-GC subtype. MAP4K4^high was associated with increased hazard ratios for both OS and DFS in both cohorts, even after adjusting for clinicopathological factors. Further analysis revealed that MAP4K4^high MSI-GC tumors exhibit a distinct molecular profile characterized by increased extracellular matrix remodeling, epithelial–mesenchymal transition, and a microenvironment enriched in monocytes and cancer-associated fibroblasts (CAFs). Notably, a subgroup of MSI-GC patients with a CIN-like phenotype and high MAP4K4 expression exhibited particularly dismal outcomes. Conclusions: Our findings establish MAP4K4 as a promising prognostic biomarker for risk stratification in MSI-GC and suggest its potential role in driving aggressive tumor behavior through modulation of the tumor microenvironment. Full article

Lung adenocarcinoma (LUAD) exhibits significant molecular heterogeneity; however, previous studies have not fully explored its classification into distinct molecular subtypes. Here, we identified LUAD-significant chromosomal instability (CIN) phenotype genes (n = 24) using a TCGA-LUAD cohort (n = 592) and evaluated their ability to predict pathologic grade. Unsupervised clustering and principal component analysis revealed that LUAD patients could be classified into CIN phenotype-related subtypes (Group^Low, Group^Moderate, and Group^High), each exhibiting distinct transcriptomic patterns. Notably, the Group^High showed significantly poor overall survival [OS; hazard ratio (HR) = 1.43, p-value < 10⁻³] and disease-free survival (DFS; HR = 1.27, p-value < 10⁻³). Univariate and multivariate analysis confirmed that its expression status was an independent prognostic predictor (p-value < 10⁻³, HR = 2.18, 95% C.I = 1.26–3.76) of the clinical outcomes, outperforming pathologic grade (p-value < 10⁻³, HR = 1.2, 95% C.I = 1.08–1.33). Moreover, analysis of surfactant metabolism-related genes revealed higher expression in the Group^Low, which was associated with a favorable prognosis. By integrating multiple independent cohorts (n = 779), we validated these findings and confirmed that CIN phenotype gene status serves as a critical prognostic marker in LUAD. Furthermore, genomic profiling showed that the Group^High exhibited frequent mutations in key genes such as KEAP1, LYST, SETD2, and TP53, with oncogenes in this group preferentially showing copy number gains. Our study highlights the significance of CIN phenotype gene status as a predictor of LUAD prognosis and its association with transcriptomic and genomic alterations, paving the way for further clinical validation and potential therapeutic interventions. Full article

Efficient sucrose transport and metabolism are vital for seed and pollen development in plants. Cell wall invertases (CINs) hydrolyze sucrose into glucose and fructose, maintaining a sucrose gradient in the apoplast of sink tissues. In rice, two CIN isoforms, OsCIN1 and OsCIN2, were identified as being specifically expressed in the anthers but not in pollen. Functional analyses through genetic crosses and mutant characterization showed that oscin1/2 double mutants exhibit a sporophytic male-sterile phenotype and produce shrunken seeds. This suggests that CIN activity is essential for proper pollen development and seed formation in rice. Observation of the progeny genotypes and phenotypes from various genetic crosses revealed that the phenotype of oscin1/2 seeds is determined by the genotype of the maternal tissue, indicating the critical role of CIN function in the apoplast between maternal and filial tissues for sucrose transport and metabolism. The CIN activity in the anthers and seeds of wild-type rice was found to be significantly higher—over 500-fold in the anthers and 5-fold in the seeds—than in the leaves, highlighting the importance of CIN in facilitating the efficient unloading of sucrose. These findings suggest that the fine-tuning of CIN activity in the apoplast, achieved through tissue-specific expression and CIN isoform regulation, plays a key role in determining the carbohydrate distribution across different tissues. Understanding this regulatory mechanism could provide opportunities to manipulate carbohydrate allocation to sink organs, potentially enhancing crop yields. Full article

Colorectal cancer (CRC) is one of the most common and severe malignancies worldwide. Recent advances in diagnostic methods allow for more accurate identification and detection of several molecular biomarkers associated with this cancer. Nonetheless, non-invasive and effective prognostic and predictive testing in CRC patients remains challenging. Classical prognostic genetic markers comprise mutations in several genes (e.g., APC, KRAS/BRAF, TGF-β, and TP53). Furthermore, CIN and MSI serve as chromosomal markers, while epigenetic markers include CIMP and many other candidates such as SERP, p14, p16, LINE-1, and RASSF1A. The number of proliferation-related long non-coding RNAs (e.g., SNHG1, SNHG6, MALAT-1, CRNDE) and microRNAs (e.g., miR-20a, miR-21, miR-143, miR-145, miR-181a/b) that could serve as potential CRC markers has also steadily increased in recent years. Among the immunohistochemical (IHC) proliferative markers, the prognostic value regarding the patients’ overall survival (OS) or disease-free survival (DFS) has been confirmed for thymidylate synthase (TS), cyclin B1, cyclin D1, proliferating cell nuclear antigen (PCNA), and Ki-67. In most cases, the overexpression of these markers in tissues was related to worse OS and DFS. However, slowly proliferating cells should also be considered in CRC therapy (especially radiotherapy) as they could represent a reservoir from which cells are recruited to replenish the rapidly proliferating population in response to cell-damaging factors. Considering the above, the aim of this article is to review the most common proliferative markers assessed using various methods including IHC and selected molecular biology techniques (e.g., qRT-PCR, in situ hybridization, RNA/DNA sequencing, next-generation sequencing) as prognostic and predictive markers in CRC. Full article

