Characterization of innate lymphoid cell subsets infiltrating melanoma and epithelial ovarian tumors.

The innate lymphoid cell (ILC) family is composed of heterogeneous innate effector and helper immune cells that preferentially reside in tissues where they promote tissue homeostasis. In cancer, they have been implicated in driving both pro- and anti-tumor responses. This apparent dichotomy highlights the need to better understand differences in the ILC composition and phenotype within different tumor types that could drive seemingly opposite anti-tumor responses. Here, we characterized the frequency and phenotype of various ILC subsets in melanoma metastases and primary epithelial ovarian tumors. We observed high PD-1 expression on ILC subsets isolated from epithelial ovarian tumor samples, while ILC populations in melanoma samples express higher levels of LAG-3. In addition, we found that the frequency of cytotoxic ILCs and NKp46+ILC3 in tumors positively correlates with monocytic cells and conventional type 2 dendritic cells, revealing potentially new interconnected immune cell subsets in the tumor microenvironment. Consequently, these observations may have direct relevance to tumor microenvironment composition and how ILC subset may influence anti-tumor immunity.

IL-6 regulates epithelial ovarian cancer EMT, invasion, and metastasis by modulating Let-7c and miR-200c through the STAT3/HIF-1α pathway.

Interleukin-6 (IL-6) and hypoxia-inducible factor-1α (HIF-1α) play important roles in epithelial-mesenchymal transformation (EMT) and tumor development. Previous studies have demonstrated that IL-6 promotes EMT, invasion, and metastasis in epithelial ovarian cancer (EOC) cells by activating the STAT3/HIF-1α pathway. MicroRNA (miRNA) is non-coding small RNAs that also play an important role in tumor development. Notably, Let-7 and miR-200 families are prominently altered in EOC. However, whether IL-6 regulates the expression of Let-7 and miR-200 families through the STAT3/HIF-1α signaling to induce EMT in EOC remains poorly understood. In this study, we conducted in vitro and in vivo investigations using two EOC cell lines, SKOV3, and OVCAR3 cells. Our findings demonstrate that IL-6 down-regulates the mRNA levels of Let-7c and miR-200c while up-regulating their target genes HMGA2 and ZEB1 through the STAT3/HIF-1α signaling in EOC cells and in vivo. Additionally, to explore the regulatory role of HIF-1α on miRNAs, both exogenous HIF blockers YC-1 and endogenous high expression or inhibition of HIF-1α can be utilized. Both approaches can confirm that the downstream molecule HIF-1α inhibits the expression and function of Let-7c and miR-200c. Further mechanistic research revealed that the overexpression of Let-7c or miR-200c can reverse the malignant evolution of EOC cells induced by IL-6, including EMT, invasion, and metastasis. Consequently, our results suggest that IL-6 regulates the expression of Let-7c and miR-200c through the STAT3/HIF-1α pathway, thereby promoting EMT, invasion, and metastasis in EOC cells.

Key players of immunosuppression in epithelial malignancies: Tumor-infiltrating myeloid cells and γδ T cells.

BACKGROUND: The tumor microenvironment of solid tumors governs the differentiation of otherwise non-immunosuppressive macrophages and gamma delta (γδ) T cells into strong immunosuppressors while promoting suppressive abilities of known immunosuppressors such as myeloid-derived suppressor cells (MDSCs) upon infiltration into the tumor beds. RECENT FINDINGS: In epithelial malignancies, tumor-associated macrophages (TAMs), precursor monocytic MDSCs (M-MDSCs), and gamma delta (γδ) T cells often acquire strong immunosuppressive abilities that dampen spontaneous immune responses by tumor-infiltrating T cells and B lymphocytes against cancer. Both M-MDSCs and γδ T cells have been associated with worse prognosis for multiple epithelial cancers. CONCLUSION: Here we discuss recent discoveries on how tumor-associated macrophages and precursor M-MDSCs as well as tumor associated-γδ T cells acquire immunosuppressive abilities in the tumor beds, promote cancer metastasis, and perspectives on how possible novel interventions could restore the effective adaptive immune responses in epithelial cancers.

