Cryptochrome 2 Suppresses Epithelial-Mesenchymal Transition by Promoting Trophoblastic Ferroptosis in Unexplained Recurrent Spontaneous Abortion.

Unexplained recurrent spontaneous abortion (URSA) is a serious reproductive issue that affects women of childbearing age. Studies have shown a close association between disrupted circadian rhythm and impaired epithelial-mesenchymal transition (EMT) process in trophoblasts during URSA, although the underlying mechanism has not been elaborated. This study aims to investigate the regulatory relationship between circadian rhythm gene cryptochrome 2 (CRY2) and ferroptosis on the migratory ability of trophoblast cells. Cell proliferation experiments, wound healing assays, and expression of related markers were conducted to verify the EMT efforts. Trophoblastic ferroptosis was confirmed by the expressions of malondialdehyde, glutathione, mitochondrial membrane potential, divalent iron ions, and related genes. The results showed significant increased expression of CRY2 and decreased expression of brain and muscle ARNT-like protein 1 (BMAL1) in the URSA villous tissues, accompanied by iron-dependent oxidative changes and abnormal expression of ferroptosis-related proteins. It was observed that CRY2 and BMAL1 were co-localized and function as a feedback loop, which regulated the dynamic changes of EMT-related markers in trophoblast cells. CRY2 promoted trophoblastic ferroptosis, whereas BMAL1 had the opposite effect. Particularly, the ferroptosis inhibitor (ferrostatin-1) effectively reversed the trophoblastic ferroptosis and EMT inhibition caused by CRY2 overexpression. Collectively, these results suggest that CRY2 regulates trophoblastic ferroptosis and hinders cellular EMT and migratory ability by suppressing BMAL1 expression.

MyD88 signaling pathways: role in breast cancer.

MyD88 plays a central role in breast cancer, exerting a multitude of effects that carry substantial implications. Elevated MyD88 expression is closely associated with aggressive tumor characteristics, suggesting its potential as a valuable prognostic marker and therapeutic target. MyD88 exerts influence over several critical aspects of breast cancer, including metastasis, recurrence, drug resistance, and the regulation of cancer stem cell properties. Furthermore, MyD88 modulates the release of inflammatory and chemotactic factors, thereby shaping the tumor's immune microenvironment. Its role in immune response modulation underscores its potential in influencing the dynamic interplay between tumors and the immune system. MyD88 primarily exerts intricate effects on tumor progression through pathways such as Phosphoinositide 3-kinases/Protein kinase B (PI3K/Akt), Toll-like Receptor/Nuclear Factor Kappa B (TLR/NF-κB), and others. Nevertheless, in-depth research is essential to unveil the precise mechanisms underlying the diverse roles of MyD88 in breast cancer. The translation of these findings into clinical applications holds great promise for advancing precision medicine approaches for breast cancer patients, ultimately enhancing prognosis and enabling the development of more effective therapeutic strategies.

Based on whole-exome sequencing to explore the rule of Herceptin and TKI resistance in breast cancer patients.

BACKGROUND: Breast cancer is the second leading cause of cancer-related death in women, and drug resistance during treatment is a major challenge. However, the mechanisms underlying drug resistance are not fully understood. Here we applied whole-exome sequencing (WES) to clarify resistant rules to Herceptin and tyrosine kinase inhibitors (TKIs). METHODS: There are 12 HER2+ breast cancer patients who were done WES. Samples from tumor and surrounding tissues underwent DNA sequencing and analysis. Various experimental and bioinformatics techniques were employed, including genomic capture, mutation analysis (Genome Analysis Toolkit (GATK), etc.), bioinformatics assessments, and drug-gene interaction investigations. Ultimately, the study explored the association of APOB gene expression with breast cancer recurrence rates, immune cell infiltration, and drug response. RESULTS: The C > T mutation frequency was highest in the Herceptin-insensitive (HI) and verification groups, codenamed YI, contrasting with the Herceptin-sensitive (HE) group. No microsatellite instability (MSI)-H patients were in the HE group, but both HI and YI groups had 1 each. Significant differences in transition-transversion (TiTv) were observed in the HI and YI groups rather than the HE group. In the TKI- insensitive (TI) group, C > T mutations were highest, differing from the TKI-sensitive (TE) group. TE group included 2 MSI-H patients. Significant differences in TiTv were found in the TI group rather than the TE group. Mutated APOB may resist Herceptin and TKI, increasing immune infiltration. We identified potential drugs targeting it. CONCLUSIONS: Our study suggested that a higher percentage of C > T mutations, significant differences in TiTv, and MSI-H status may indicate Herceptin resistance, while a higher percentage of C > T mutations, significant differences in TiTv, and the absence of MSI-H may indicate TKI resistance in breast cancer patients. For patients resistant to both Herceptin and TKI, mutated APOB may play a crucial role in resistance.