The objective of this research is to evaluate cervical regeneration after large loop excision of the transformation zone (LLETZ) through the identification of a new sonographic reference point at the level of the uterine margins. In the period March 2021–January 2022, a total of 42 patients affected by CIN 2–3 were treated with LLETZ at the University Hospital of Bari (Italy). Before performing LLETZ, cervical length and volume were measured with trans-vaginal 3D ultrasound. From the multiplanar images, the cervical volume was obtained using the Virtual Organ Computer-aided AnaLysis (VOCAL™) program with manual contour mode. The line that connects the points where the common trunk of the uterine arteries reaches the uterus splitting into the ascending major branch and the cervical branch was considered as the upper limit of the cervical canal. From the acquired 3D volume, the length and the volume of the cervix were measured between this line and the external uterine os. Immediately after LLETZ, the removed cone was measured using Vernier’s caliper, and before fixation in formalin, the volume of the excised tissue was evaluated by the fluid displacement technique based on the Archimedes principle. The proportion of excised cervical volume was 25.50 ± 17.43%. The volume and the height of the excised cone were 1.61 ± 0.82 mL and 9.65 ± 2.49 mm corresponding to 14.74 ± 11.91% and 36.26 ± 15.49% of baseline values, respectively. The volume and length of the residual cervix were also assessed using 3D ultrasound up to the sixth month after excision. At 6 weeks, about 50% of cases reported an unchanged or lower cervical volume compared to the baseline pre-LLETZ values. The average percentage of volume regeneration in examined patients was equal to 9.77 ± 55.33%. In the same period, the cervical length regeneration rate was 69.41 ± 14.8%. Three months after LLETZ, a volume regeneration rate of 41.36 ± 28.31% was found. For the length, an average regeneration rate of 82.48 ± 15.25% was calculated. Finally, at 6 months, the percentage of regeneration of the excised volume was 90.99 ± 34.91%. The regrowth percentage of the cervical length was 91.07 ± 8.03%. The cervix measurement technique that we have proposed has the advantage of identifying an unequivocal reference point in 3D cervical measurement. Ultrasound 3D evaluation could be useful in the clinical practice to evaluate the cervical tissue deficit and express the “potential of cervical regeneration” as well as provide the surgeon useful information about the cervical length. Full article

Hodgkin’s lymphoma carries an excellent prognosis with modern chemotherapy, but a significant proportion of patients remain refractory to or relapse after first-line treatment. Immunological changes post-treatment, such as chemotherapy-induced neutropenia (CIN) or lymphopenia, have shown prognostic significance in multiple tumor types. Our study aims to investigate the prognostic value of immunologic changes in Hodgkin’s lymphoma by examining the post-treatment lymphocyte count (pALC), neutrophil count (pANC) and the neutrophil-lymphocyte ratio (pNLR). Patients treated for classical Hodgkin’s lymphoma at the National Cancer Centre Singapore using ABVD-based regimens were retrospectively analyzed. An optimal cut-off value for high pANC, low pALC and high pNLR in predicting progression-free survival was determined by receiver operating curve analysis. Survival analysis was performed using the Kaplan–Meier method and multivariable Cox proportional models. Overall OS and PFS were excellent, with a 5-year OS of 99.2% and a 5-year PFS of 88.2%. Poorer PFS was associated with high pANC (HR 2.99, p = 0.0392), low pALC (HR 3.95, p = 0.0038) and high pNLR (p = 0.0078). In conclusion, high pANC, low pALC and high pNLR confer a poorer prognosis for Hodgkin’s lymphoma. Future studies should evaluate the potential of improving treatment outcomes by the adjustment of chemotherapy dose intensity based on post-treatment blood counts. Full article

Ongoing chromosomal instability in neoplasia (CIN) generates intratumor genomic heterogeneity and limits the efficiency of oncotherapeutics. Neoplastic human cells utilizing the alternative lengthening of telomeres (ALT)-pathway, display extensive structural and numerical CIN. To unravel patterns of genome evolution driven by oncogene-replication stress, telomere dysfunction, or genotoxic therapeutic interventions, we examined by comparative genomic hybridization five karyotypically-diverse outcomes of the ALT osteosarcoma cell line U2-OS. These results demonstrate a high tendency of the complex cancer genome to perpetuate specific genomic imbalances despite the karyotypic evolution, indicating an ongoing process of genome dosage maintenance. Molecular karyotyping in four ALT human cell lines showed that mitotic cells with low levels of random structural CIN display frequent evidence of whole genome doubling (WGD), suggesting that WGD may protect clonal chromosome aberrations from hypermutation. We tested this longstanding hypothesis in ALT cells exposed to gamma irradiation or to inducible DNA replication stress under overexpression of p21. Single-cell cytogenomic analyses revealed that although polyploidization promotes genomic heterogeneity, it also protects the complex cancer genome and hence confers genotoxic therapy resistance by generating identical extra copies of driver chromosomal aberrations, which can be spared in the process of tumor evolution if they undergo unstable or unfit rearrangements. Full article