Autoimmunity in thymic epithelial tumors: a not yet clarified pathologic paradigm associated with several unmet clinical needs.

Thymic epithelial tumors (TETs) are rare mediastinal cancers originating from the thymus, classified in two main histotypes: thymoma and thymic carcinoma (TC). TETs affect a primary lymphoid organ playing a critical role in keeping T-cell homeostasis and ensuring an adequate immunological tolerance against "self". In particular, thymomas and not TC are frequently associated with autoimmune diseases (ADs), with Myasthenia Gravis being the most common AD present in 30% of patients with thymoma. This comorbidity, in addition to negatively affecting the quality and duration of patients' life, reduces the spectrum of the available therapeutic options. Indeed, the presence of autoimmunity represents an exclusion criteria for the administration of the newest immunotherapeutic treatments with checkpoint inhibitors. The pathophysiological correlation between TETs and autoimmunity remains a mystery. Several studies have demonstrated the presence of a residual and active thymopoiesis in adult patients affected by thymomas, especially in mixed and lymphocytic-rich thymomas, currently known as type AB and B thymomas. The aim of this review is to provide the state of art in regard to the histological features of the different TET histotype, to the role of the different immune cells infiltrating tumor microenvironments and their impact in the break of central immunologic thymic tolerance in thymomas. We discuss here both cellular and molecular immunologic mechanisms inducing the onset of autoimmunity in TETs, limiting the portfolio of therapeutic strategies against TETs and greatly impacting the prognosis of associated autoimmune diseases.

Diagnosing and staging epithelial ovarian cancer by serum glycoproteomic profiling.

BACKGROUND: There is a need for diagnostic tests for screening, triaging and staging of epithelial ovarian cancer (EOC). Glycoproteomics of blood samples has shown promise for biomarker discovery. METHODS: We applied glycoproteomics to serum of people with EOC or benign pelvic masses and healthy controls. A total of 653 analytes were quantified and assessed in multivariable models, which were tested in an independent cohort. Additionally, we analyzed glycosylation patterns in serum markers and in tissues. RESULTS: We identified a biomarker panel that distinguished benign lesions from EOC with sensitivity and specificity of 83.5% and 90.1% in the training set, and of 86.7 and 86.7% in the test set, respectively. ROC analysis demonstrated strong performance across a range of cutoffs. Fucosylated multi-antennary glycopeptide markers were higher in late-stage than in early-stage EOC. A comparable pattern was found in late-stage EOC tissues. CONCLUSIONS: Blood glycopeptide biomarkers have the potential to distinguish benign from malignant pelvic masses, and early- from late-stage EOC. Glycosylation of circulating and tumor tissue proteins may be related. This study supports the hypothesis that blood glycoproteomic profiling can be used for EOC diagnosis and staging and it warrants further clinical evaluation.

The evaluation of miR-1181 and miR-4314 as serum microRNA biomarkers for epithelial ovarian cancer diagnosis and prognosis.

AIM: Epithelial ovarian cancer (EOC) is the most ominous tumor of gynecological cancers due to its poor early detection rate and unfavorable prognosis. To date, there is no reliable screening method for the diagnosis of ovarian cancer at an early stage. MiRNAs are small non-coding RNA molecules, and their main function is to regulate gene expression. The present study compared the serum miR-1181 and miR-4314 levels in patients with EOC and healthy controls to measure the diagnostic and prognostic value as candidate biomarkers. MATERIALS AND METHODS: We collected serum samples from a total of 135 participants (69 patients with EOC and 66 healthy controls). Relative expressions of miR-1181 and miR-4314 were measured by quantitative real-time polymerase chain reaction assay (qPCR). RESULTS: The present study revealed that both serum miR-1181 and miR-4314 levels in patients with EOC were significantly increased compared to healthy controls for each marker. In addition, there was a significant relationship between miR-1181 and miR-4314 overexpressions and the stage and prognosis of the disease. Finally, patients with high expression levels of miR-1181 and miR-4314 had significantly shorter survival rates than those with low expression levels. CONCLUSION: The current study proposed that serum miR-1181 and miR-4314 could discriminate the EOC patients from healthy controls. In addition, both miR-1181 and miR-4314 may be predictive biomarkers for ovarian cancer prognosis. Further studies are needed to confirm the findings of the present study.