SIX1 amplification modulates stemness and tumorigenesis in breast cancer.

BACKGROUND: Sine oculis homeobox homolog 1 (SIX1) is a transcription factor that has recently been identified as a crucial regulator of embryonic development and tumorigenesis. SIX1 is upregulated in different types of tumors, including breast cancer. However, the role and mechanism of SIX1 upregulation in breast cancer carcinogenesis remains uncertain. METHODS: In this study, we utilized various databases such as UALCAN, TCGA, STRING, and Kaplan-Meier Plotter to investigate the mRNA expression, prognosis, transcriptional profile changes, signal pathway rewiring, and interaction with cancer stem cells of SIX1 in breast cancer. We also conducted both in vitro and in vivo experiments to validate its positive regulation effect on breast cancer stem cells. RESULTS: Our findings demonstrated that the expression of SIX1 varies among different subtypes of breast cancer and that it upregulates breast cancer grading and lymph node metastasis. Besides, SIX1 participates in the rewiring of several cancer signaling pathways, including estrogen, WNT, MAPK, and other pathways, and interacts with cancer stem cells. SIX1 showed a significant positive correlation with breast cancer stem cell markers such as ALDH1A1, EPCAM, ITGB1, and SOX2. Moreover, our in vitro and in vivo experiments confirmed that SIX1 can promote the increase in the proportion of stem cells and tumor progression. CONCLUSIONS: Altogether, our results suggest that SIX1 plays an essential regulatory role in breast cancer's occurrence, and its amplification can be utilized as a diagnostic and prognostic predictor. The interaction between SIX1 and cancer stem cells may play a critical role in regulating breast cancer's initiation and metastasis.

Searching for Essential Genes and Targeted Drugs Common to Breast Cancer and Osteoarthritis.

BACKGROUND: It is documented that osteoarthritis can promote the progression of breast cancer (BC). OBJECTIVE: This study aims to search for the essential genes associated with breast cancer (BC) and osteoarthritis (OA), explore the relationship between epithelial-mesenchymal transition (EMT)-related genes and the two diseases, and identify the candidate drugs. METHODS: The genes related to both BC and OA were determined by text mining. Protein-protein Interaction (PPI) analysis was carried out, and as a result, the exported genes were found to be related to EMT. PPI and the correlation of mRNA of these genes were also analyzed. Different kinds of enrichment analyses were performed on these genes. A prognostic analysis was performed on these genes for examining their expression levels at different pathological stages, in different tissues, and in different immune cells. Drug-gene interaction database was employed for potential drug discovery. RESULTS: A total number of 1422 genes were identified as common to BC and OA and 58 genes were found to be related to EMT. We found that HDAC2 and TGFBR1 were significantly poor in overall survival. High expression of HDAC2 plays a vital role in the increase of pathological stages. Four immune cells might play a role in this process. Fifty-seven drugs were identified that could potentially have therapeutic effects. CONCLUSION: EMT may be one of the mechanisms by which OA affects BC. Using the drugs can have potential therapeutic effects, which may benefit patients with both diseases and broaden the indications for drug use.

Distinct invasive patterns in situ between estrogen receptor-positive and triple-negative breast cancer through the intraductal tracking of carbon nanoparticles.