Global epidemiology of epithelial ovarian cancer.

Globally, ovarian cancer is the eighth most common cancer in women, accounting for an estimated 3.7% of cases and 4.7% of cancer deaths in 2020. Until the early 2000s, age-standardized incidence was highest in northern Europe and North America, but this trend has changed; incidence is now declining in these regions and increasing in parts of eastern Europe and Asia. Ovarian cancer is a very heterogeneous disease and, even among the most common type, namely epithelial ovarian cancer, five major clinically and genetically distinct histotypes exist. Most high-grade serous ovarian carcinomas are now recognized to originate in the fimbrial ends of the fallopian tube. This knowledge has led to more cancers being coded as fallopian tube in origin, which probably explains some of the apparent declines in ovarian cancer incidence, particularly in high-income countries; however, it also suggests that opportunistic salpingectomy offers an important opportunity for prevention. The five histotypes share several reproductive and hormonal risk factors, although differences also exist. In this Review, we summarize the epidemiology of this complex disease, comparing the different histotypes, and consider the potential for prevention. We also discuss how changes in the prevalence of risk and protective factors might have contributed to the observed changes in incidence and what this might mean for incidence in the future.

Cytomorphology of monomorphic spindle epithelial tumor with thymus-like elements: A case with local recurrence after subtotal resection.

Spindle epithelial tumor with thymus-like elements (SETTLE) is a rare biphasic thyroid tumor with low malignant potential that has a distinct morphology. Despite fine needle aspiration (FNA) being a common method for evaluating thyroid nodules and lymph nodes, there are limited cytologic descriptions of SETTLE in the literature due to its rarity. As a result, SETTLE is frequently underdiagnosed or misdiagnosed as medullary carcinoma, thymoma, teratoma, synovial sarcoma, or solitary fibrous tumor, among others. We present a case of a 28-year-old man with a history of a hemithyroidectomy diagnosed as SETTLE found to have a neck nodule along the strap muscle suspicious for recurrence 5 years post-surgery. The ultrasound-guided FNA cytology specimen of the neck nodule showed loosely cohesive, monomorphous ovoid to spindled cells with scant cytoplasm and nuclei with fine to granular chromatin. In addition, there were occasional clusters of cells with a papillary configuration. The tumor cells were associated with magenta, amorphous extracellular material. Immunocytochemical staining of the cell block material revealed that tumor cells were positive for p63, cytokeratin AE1/3, and CK8/18 and negative for TTF-1 and thyroglobulin. Overall, the morphological and immunocytochemical findings were consistent with a local recurrence of SETTLE. The subsequent left anterior strap mass excision revealed a 4 cm encapsulated tumor consistent with SETTLE. Because ofits rarity and low level of awareness, SETTLE poses a diagnostic and therapeutic challenge. We herein present the cytologic findings of monomorphic SETTLE and highlight the potential cytomorphologic and immunophenotypic pitfalls. We also highlight how tumors with high-risk features can be a therapeutic challenge.

Epithelial ovarian cancer in younger age versus older age groups: Survival and clinicopathological features.