Given that the transition from ductal carcinoma in situ (DCIS) to invasive breast cancer (BC) is crucial during the BC progression, the mechanism involved in the invasion transition behind triple-negative breast cancer (TNBC) and estrogen receptor-positive (ER-positive) subtype has remained elusive. This article detected distinct invasion patterns of BC cells between the ER-positive and TNBC using intraductal murine models with intraductal administration of carbon nanoparticles (CNPs). First, the feasibility of the utility of CNPs as a tracer was proved. The area ratio of CNPs and tumor cells invading the stroma at the late stage was found significantly higher than that in the early stage in MNU-induced ER-positive BC. However, opposite results were obtained in the triple-negative model. Consequently, we proposed that the ER-positive phenotype cells behave differently between different stages during tumor progression while there is no such difference in the invasion process of TNBC cells. The analysis regarding the duct integrity along with immunohistochemical characteristics further explained the distinct invasion features between the ER-positive and triple-negative subtypes. Last, the relationship between the duct thickness and the duct integrity suggested that ER-positive tumors gradually increased in size within the lumen before the invasion. Overall, this study suggested the different invasion characteristics of ER-positive BC and TNBC in vivo.

Breast cancer heterogeneity and its implication in personalized precision therapy.

Breast cancer heterogeneity determines cancer progression, treatment effects, and prognosis. However, the precise mechanism for this heterogeneity remains unknown owing to its complexity. Here, we summarize the origins of breast cancer heterogeneity and its influence on disease progression, recurrence, and therapeutic resistance. We review the possible mechanisms of heterogeneity and the research methods used to analyze it. We also highlight the importance of cell interactions for the origins of breast cancer heterogeneity, which can be further categorized into cooperative and competitive interactions. Finally, we provide new insights into precise individual treatments based on heterogeneity.

Accurate Diagnosis and Survival Prediction of Bladder Cancer Using Deep Learning on Histological Slides.

(1) Background: Early diagnosis and treatment are essential to reduce the mortality rate of bladder cancer (BLCA). We aimed to develop deep learning (DL)-based weakly supervised models for the diagnosis of BLCA and prediction of overall survival (OS) in muscle-invasive bladder cancer (MIBC) patients using whole slide digitized histological images (WSIs). (2) Methods: Diagnostic and prognostic models were developed using 926 WSIs of 412 BLCA patients from The Cancer Genome Atlas cohort. We collected 250 WSIs of 150 BLCA patients from the Renmin Hospital of Wuhan University cohort for external validation of the models. Two DL models were developed: a BLCA diagnostic model (named BlcaMIL) and an MIBC prognostic model (named MibcMLP). (3) Results: The BlcaMIL model identified BLCA with accuracy 0.987 in the external validation set, comparable to that of expert uropathologists and outperforming a junior pathologist. The C-index values for the MibcMLP model on the internal and external validation sets were 0.631 and 0.622, respectively. The risk score predicted by MibcMLP was a strong predictor independent of existing clinical or histopathologic indicators, as demonstrated by univariate Cox (HR = 2.390, p < 0.0001) and multivariate Cox (HR = 2.414, p < 0.0001) analyses. The interpretability of DL models can help in the analysis of critical regions associated with tumors to enrich the information obtained from WSIs. Furthermore, the expression of six genes (ANAPC7, MAPKAPK5, COX19, LINC01106, AL161431.1 and MYO16-AS1) was significantly associated with MibcMLP-predicted risk scores, revealing possible potential biological correlations. (4) Conclusions: Our study developed DL models for accurately diagnosing BLCA and predicting OS in MIBC patients, which will help promote the precise pathological diagnosis of BLCA and risk stratification of MIBC to improve clinical treatment decisions.

In situ Injection of pH- and Temperature-Sensitive Nanomaterials Increases Chemo-Photothermal Efficacy by Alleviating the Tumor Immunosuppressive Microenvironment.