OBJECTIVES: This study aimed to analyze the survivals and clinicopathological features of epithelial ovarian cancer (EOC) in younger age patients and to determine the impact of age on survival. METHODS: EOC patients aged ≤40 years were matched to patients aged >40 years at a 1:4 ratio. Disease-specific survival (DSS), progression-free survival (PFS), and clinicopathological and treatment features were compared between patients aged ≤40 and >40 years. RESULTS: A total of 763 EOC patients were reviewed. During a median follow-up period of 41 (range, 1-195) months, EOC patients aged ≤40 and >40 years did not show any statistically significant difference in median DSS (120 versusversus 84.7 months; hazard ratio, 0.78; 95% confidence interval, 0.58, 1.06); however, the median PFS was better in patients aged ≤40 years (median PFS not reached versusversus 41 months; HR, 0.65; 95% CI, 0.5, 0.85). Age ≤40 years was an independent favorable prognostic factor for DSS at 3 years after diagnosis. In contrast, younger age was an independent poor prognostic factor prior to this time point. EOC patients aged ≤40 years exhibited a significantly higher rate of early-stage disease, a higher proportion of mucinous subtype, and lower cancer antigen-125 level. CONCLUSION: Overall, EOC patients in the younger age group were associated with more favorable prognostic factors and showed better PFS, but not DSS, than those in the older age group. Younger age was identified as an unfavorable prognostic factor within 3 years of diagnosis and became a favorable prognostic factor after 3 years.

Immunotherapy experience in sinonasal NUT midline carcinoma, case report.

NUT midline carcinoma (NMC) is an aggressive malignant neoplasm arising from midline structures. Although it is classified as a rare disease, the pathological nonspecific appearance as undifferentiated/poorly differentiated carcinoma and the difficulty in making the definitive diagnosis are probably the reasons for the underdiagnosis; the disease is thought to be more prevalent. There is no standard treatment for the disease. The disease shows a poor response to chemotherapy and radiotherapy, and patients' survival is poor. We present a case of sinonasal NMC treated with chemotherapy and immunotherapy in first-line, which is the first in the literature. The patient presented with metastatic disease and received cisplatin-fluorouracil-docetaxel-pembrolizumab treatment. The tumor's PD-L1 expression was 10%, evaluated by tumor proportion score. The response to the therapy was poor, and the patient died of disease progression 5.4 months after the diagnosis. The efficacy of immunotherapy in NMC is not known. More reports are needed to draw conclusions.

Carcinoma showing thymus-like elements (CASTLE) with amyloid deposition in the parotid gland.

Carcinoma showing thymus-like elements (CASTLE) is a rare tumor that commonly occurs in the thyroid gland. Extrathyroidal CASTLE is rarer, and only 11 cases of CASTLE of major salivary glands have been reported to date. We report the first case of amyloid deposition in parotid CASTLE. A 63-year-old man presented with a slowly growing mass in the left parotid region. Computed tomography revealed an approximately 28 × 23 mm mass lesion in the left parotid gland, and squamous cell carcinoma was suspected on biopsy. The patient underwent a parotidectomy with neck dissection. Morphologically, the tumor cells were squamoid and formed nests with lymphoid infiltration. Immunohistochemically, the tumor cells exhibited immunoreactivity for CD5, CD117/c-kit and Bcl-2, p40, and CK5 but not for p16. We diagnosed the tumor as parotid CASTLE. Amyloid deposition was also observed in the primary tumor and metastatic lymph node lesions, which were immunoreactive for cytokeratin 5. Tumor cytokeratin-derived amyloid deposition may be one of characteristics of parotid CASTLE.

MHD-Net: Memory-Aware Hetero-Modal Distillation Network for Thymic Epithelial Tumor Typing With Missing Pathology Modality.

Fusing multi-modal radiology and pathology data with complementary information can improve the accuracy of tumor typing. However, collecting pathology data is difficult since it is high-cost and sometimes only obtainable after the surgery, which limits the application of multi-modal methods in diagnosis. To address this problem, we propose comprehensively learning multi-modal radiology-pathology data in training, and only using uni-modal radiology data in testing. Concretely, a Memory-aware Hetero-modal Distillation Network (MHD-Net) is proposed, which can distill well-learned multi-modal knowledge with the assistance of memory from the teacher to the student. In the teacher, to tackle the challenge in hetero-modal feature fusion, we propose a novel spatial-differentiated hetero-modal fusion module (SHFM) that models spatial-specific tumor information correlations across modalities. As only radiology data is accessible to the student, we store pathology features in the proposed contrast-boosted typing memory module (CTMM) that achieves type-wise memory updating and stage-wise contrastive memory boosting to ensure the effectiveness and generalization of memory items. In the student, to improve the cross-modal distillation, we propose a multi-stage memory-aware distillation (MMD) scheme that reads memory-aware pathology features from CTMM to remedy missing modal-specific information. Furthermore, we construct a Radiology-Pathology Thymic Epithelial Tumor (RPTET) dataset containing paired CT and WSI images with annotations. Experiments on the RPTET and CPTAC-LUAD datasets demonstrate that MHD-Net significantly improves tumor typing and outperforms existing multi-modal methods on missing modality situations.

International reproducibility study of thymic epithelial tumors staging: pT stage is an issue. proposals for improvement. A RYTHMIC/ITMIG study.

INTRODUCTION: Pathologists are staging thymic epithelial tumors (TET) according to the 8th UICC/AJCC TNM system. Within the French RYTHMIC network, dedicated to TET, agreement on pathologic tumor stage (pT) among the pathology panelists was difficult. The aim of our study was to determine the interobserver reproducibility of pT at an international level, to explore the source of discrepancies and potential interventions to address these. METHODS: An international panel of pathologists was recruited through the International Thymic Malignancy Interest Group (ITMIG). The study focused on invasion of mediastinal pleura, pericardium, and lung. From a cohort of cases identified as challenging within the RYTHMIC network, we chose a series of test and validation cases (n = 5 and 10, respectively). RESULTS: Reproducibility of the pT stage was also challenging at an international level as none of the 15 cases was classified as the same pT stage by all ITMIG pathologists. The agreement rose from slight (κ = 0.13) to moderate (κ = 0.48) between test and validation series. Discussion among the expert pathologists pinpointed two major reasons underlying discrepancies: 1) Thymomas growing with their "capsule" and adhering to the pleurae, pericardium, or lung were often misinterpreted as invading these structures. 2) Recognition of the mediastinal pleura was identified as challenging. CONCLUSION: Our study underlines that the evaluation of the pT stage of TET is problematic and needs to be addressed in more detail in an upcoming TNM classification. The publication of histopathologic images of landmarks, including ancillary tests could improve reproducibility for future TNM classifications.

[Clinical diagnosis and treatment analysis of 21 cases of intrathyroid thymic carcinoma].

Objective: To analyze the clinical efficacy of intrathyroid thymic carcinoma (ITTC). Methods: This study retrospectively analyzed the clinical data of 21 patients with ITTC diagnosed and treated at the First Affiliated Hospital of Zhengzhou University from January 2018 to July 2023, including 9 males and 12 females, with a median age of 52 years (40-60 years old). Results: There is a correlation between the maximum diameter of the tumor (≥40 mm) and lymph node metastasis (P=0.044). Seventeen patients received surgical treatment, and 4 patients only received chemotherapy. During the follow-up period, a total of 4 patients experienced death or progression, with a 2-year mortality or progression free survival rate of 74.8%. Conclusions: The prognosis of ITTC is good, and surgical treatment is the preferred treatment option, lymph node metastasis is significantly correlated with prognosis. The radiotherapy and chemotherapy of ITTC need to be determined based on the patient's condition.

ZSWIM4 inhibition improves chemosensitivity in epithelial ovarian cancer cells by suppressing intracellular glycine biosynthesis.