Purpose: Triple-negative breast cancer (TNBC) is challenging to treat with traditional "standard of care" therapy due to the lack of targetable biomarkers and rapid progression to distant metastasis. Methods: We synthesized a novel combination regimen that included chemotherapy and photothermal therapy (PTT) to address this problem. Here, we tested a magnetic nanosystem (MNs-PEG/IR780-DOX micelles) loaded with the near-infrared (NIR) photothermal agent IR780 and doxorubicin (DOX) to achieve chemo-photothermal and boost antitumor immunity. Intraductal (i.duc) administration of MNs-PEG/IR780-DOX could increase the concentration of the drug in the tumor while reducing systemic side effects. Results: We showed more uptake of MNs-PEG/IR780-DOX by 4T1-luc cells and higher penetration in the tumor. MNs-PEG/IR780-DOX exhibited excellent photothermal conversion in vivo and in vitro. The release of DOX from MNs-PEG/IR780-DOX is pH- and temperature-sensitive. Facilitated by i.duc administration, MNs-PEG/IR780-DOX displayed antitumor effects and prevented distant organs metastasis under NIR laser (L) irradiation and magnetic field (MF)while avoiding DOX-induced toxicity. More importantly, MNs-PEG/IR780-DOX alleviated tumor immunosuppressive microenvironment by increasing tumor CD8+ T cells infiltration and reducing the proportion of myeloid-derived suppressor cells (MDSCs) and Tregs. Conclusion: Intraductal administration of pH- and temperature-sensitive MNs-PEG/IR780-DOX with L and MF had the potential for achieving minimally invasive, targeted, and accurate treatment of TNBC.

More Aggressive Cancer Behaviour in Thyroid Cancer Patients in the Post-COVID-19 Pandemic Era: A Retrospective Study.

PURPOSE: Many thyroid cancer patients have suffered from treatment delays caused by the coronavirus disease 2019 pandemic. Although there have been many reviews, recommendations, or clinical experiences, clinical evidence that evaluates patient disease status is lacking. The aim of our research was to evaluate thyroid cancer behaviour in the post-COVID-19 era. PATIENTS AND METHODS: A retrospective study was conducted and thyroid cancer patient data from February 1, 2017 to September 15, 2020 were pooled for analysis. The demographic, ultrasound and pathological data of the pre- and post-COVID-19 groups were compared. Lymph node metastases, tumour size, extrathyroidal extension, and multifocality were compared year-by-year to evaluate annual changes in patient characteristics. Regression analyses were adopted to reveal cancer behaviour along with the admission date interval and to reveal risk factors for lymph node metastasis. Patient ultrasound data were compared before and after the lockdown to assess tumour progression. The outcomes of delays in treatment ≤180 days were then studied. RESULTS: The post-lockdown patients were more likely to have multiple lesions (31.2% vs 36.5%, p = 0.040), extrathyroidal extension (65.5% vs 72.2%, p = 0.011) and lymph node metastases (37.7% vs 45.0%, p = 0.007), while tumour size remained stable (1.01cm vs.1.02cm, p = 0.758). The lymph node metastasis rate increased by year (p < 0.001). The tumour size correlated negatively with the post-lockdown admission date (p = 0.002). No significant difference in tumour size, multifocality or lymph node metastasis on ultrasound was revealed between the pre- and post-lockdown group. No significant difference in tumour size, multifocality, extrathyroidal extension or lymph node metastasis was revealed among patients with a delayed treatment time ≤180 days. CONCLUSION: Patients with a COVID-19-induced treatment delay had more aggressive cancer behaviour. Rebound medical visits and annually increasing aggressiveness may be potential reasons for this observation, as individual patient tumour did not progress during the delay.

Immune Checkpoint Inhibitors-Related Thyroid Dysfunction: Epidemiology, Clinical Presentation, Possible Pathogenesis, and Management.

Immune checkpoint inhibitors (ICIs) are a group of drugs employed in the treatment of various types of malignant tumors and improve the therapeutic effect. ICIs blocks negative co-stimulatory molecules, such as programmed cell death gene-1 (PD-1) and its ligand (PD-L1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), reactivating the recognition and killing effect of the immune system on tumors. However, the reactivation of the immune system can also lead to the death of normal organs, tissues, and cells, eventually leading to immune-related adverse events (IRAEs). IRAEs involve various organs and tissues and also cause thyroid dysfunction. This article reviews the epidemiology, clinical manifestations, possible pathogenesis, and management of ICIs-related thyroid dysfunction.