BACKGROUND: Zinc finger SWIM-type containing 4 (ZSWIM4) induces drug resistance in breast cancer cells. However, its role in epithelial ovarian cancer (EOC) remains unknown. In this study, we aimed to investigate the clinical significance of ZSWIM4 expression in EOC and develop new clinical therapeutic strategies for EOC. METHODS: ZSWIM4 expression in control and EOC tumor tissues was examined using immunohistochemistry. Lentiviral transduction, Cell Counting Kit-8 assay, tumorsphere formation assay, flow cytometry, western blotting, and animal xenograft model were used to assess the role of ZSWIM4 in chemotherapy. Cleavage Under Targets and Tagmentation (CUT&Tag) assays, chromatin immunoprecipitation assays, and luciferase reporter assays were used to confirm FOXK1-mediated upregulation of ZSWIM4 expression. The mechanism by which ZSWIM4 inhibition improves chemosensitivity was evaluated using RNA-sequencing. A ZSWIM4-targeting inhibitor was explored by virtual screening and surface plasmon resonance analysis. Patient-derived organoid (PDO) models were constructed from EOC tumor tissues with ZSWIM4 expression. RESULTS: ZSWIM4 was overexpressed in EOC tumor tissues and impaired patient prognoses. Its expression correlated positively with EOC recurrence. ZSWIM4 expression was upregulated following carboplatin treatment, which, in turn, contributed to chemoresistance. Silencing ZSWIM4 expression sensitized EOC cells to carboplatin treatment in vitro and in vivo. FOXK1 could bind to the GTAAACA sequence of the ZSWIM4 promoter region to upregulate ZSWIM4 transcriptional activity and FOXK1 expression increased following carboplatin treatment, leading to an increase in ZSWIM4 expression. Mechanistically, ZSWIM4 knockdown downregulated the expression of several rate-limiting enzymes involved in glycine synthesis, causing a decrease in intracellular glycine levels, thus enhancing intracellular reactive oxygen species production induced by carboplatin treatment. Compound IPN60090 directly bound to ZSWIM4 protein and exerted a significant chemosensitizing effect in both EOC cells and PDO models. CONCLUSIONS: ZSWIM4 inhibition enhanced EOC cell chemosensitivity by ameliorating intracellular glycine metabolism reprogramming, thus providing a new potential therapeutic strategy for EOC.

Genomic analysis of primary epithelial neoplasms of the seminal vesicle identifies a subset of mucinous cystic tumours driven by KRAS mutations.

BACKGROUND: Carcinomas of the seminal vesicle are exceedingly rare, with a limited number of cases described in the literature. Reported cases span a relatively wide morphological spectrum, and their genomic features remain unexplored. DESIGN: In this study, we interrogated five primary epithelial neoplasms of the seminal vesicle using a targeted DNA sequencing platform (OncoPanel, 447 genes). RESULTS: The tumours included one adenocarcinoma with intestinal phenotype presenting after external beam radiation (for prostatic adenocarcinoma), one carcinoma with Müllerian-type clear cell phenotype, two mucinous tumours resembling low-grade mucinous neoplasms of the appendix (LAMN) and one mucinous cystadenoma. The post-radiation mucinous adenocarcinoma had genomic findings consistent with bi-allelic inactivation of TP53, as well as multiple copy-number changes with regional and chromosomal arm-level copy-number losses. The Müllerian-type clear cell carcinoma exhibited a complex copy-number profile with numerous regional and arm-level copy-number changes, as well as focal amplification events, including copy-number gain of 8q and amplification of a region within 20q13. Both low-grade mucinous tumours resembling LAMN harboured hot-spot gain-of-function KRAS variants (p.G12V and p.G13D) as the only genomic alteration. No genomic alterations were detected inthe lesion diagnosed as mucinous cystadenoma. CONCLUSION: Our results suggest that primary low-grade mucinous neoplasms of the seminal vesicle may represent a distinct entity equivalent to appendiceal counterparts, driven by gain-of-function variants of RAS GTPases. The remaining tumours showed genomic features that closely resembled those of neoplasms with comparable phenotypes and/or biological characteristics arising in other sites, suggesting that they could be managed similarly, with special considerations related to their anatomical location.

CD47-a novel prognostic predicator in epithelial ovarian cancer and correlations with clinicopathological and gene mutation features.

BACKGROUND: Epithelial ovarian cancer (EOC) is insensitive to immunotherapy due to its poor immunogenicity; thus, suitable biomarkers need to be identified for better prognostic stratification and individualized treatment. CD47 is a novel immunotherapy target; however, its impact on EOC prognosis is controversial and correlation with genetic features is unclear. The aim of this study was to investigate the prognostic significance of CD47 and its correlations with biological behaviors and genetic features of EOC. METHODS: Immunohistochemistry (IHC) and next-generation sequencing (NGS) were performed to examine expressions of CD47, PD-L1, and genomic mutations in the tissue samples of 75 EOC patients. Various clinicopathologic and genomic features were then evaluated to determine their correlation with CD47 expression. Kaplan-Meier analysis and Cox regression analysis were used to identify independent prognostic factors. Risk score modeling was then established, and the predictive capacity of this model was further confirmed by nomogram analysis. RESULTS: CD47 was mainly expressed in the tumor cell membrane and cytoplasm, and the rate of high CD47 expression was 63.7%. CD47 expression was associated with various clinicopathological factors, including FIGO stage, CA125 and HE4 value, presence of multidisciplinary surgeries, presence and volume of ascites, lymph-node metastasis, Ki-67 index and platinum-resistant, as well as genetic characteristics like BRCA mutation, HRD status, and TP53 mutation in EOC. Patients with high CD47 expression showed worse prognosis than the low-expression group. Cox regression analysis demonstrated that CA125, CD47, and BRCA mutation were independent factors for EOC prognosis. Patients were then categorized into high-risk and low-risk subgroups based on the risk score of the aforementioned independent factors, and the prognosis of the high-risk group was worse than those of the low-risk group. The nomogram showed adequate discrimination with a concordance index of 0.777 (95% CI, 0.732-0.822). The calibration curve showed good consistency. CONCLUSION: CD47 correlated with various malignant biology and genetic characteristics of EOC and may play pivotal and multifaceted roles in the tumor microenvironment of EOC Finally, we constructed a reliable prediction model centered on CD47 and integrated CA125 and BRCA to better guide high-risk population management.

Mechanical activation and expression of HSP27 in epithelial ovarian cancer.

Understanding the complex biomechanical tumor microenvironment (TME) is of critical importance in developing the next generation of anti-cancer treatment strategies. This is especially true in epithelial ovarian cancer (EOC), the deadliest of the gynecologic cancers due to recurrent disease or chemoresistance. However, current models of EOC progression provide little control or ability to monitor how changes in biomechanical parameters alter EOC cell behaviors. In this study, we present a microfluidic device designed to permit biomechanical investigations of the ovarian TME. Using this microtissue system, we describe how biomechanical stimulation in the form of tensile strains upregulate phosphorylation of HSP27, a heat shock protein implicated in ovarian cancer chemoresistance. Furthermore, EOC cells treated with strain demonstrate decreased response to paclitaxel in the in vitro vascularized TME model. The results provide a direct link to biomechanical regulation of HSP27 as a mediator of EOC chemoresistance, possibly explaining the failure of such therapies in some patients. The work presented here lays a foundation to elucidating mechanobiological regulation of EOC progression, including chemoresistance and could provide novel targets for anti-cancer therapeutics.

The Molecular Landscape of Thymic Epithelial Tumors: A Comprehensive Review.

Thymic epithelial tumors (TETs) are characterized by their extreme rarity and variable clinical presentation, with the inadequacy of the use of histological classification alone to distinguish biologically indolent from aggressive cases. The utilization of Next Generation Sequencing (NGS) to unravel the intricate genetic landscape of TETs could offer us a comprehensive understanding that is crucial for precise diagnoses, prognoses, and potential therapeutic strategies. Despite the low tumor mutational burden of TETS, NGS allows for exploration of specific genetic signatures contributing to TET onset and progression. Thymomas exhibit a limited mutational load, with prevalent GTF2I and HRAS mutations. On the other hand, thymic carcinomas (TCs) exhibit an elevated mutational burden, marked by frequent mutations in TP53 and genes associated with epigenetic regulation. Moreover, signaling pathway analyses highlight dysregulation in crucial cellular functions and pathways. Targeted therapies, and ongoing clinical trials show promising results, addressing challenges rooted in the scarcity of actionable mutations and limited genomic understanding. International collaborations and data-sharing initiatives are crucial for breakthroughs in TETs research.